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The CO releasing ability of the complex [CpMo(CO) 3 Me] (1) (Cp = η 5 -C 5 H 5 ) has been assessed using a deoxymyoglobin-carbonmonoxymyoglobin assay. In the dark, CO release was shown to be promoted by the reducing agent sodium dithionite in a concentration-dependent manner. At lower dithionite concentrations, where dithionite-induced CO release was minimised, irradiation at 365 nm with a low-power UV lamp resulted in a strongly enhanced release of CO (half-life ( t 1/2 ) = 6.3 min), thus establishing complex 1 as a photochemically activated CO-releasing molecule. To modify the CO release behaviour of the tricarbonyl complex, the possibility of obtaining inclusion complexes between 1 and β-cyclodextrin (βCD) or cucurbit[7]uril (CB7) by liquid-liquid interfacial precipitation (1@βCD(IP)), liquid antisolvent precipitation (1@CB7), and mechanochemical ball-milling (1@βCD(BM)) was evaluated. All these methods led to the isolation of a true inclusion compound (albeit mixed with nonincluded 1 for 1@βCD(BM)), as evidenced by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), FT-IR and FT-Raman spectroscopies, and 13 C{ 1 H} magic angle spinning (MAS) NMR. PXRD showed that 1@βCD(IP) was microcrystalline with a channel-type crystal packing structure. High resolution mass spectrometry studies revealed the formation of aqueous phase 1 : 1 complexes between 1 and CB7. For 1@βCD(IP) and 1@CB7, the protective effects of the hosts led to a decrease in the CO release rates with respect to nonincluded 1. βCD had the strongest effect, with a ca. 10-fold increase in t 1/4 for dithionite-induced CO release, and a ca. 2-fold increase in t 1/2 for photoinduced CO release.

Candida albicans is the primary species causing oral candidiasis. Its increasing drug resistance drives the search for more effective antifungal agents. Therefore, we assessed toxicological parameters and the antimicrobial activity and mechanisms of action of the monoterpene (-)-fenchone against oral C. albicans. We conducted an in silico study using PASS online and AdmetSAR, followed by evaluation of antifungal activity through Minimum Inhibitory Concentration (MIC), Minimum Fungicidal Concentration (MFC), association study with miconazole, and assays with sorbitol and ergosterol. Inhibition of biofilm formation and disruption of preformed biofilm were considered. Toxicity was also assessed through hemolysis assay. The in silico study revealed a higher likelihood of the compound being active for antifungal activity, as well as promising pharmacokinetic and toxicity characteristics. Subsequently, (-)-fenchone exhibited predominantly fungicidal activity (MIC90 = 8 μg/mL; MFC = 16 μg/mL), including against miconazole-resistant C. albicans isolates. The substance does not appear to act by damaging the fungal cell wall or plasma membrane, and exhibited synergy with miconazole. There was activity in inhibiting biofilm formation but not in disrupting preformed biofilm. Finally, the product exerted low hemolytic activity at more than MIC×10. Based on these results, (-)-fenchone may represent a promising therapeutic alternative for oral candidiasis.

Purpose: Blepharocheilodontic (BCD) syndrome is a rare condition with eyelid ectropion, euryblepharon, lagophthalmos, congenital cleft lip/palate, and oligodontia. BCD syndrome is an autosomal dominant inherited disorder and has multiple associations with systemic diseases. We present three new cases of BCD syndrome and a literature review of the periocular manifestations of BCD and their management., Methods: A multi-institutional retrospective case series of patients with BCD syndrome. Clinical characteristics, imaging findings, surgical management, and outcomes were analysed. Further, a comprehensive review of the literature identified all previously published cases of BCD syndrome., Results: Three cases of BCD syndrome in children with autosomal dominant inheritance were included. Periocular manifestations in BCD syndrome include lower lid ectropion, euryblepharon, and lagophthalmos. Systemic manifestations including cleft lip or palate and dental abnormalities were also observed. Multiple surgical procedures including lateral canthoplasty, tarsorrhaphy, and midface augmentation may be necessary for correction of eyelid malposition and achieving cosmetic and functional improvements., Conclusions: BCD syndrome presents with a spectrum of periocular manifestations requiring multidisciplinary management. Children that present with cleft lip and palate, dental, and eyelid abnormalities should be suspected to have BCD syndrome. Surgical management of the eyelid in BCD remains challenging. Ophthalmologists should be aware of BCD syndrome and its systemic associations.

It is well-established that dysfunction of megalin-mediated albumin endocytosis by proximal tubule epithelial cells (PTECs) and the activation of the Renin-Angiotensin System (RAS) play significant roles in the development of Diabetic Kidney Disease (DKD). However, the precise correlation between these factors still requires further investigation. In this study, we aimed to elucidate the potential role of angiotensin II (Ang II), a known effector of RAS, as the mediator of albumin endocytosis dysfunction induced by high glucose (HG) in PTECs. To achieve this, we utilized LLC-PK1 and HK-2 cells, which are well-established in vitro models of PTECs. Using albumin-FITC or DQ-albumin as tracers, we observed that incubation of LLC-PK1 and HK-2 cells with HG (25 mM for 48 h) significantly reduced canonical receptor-mediated albumin endocytosis, primarily due to the decrease in megalin expression. HG increased the concentration of Ang II in the LLC-PK1 cell supernatant, a phenomenon associated with an increase in angiotensin-converting enzyme (ACE) expression and a decrease in prolyl carboxypeptidase (PRCP) expression. ACE type 2 (ACE2) expression remained unchanged. To investigate the potential impact of Ang II on HG effects, the cells were co-incubated with angiotensin receptor inhibitors. Only co-incubation with 10 -7  M losartan (an antagonist for type 1 angiotensin receptor, AT 1 R) attenuated the inhibitory effect of HG on albumin endocytosis, as well as megalin expression. Our findings contribute to understanding the genesis of tubular albuminuria observed in the early stages of DKD, which involves the activation of the Ang II/AT 1 R axis by HG., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: To describe the use of coronofrontal rhytidectomy (CFR) for the treatment of severe pseudoptosis and superior entropion in dogs, and to provide guidelines for the selection of surgical technique depending on presentation., Methods: A review of medical records of dogs that underwent rhytidectomy from 2002 to 2023 was carried out, including signalment, clinical signs, type of rhytidectomy, concurrent surgical techniques, re-interventions, post-operative complications, follow-up time, and outcome., Results: Twenty dogs with a median age of 5.1 years were included in this study. English Cocker Spaniel was the most common breed (8 dogs:40%) and males were overrepresented (13 dogs: 65%). Besides pseudoptosis and visual impairment (100%), the other most common clinical signs were entropion and/or ectropion (19 dogs: 95%), conjunctivitis (17 dogs: 85%), euryblepharon (12 dogs: 60%) and non-ulcerative keratitis (10 dogs: 50%). CFR was performed in 12 dogs (60%), frontal rhytidectomy in 5 (25%), coronal in 2 (10%), and modified shared in 1 (5%). Concurrent surgical techniques were performed in 17 dogs (85%), being lateral canthoplasty (13 dogs; 65%), and Celsus-Hotz (10 dogs; 50%) the most common. The median follow-up time was 115 days with no complications and good outcomes reported in all dogs. At last re-recheck, complete correction of the eyelid positioning was obtained in 92% (11/12) and 87.5% (7/8) of the cases that underwent CFR and other rhytidectomy techniques, respectively., Conclusion: CFR is an effective surgical treatment for severe pseudoptosis and superior entropion in dogs. The provided guidelines will assist in the selection of the most appropriate eyelid lifting technique., (© 2024 The Author(s). Veterinary Ophthalmology published by Wiley Periodicals LLC on behalf of American College of Veterinary Ophthalmologists.)

Introduction: Catatonia, documented since the 19th century, remains a significant challenge in terms of recognition and treatment. Over the last two decades, ketamine has brought new perspectives to psychiatry, sparking widespread interest. Concurrently, catatonia has attracted heightened scientific attention. Preliminary evidence suggests the therapeutic potential of ketamine for catatonia., Methods: We systematically searched Medline/PubMed, Embase, PsycINFO, Lilacs, and Cochrane Library databases, as well as Google Scholar, for studies with ketamine or its enantiomers as intervention for catatonia, with no restrictions to underlying diagnosis, date, language, or study design., Results: Twenty articles were included, encompassing a total of 25 catatonic patients receiving ketamine or esketamine. Predominantly female (61.9 %), with a mean age of 44.4 years, patients mostly exhibited manifestations compatible with the retarded subtype of catatonia. Mood disorders were the most prevalent underlying diagnoses. Ketamine was primarily administered intravenously over a 40-minute period and in multiple-dosing schemes. Mean response and remission rates of catatonic manifestations for the whole sample were 80 % and 44 %, respectively, with no reports of worsening catatonic features or psychotic symptoms. Only one patient discontinued treatment due to intolerable dissociative effects., Conclusion: Challenging the conventional contraindication of ketamine in psychotic disorders, current evidence highlights its potential efficacy, particularly in treating catatonia. Pending further research, we advocate reevaluating this contraindication, as it may offer a promising therapeutic option, especially for challenging cases. Preliminary evidence suggests potentially greater benefits for catatonic patients with underlying mood disorders compared to primary psychotic disorders., Competing Interests: Declaration of competing interest LCQ reports consulting fees from Allergan, Abbot, Janssen Pharmaceutical and Lundbeck, and research fees from Janssen Pharmaceutical. ALTL has received consulting fees from Hoffmann–La Roche, Genentech, Janssen Pharmaceutical, Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Pfizer, Mantecorp Indústria Química e Farmacêutica, Libbs Farmacêutica, FQM Farma, and Sanofi-Aventis over the last 24 months and has received research fees from Janssen Pharmaceutical, Eli Lilly, Novartis, Biophytis, Celltrion, Azidus, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, FQM Farma, and Forum Pharmaceuticals. AG has been a consultant and/or advisor to or has received honoraria from Aché, Daiichi Sankyo, Torrent, Bayer, Cristália, and Janssen. We declare no other conflicts of interest concerning the publication of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To compare characteristics and treatment outcomes of spontaneous chronic corneal epithelial defects (SCCEDs) in brachycephalic non-Boxers and Boxers. We hypothesized that brachycephalic non-Boxers develop SCCEDs at a younger age and develop complications more frequently than Boxers., Animals Studied: Retrospective review of medical records of brachycephalic dogs treated for SCCEDs between January 2018 and December 2022 in multiple ophthalmology referral centers in the UK., Procedure: Data recorded included breed, age, time of onset, treatment prior to referral, treatment at referral, time to heal, need for further procedures, and complications., Results: A total of 464 SCCEDs in 420 dogs were included composed of 173 Boxers with 200 SCCEDs and 247 brachycephalic non-Boxer dogs with 264 SCCEDs. Boxers were significantly older (median 8.2, range 4.5-12.7 years) than brachycephalic non-Boxers (median 7.2, range 1.6-15.9 years) (p < .001). The first treatment (cotton-tipped applicator [CTA] debridement, diamond burr debridement, superficial keratectomy, grid keratotomy, punctate keratotomy, or combinations of these) selected was significantly different between groups (p < .001). Healing, excluding cases addressed by CTA debridement, following the first procedure was significantly more successful in Boxers (p = .049). Excluding cases addressed by CTA debridement, 9.6% of SCCEDs in Boxers (20/200) and 13.4% (32/239) of non-Boxers required more than one procedure. In the non-Boxer group, 9.5% (25/264) developed complications, contrasting with 4% (8/200) in the Boxer group. Non-Boxers were more likely to develop complications after the first treatment (p = .006)., Conclusion: Non-Boxer brachycephalic dogs develop SCCEDs younger than Boxers. This study suggests SCCEDs in brachycephalic non-Boxers may be less likely to heal following one mechanical treatment and are more likely to develop complications., (© 2024 American College of Veterinary Ophthalmologists.)

The siderophore-cephalosporin cefiderocol (FDC) presents a promising treatment option for carbapenem-resistant (CR) P. aeruginosa (PA). FDC circumvents traditional porin and efflux-mediated resistance by utilizing TonB-dependent receptors (TBDRs) to access the periplasmic space. Emerging FDC resistance has been associated with loss of function mutations within TBDR genes or the regulatory genes controlling TBDR expression. Further, difficulties with antimicrobial susceptibility testing (AST) and unexpected negative clinical treatment outcomes have prompted concerns for heteroresistance, where a single lineage isolate contains resistant subpopulations not detectable by standard AST. This study aimed to evaluate the prevalence of TBDR mutations among clinical isolates of P. aeruginosa and the phenotypic effect on FDC susceptibility and heteroresistance. We evaluated the sequence of pirR , pirS , pirA , piuA , or piuD from 498 unique isolates collected before the introduction of FDC from four clinical sites in Portland, OR (1), Houston, TX (2), and Santiago, Chile (1). At some clinical sites, TBDR mutations were seen in up to 25% of isolates, and insertion, deletion, or frameshift mutations were predicted to impair protein function were seen in 3% of all isolates ( n = 15). Using population analysis profile testing, we found that P. aeruginosa with major TBDR mutations were enriched for a heteroresistant phenotype and undergo a shift in the susceptibility distribution of the population as compared to susceptible strains with wild-type TBDR genes. Our results indicate that mutations in TBDR genes predate the clinical introduction of FDC, and these mutations may predispose to the emergence of FDC resistance., Competing Interests: W.R.M. has received grant support from Merck and royalties from UpToDate. C.A.A. has received royalties from UpToDate. All other authors have no conflicts to disclose.

Tubular proteinuria is a common feature in COVID-19 patients, even in the absence of established acute kidney injury. SARS-CoV-2 spike protein (S protein) was shown to inhibit megalin-mediated albumin endocytosis in proximal tubule epithelial cells (PTECs). Angiotensin-converting enzyme type 2 (ACE2) was not directly involved. Since Toll-like receptor 4 (TLR4) mediates S protein effects in various cell types, we hypothesized that TLR4 could be participating in the inhibition of PTECs albumin endocytosis elicited by S protein. Two different models of PTECs were used: porcine proximal tubule cells (LLC-PK1) and human embryonic kidney cells (HEK-293). S protein reduced Akt activity by specifically inhibiting of threonine 308 (Thr308) phosphorylation, a process mediated by phosphoinositide-dependent kinase 1 (PDK1). GSK2334470, a PDK1 inhibitor, decreased albumin endocytosis and megalin expression mimicking S protein effect. S protein did not change total TLR4 expression but decreased its surface expression. LPS-RS, a TLR4 antagonist, also counteracted the effects of the S protein on Akt phosphorylation at Thr308, albumin endocytosis, and megalin expression. Conversely, these effects of the S protein were replicated by LPS, an agonist of TLR4. Incubation of PTECs with a pseudovirus containing S protein inhibited albumin endocytosis. Null or VSV-G pseudovirus, used as control, had no effect. LPS-RS prevented the inhibitory impact of pseudovirus containing the S protein on albumin endocytosis but had no influence on virus internalization. Our findings demonstrate that the inhibitory effect of the S protein on albumin endocytosis in PTECs is mediated through TLR4, resulting from a reduction in megalin expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To build a model based on cardiometabolic indicators that allow the identification of overweight adolescents at higher risk of subclinical atherosclerotic disease (SAD)., Methods: Cross-sectional study involving 161 adolescents with a body mass index ≥ +1 z-Score, aged 10 to 19 years. Carotid intima-media complex thickness (IMT) was evaluated using ultrasound to assess subclinical atherosclerotic disease. Cardiometabolic indicators evaluated included nutritional status, central adiposity, blood pressure, lipidic profile, glycemic profile, as well as age and sex. Data was presented using measures of central tendency and dispersion, as well as absolute and relative frequency. The relationship between IMT measurement (outcome variable) and other variables (independent variables) was assessed using Pearson or Spearman correlation, followed by multiple regression modeling with Gamma distribution to analyze predictors of IMT. Statistical analysis was performed using SPSS and R software, considering a significance level of 5 %., Results: It was observed that 23.7 % had Carotid thickening, and the prevalence of abnormal fasting glucose was the lowest. Age and fasting glucose were identified as predictors of IMT increase, with IMT decreasing with age by approximately 1 % per year and increasing with glucose by around 0.24 % per mg/dL., Conclusion: The adolescent at higher risk is younger with higher fasting glycemia levels., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2024 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Background: Adverse events in the primary care setting result in a direct cost equivalent to at least 2.5% of total healthcare spending. Across OECD countries, they lead to more than seven million avoidable hospital admissions annually. In this manuscript, we describe the protocol of a trial aimed at evaluating the effectiveness of SinergiAPS (a patient-centered audit and feedback intervention) in reducing avoidable hospital admission and explore the factors that may affect its implementation., Methods: We will conduct a 24-month, parallel, open-label, multicenter, pragmatic, hybrid type 1 randomized clinical trial. 118 primary healthcare centers with wide geographical distribution in Spain will be randomly assigned (ratio 1:1) to two groups. The intervention group will receive two audits (baseline and intermediate at 12 months) based on information collected through the administration of the PREOS-PC questionnaire (a measure of patient-reported patient safety) to a convenience sample of 100 patients per center. The intervention group will receive reports on the results of both audits, along with educational resources aimed at facilitating the design and implementation of safety improvement plans. The control group will receive care as usual. The primary outcome will be the rate of avoidable hospitalizations (administrative data). Secondary outcomes: patient-reported patient safety experiences and outcomes (PREOS-PC questionnaire); patient safety culture as perceived by professionals (MOSPSC questionnaire); adverse events reported by healthcare professionals ( ad hoc questionnaire); the number of safety improvement actions which the re has implemented ( ad hoc questionnaire). Outcome data will be collected at baseline and 24 months follow-up. For the evaluation of the implementation of the SinergiAPS intervention, we will draw on the Consolidated Framework for Implementation Research (CFIR). We will collect and analyze qualitative and quantitative data (30 individual interviews, implementation logbooks; questionnaires for professionals from intervention centers, and level of use of the SinergiAPS web tool)., Discussion: This study will expand the scarce body of evidence existing regarding the effects and implementation of interventions aimed at promoting patient and family engagement in primary healthcare, specifically for enhancing patient safety. The study has the potential to produce an impact on clinical practice, healthcare systems, and population health. Clinical Trial Registration : https://clinicaltrials.gov/study/NCT05958108?term=sinergiAPS&rank=1 (NCT05958108)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fiol-deRoque, Mansilla, Maderuelo-Fernández, Tamayo-Morales, Martín-Luján, Astier-Peña, Chacón-Docampo, Orrego, Gens-Barberà and Andreu-Rodrigo, Ricci-Cabello.)

Inflammasome-mediated caspase-1 activation facilitates innate immune control of Plasmodium in the liver, thereby limiting the incidence and severity of clinical malaria. However, caspase-1 processing occurs incompletely in both mouse and human hepatocytes and precludes the generation of mature IL-1β or IL-18, unlike in other cells. Why this is so or how it impacts Plasmodium control in the liver has remained unknown. We show that an inherently reduced expression of the inflammasome adaptor molecule apoptosis-associated specklike protein containing CARD (ASC) is responsible for the incomplete proteolytic processing of caspase-1 in murine hepatocytes. Transgenically enhancing ASC expression in hepatocytes enabled complete caspase-1 processing, enhanced pyroptotic cell death, maturation of the proinflammatory cytokines IL-1β and IL-18 that was otherwise absent, and better overall control of Plasmodium infection in the liver of mice. This, however, impeded the protection offered by live attenuated antimalarial vaccination. Tempering ASC expression in mouse macrophages, on the other hand, resulted in incomplete processing of caspase-1. Our work shows how caspase-1 activation and function in host cells are fundamentally defined by ASC expression and offers a potential new pathway to create better disease and vaccination outcomes by modifying the latter., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Background: 3D computed tomography (CT) has been seldom used for the evaluation of hiatal hernias (HH) in surgical patients. This study aims to describe the 3D CT findings in candidates for laparoscopic or robotic antireflux surgery or HH repair and compare them with other tests., Methods: Thirty patients with HH and/or gastroesophageal reflux disease (GERD) who were candidates for surgical treatment and underwent high-resolution CT were recruited. The variables studied were distance from the esophagogastric junction (EGJ) to the hiatus; total gastric volume and herniated gastric volume, percentage of herniated volume in relation to the total gastric volume; diameters and area of the esophageal hiatus., Results: HH was diagnosed with CT in 21 (70%) patients. There was no correlation between the distance EGJ-hiatus and the herniated gastric volume. There was a statistically significant correlation between the distance from the EGJ to the hiatus and the area of the esophageal hiatus of the diaphragm. There was correlation between tomographic and endoscopic findings for the presence and size of HH. HH was diagnosed with manometry in 9 (50%) patients. There was no correlation between tomographic and manometric findings for the diagnosis of HH and between hiatal area and lower esophageal sphincter basal pressure. There was no correlation between any parameter and DeMeester score., Conclusions: The anatomy of HH and the hiatus can be well defined by 3D CT. The EGJ-hiatus distance may be equally measured by 3D CT or upper digestive endoscopy. DeMeester score did not correlate with any anatomical parameter., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Accumulation of senescent cells with age leads to tissue dysfunction and related diseases. Their detection in vivo still constitutes a challenge in aging research. We describe the generation of a fluorogenic probe (sulfonic-Cy7Gal) based on a galactose derivative, to serve as substrate for β-galactosidase, conjugated to a Cy7 fluorophore modified with sulfonic groups to enhance its ability to diffuse. When administered to male or female mice, β-galactosidase cleaves the O-glycosidic bond, releasing the fluorophore that is ultimately excreted by the kidneys and can be measured in urine. The intensity of the recovered fluorophore reliably reflects an experimentally controlled load of cellular senescence and correlates with age-associated anxiety during aging and senolytic treatment. Interestingly, our findings with the probe indicate that the effects of senolysis are temporary if the treatment is discontinued. Our strategy may serve as a basis for developing fluorogenic platforms designed for easy longitudinal monitoring of enzymatic activities in biofluids., (© 2024. The Author(s).)

Background: Influenza vaccination prevents major cardiovascular events in individuals presenting a recent acute coronary syndrome (ACS), however the early effect of an in-hospital double-dose vaccination strategy remains uncertain., Methods: The VIP-ACS was a randomized, pragmatic, multicenter, open-label trial with a blinded-adjudication endpoint. Patients with ACS ≤ 7 days of hospitalization were randomized to an in-hospital double-dose quadrivalent inactivated influenza vaccine (double-dose) or a standard-dose influenza vaccine at 30 days post-randomization. The primary endpoint was a hierarchical composite of death, myocardial infarction, stroke, hospitalization for unstable angina, hospitalization for heart failure, urgent coronary revascularization, and hospitalization for respiratory infections, analyzed with the win ratio (WR) method in short-term follow-up (45-days after randomization)., Results: The trial enrolled 1,801 patients (≥18 years old). Median participant age was 57 years, 70 % were male. There were no significant differences between groups on the primary hierarchical endpoint: there were 5.7 % wins in the double-dose in-hospital group and 5.5 % wins in the standard-dose delayed vaccination group (WR: 1.03; 95 % CI: 0.70---1.53; P = 0.85). In a sensitivity analysis including COVID-19 infection in the hospitalizations for respiratory infections endpoint, overall results were maintained (WR: 1.03; 95 % CI 0.71---1.51; P = 0.87). Results were consistent for major cardiovascular events only (WR: 0.82; 95 % CI: 0.48---1.39; P = 0.46). No serious adverse events were observed., Conclusion: In patients with recent ACS, in-hospital double-dose influenza vaccination did not significantly reduce cardiorespiratory events at 45 days compared with standard-dose vaccination at 30 days post-randomization., Competing Interests: Declaration of competing interest H.A. Fonseca has received research grants from AstraZeneca, Pfizer, Essity, Achè, and Brazilian Ministry of Health; A. Zimerman reports research scholarships from the Lemann Foundation; M.P. Okoshi received research grants (paid to her institution) from Kiniksa, AstraZeneca, Abivax, Regeneron, Apellis, BeiGene, and Theravance, and is partially supported by CNPq, Brazil (Bolsa de Produtividade em Pesquisa, 307703/2022–3); B.R. Nascimento is partially financed CNPq (Bolsa de produtividade em pesquisa, 312382/2019–7), by the Edwards Lifesciences Foundation (Improving the Prevention and Detection of Heart Valve Disease Across the Lifespan, 2021) and by FAPEMIG (grant APQ-000627–20); J.C. Nicolau reports research grants from Amgen, Astrazeneca, Bayer, CSL Behring, Daiichi Sankyo, Dalcor, Esperion, Janssen, Novartis, NovoNordisk, Sanofi and Vifor, research support from the Brazilian Council for Scientific and Technological Development (CNPq); O. Berwanger received research grants (paid to his institution) from AstraZeneca, Pfizer, Bayer, Amgen, Servier, BMS, and Novartis. VIP-ACS trial team Ricardo Reinaldo Bergo; Gislayne Rogante Ribeiro; Hospital Santa Lucia – Poços de Caldas Carlos Eduardo da Costa Nunes Bosso; Renato Dassaev Jorge Caetano; Santa Casa de Misericórdia de Presidente Prudente – Presidente Prudente. Diego Martins de Mesquita; Instituto de Cardiologia do Distrito Federal – Brasília. Rui Fernando Ramos; Renata Mirelli de Melo Viana; Instituto Dante Pazzanese – São Paulo. João Batista de Moura Xavier de Moraes Junior; Hospital Agamenon Magalhães – Recife. Bruno Francisco de Almeida Penha; Hospital Dona Helena – Joinville. Manoel Fernandes Canesin; Hospital Universitário da Universidade Estadual de Londrina – Londrina. Luiz Eduardo Fonteles Ritt; Hospital CárdioPulmonar – Salvador. Ricardo D́Oliveira Vieira; Hospital e Clínica São Roque – Ipiaú. Magnus Gidlund; Universidade de São Paulo – São Paulo. Ricardo Pereira Silva; Universidade Federal do Ceará / Hospital Universitário Walter Cantídio. Larissa Pamela Vomeiro, Roberta Possato Fernandes, Adílio Roberto Bernardes; Academic Research Organization, Hospital Israelita Albert Einstein;, (Copyright © 2023. Published by Elsevier Ltd.)

Cefiderocol is a siderophore cephalosporin designed to target multi-drug-resistant Gram-negative bacteria. Previously, the emergence of cefiderocol non-susceptibility has been associated with mutations in the chromosomal cephalosporinase (PDC) along with mutations in the PirA and PiuA/D TonB-dependent receptor pathways. Here, we report a clinical case of cefiderocol-resistant P. aeruginosa that emerged in a patient during treatment. This resistance was associated with mutations not previously reported, suggesting potential novel pathways to cefiderocol resistance., Competing Interests: V.H.T. has received consultant fees from Taxis Pharmaceuticals, Inc. W.R.M. has received research support from Merck and royalties from UpToDate. S.L.E., R.P.B., N.T. and K.P.: none to declare.

Parasites and their hosts are engaged in reciprocal coevolution that balances competing mechanisms of virulence, resistance, and evasion. This often leads to host specificity, but genomic reassortment between different strains can enable parasites to jump host barriers and conquer new niches. In the apicomplexan parasite Cryptosporidium , genetic exchange has been hypothesized to play a prominent role in adaptation to humans. The sexual lifecycle of the parasite provides a potential mechanism for such exchange; however, the boundaries of Cryptosporidium sex are currently undefined. To explore this experimentally, we established a model for genetic crosses. Drug resistance was engineered using a mutated phenylalanyl tRNA synthetase gene and marking strains with this and the previously used Neo transgene enabled selection of recombinant progeny. This is highly efficient, and genomic recombination is evident and can be continuously monitored in real time by drug resistance, flow cytometry, and PCR mapping. Using this approach, multiple loci can now be modified with ease. We demonstrate that essential genes can be ablated by crossing a Cre recombinase driver strain with floxed strains. We further find that genetic crosses are also feasible between species. Crossing Cryptosporidium parvum, a parasite of cattle and humans, and Cryptosporidium tyzzeri a mouse parasite resulted in progeny with a recombinant genome derived from both species that continues to vigorously replicate sexually. These experiments have important fundamental and translational implications for the evolution of Cryptosporidium and open the door to reverse- and forward-genetic analysis of parasite biology and host specificity., Competing Interests: Competing interests statement:The authors declare no competing interest.

Grapevine virus A (GVA) is an economically important virus and a member of the genus Vitivirus (family Betaflexiviridae ) that causes a range of symptoms with qualitative and quantitative effects on grape production. Wild and domesticated species of Vitis , including hybrids used as rootstocks, are considered important natural hosts of GVA. Mechanical transmission to some herbaceous plant species, graft transmission, and vector transmission from grape to grape by various mealybugs and soft scale insects have been reported. Under laboratory and greenhouse conditions, this study demonstrates the transmission of GVA from grapes to alternative hosts by the vine mealybug ( Planococcus ficus ). Results of ELISA, end-point one-step RT-PCR, and real-time RT-PCR, and in some cases electron microscopy and genome sequencing, confirmed successful transmission to three new plant species commonly found in Croatian vineyards: velvetleaf ( Abutilon theophrasti ), redroot pigweed ( Amaranthus retroflexus ), and field poppy ( Papaver rhoeas ), along with Chenopodium murale and the previously known host Nicotiana benthamiana , with variable infection rates. Depending on the host species, symptoms in the form of leaf reddening, yellow spots, reduced growth of lateral shoots, systemic vein clearing, foliar deformation and rugosity, and dwarfism were observed in GVA-infected plants, whereas no symptoms were observed in infected plants of A. theophrasti . Reverse transmission from these new hosts to grapevines by Pl. ficus was not successful. These results confirm four new GVA host species and open new research venues., Competing Interests: The author(s) declare no conflict of interest.

Canine respiratory coronavirus (CRCoV) is one of the main causative agents of canine infectious respiratory disease (CIRD), an illness whose epidemiology is poorly understood. We assessed the prevalence, risk factors, and genetic characterization of CRCoV in privately owned dogs in the Southeastern United States. We PCR-screened 189 nasal swabs from dogs with and without CIRD clinical signs for 9 CIRD-related pathogens, including CRCoV; 14% of dogs, all diagnosed with CIRD, were positive for CRCoV, with a significantly higher rate of cases in younger dogs and during warmer weather. Notably, the presence of CRCoV, alone or in coinfection with other CIRD pathogens, was statistically associated with a worse prognosis. We estimated a CRCoV seroprevalence of 23.7% retrospectively from 540 serum samples, with no statistical association to dog age, sex, or season, but with a significantly higher presence in urban counties. Additionally, the genomes of 6 CRCoVs were obtained from positive samples using an in-house developed targeted amplicon-based approach specific to CRCoV. Subsequent phylogeny clustered their genomes in 2 distinct genomic groups, with most isolates sharing a higher similarity with CRCoVs from Sweden and only 1 more closely related to CRCoVs from Asia. We provide new insights into CIRD and CRCoV epidemiology in the Southeastern United States and further support the association of CRCoV with more severe cases of CIRD. Additionally, we developed and successfully tested a new amplicon-based approach for whole-genome sequencing of CRCoV that can be used to further investigate the genetic diversity within CRCoVs., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Global travel and trade in combination with climate change are expanding the geographic distribution of plant pathogens. The bacterium Xylella fastidiosa is a prime example. Native to the Americas, it has spread to Europe, Asia, and the Middle East. To assess the risk that pathogen introductions pose to crops in newly invaded areas, it is key to survey their diversity, host range, and disease incidence in relation to climatic conditions where they are already present. We performed a survey of X. fastidiosa in grapevine in Virginia using a combination of quantitative PCR, multilocus sequencing, and metagenomics. We also analyzed samples from deciduous trees with leaf scorch symptoms. X. fastidiosa subspecies fastidiosa was identified in grapevines in all regions of the state, even in Northern Virginia, where the temperature was below -9°C for 10 days per year on average in the years preceding sampling. Unexpectedly, we also found for the first time grapevine samples infected with X. fastidiosa subspecies multiplex ( Xfm ). The Xfm lineage found in grapevines had been previously isolated from blueberries in the Southeastern United States and was distinct from that found in deciduous trees in Virginia. The obtained results will be important for risk assessment of X. fastidiosa introductions in other parts of the world., Competing Interests: The author(s) declare no conflict of interest.

Objective: Converging evidence supports the role of the glutamate, an excitatory amino acid neurotransmitter, in the pathophysiology of obsessive-compulsive disorder (OCD). Ketamine and esketamine, both noncompetitive N -methyl- d -aspartate antagonists, have emerged as a promising medication for this psychiatric disorder, given its possible efficacy with faster onset and good tolerability. The purpose of this retrospective chart review is to evaluate whether unbiased clinical documentation supports formal clinical trials of esketamine for an OCD indication., Methods: A retrospective chart review of patients with treatment-resistant OCD receiving a single dose of esketamine (0.5mg/kg) added to standard therapy was conducted. The Yale-Brown Obsessive-Compulsive Scale and the Montgomery-Åsberg Depression Rating Scale were used to evaluate OCD and depressive symptoms respectively at baseline, 24 hours, and 7 days after esketamine administration. Descriptive statistics were used to analyze the data., Results: Eight subjects were identified in this retrospective chart review: esketamine was administered subcutaneously in 7 and intravenously in 1. One week after infusion, 25% of the sample met criteria for treatment response and 50% for partial response. Major depressive disorder was a comorbid diagnosis in 75% of the sample and 2 of these subjects showed a positive antidepressant response., Conclusions: Our findings provide preliminary evidence that esketamine may reduce obsessive-compulsive symptoms in a subset of treatment-resistant OCD patients., Competing Interests: Conflicts of Interest and Source of Funding: This study was supported by a grant from Programa Pesquisa para o SUS (PPSUS/BA—research grant number 003/2017), a public research-funding program, and by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brazil (CAPES)—Finance Code 001. The sponsors had no role in either the study design, the writing of the manuscript, or the decision to submit it for publication. In addition, the University Hospital involved provided hospital structure, medications, and human resources. L.C.Q. reports consulting fees from Abbot, Allergan, Cristalia, Janssen Pharmaceutical, and Lundbeck and research fees from Janssen Pharmaceutical., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

There are few reports of Trypanosoma in snakes, as well as little information about its pathogenicity in these animals. Thus, the present study aimed to characterize Trypanosoma found in Boa constrictor snakes, to verify the influence of the parasitism on hematological and clinical biochemistry parameters, and to perform a phylogenetic study of the isolates. Blood samples from sixty-one boas were analyzed for the presence of trypanosomatids and by hematological and clinical biochemistry assays. The flagellates that were found in this analysis were used for cell culture, morphometry, and molecular analysis. Later, molecular typing phylogenetic studies were performed. Nine positive animals (14.75%) were identified by microscopy analysis. The hematological results showed that parasitized animals presented significantly lower levels of packed cell volume, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. In the leukogram, eosinophils and heterophils counts were higher in parasitized animals. Considering the molecular analyses, the isolates presented a higher identity of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the 18S small subunit ribosomal RNA (SSU rRNA) gene fragments with Trypanosoma serpentis. The phylogenetic tree, using the GAPDH, clustered all isolates with T. serpentis and Trypanosoma cascavelli. This is the first description of T. serpentis parasitizing boas and of the clinical changes caused by trypanosomatid infection in snakes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Vigorous physical activity has been associated with a reduced risk of developing obstructive sleep apnea (OSA). However, whether high-intensity interval training (HIIT) reduces OSA severity remains unclear. Thus, this study aimed to investigate the impact of 12 weeks of HIIT on the apnea-hypopnea index (AHI) and sleep parameters in participants with moderate-severe OSA. In this randomized controlled trial, 36 adults (19 males; 52.2 ± 9.8 years; body mass index = 34.2 ± 5.8) with moderate to severe OSA (AHI = 42.0 ± 22.9 e/h) were randomly assigned to HIIT [5 periods of 4 min of walking or running on a treadmill at 90-95 % of maximum heart rate (HR max ) interspersed with 3 min of walking at 50-55 % of HR max performed three times per week for 12 weeks] or a control group (CG; stretching exercises performed two times per week for 12 weeks). Sleep parameters were assessed at baseline and after 12 weeks through overnight polysomnography. Generalized estimated equations assessed differences between groups over time. There was not group × time interaction for body mass index between groups (p = 0.074). However, significant group × time interactions were observed for AHI (CG change = 8.2 ± 3.7, HIIT change = -8.6 ± 4.8; p = 0.005), SaO 2 minimum (CG change = -1.6 ± 1.6 %, HIIT change = 0.4 ± 2.3 %; p = 0.030), total sleep time (CG change = -31.5 ± 19.5 min, HIIT change = 33.7 ± 19.3 min; p = 0.049), and sleep efficiency (CG change = -3.2 ± 4.4 %, HIIT change = 9.9 ± 3.5 %; p = 0.026). Moreover, there was a significant time × group interaction for maximum oxygen consumption (VO 2max ; CG change = -1.1 ± 1.0 mL/kg/min, HIIT change = 4.8 ± 0.9 mL/kg/min; p < 0.001)]. However, In patients with OSA, 12 weeks of HIIT decreases sleep apnea severity, improves sleep quality, and cardiorespiratory fitness. CLINICAL TRIAL REGISTRATION: (Registro Brasileiro de Ensaios Clínicos [ReBec]): # RBR-98jdt3., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus (DM). It has been proposed that modifications in the function of proximal tubule epithelial cells (PTECs) precede glomerular damage during the onset of DKD. This study aimed to identify modifications in renal sodium handling in the early stage of DM and its molecular mechanism., Methods: Streptozotocin (STZ)-induced diabetic BALB/c mice (STZ group) and LLC-PK1 cells, a model of PTECs, were used. All parameters were assessed in the 4th week after an initial injection of STZ., Results: Early stage of DKD was characterized by hyperfiltration and PTEC dysfunction. STZ group exhibited increased urinary sodium excretion due to impairment of tubular sodium reabsorption. This was correlated to a decrease in cortical (Na + +K + )ATPase (NKA) α1 subunit expression and enzyme activity and an increase in O-GlcNAcylation. RNAseq analysis of patients with DKD revealed an increase in expression of the glutamine-fructose aminotransferase (GFAT) gene, a rate-limiting step of hexosamine biosynthetic pathway, and a decrease in NKA expression. Incubation of LLC-PK1 cells with 10 μM thiamet G, an inhibitor of O-GlcNAcase, reduced the expression and activity of NKA and increased O-GlcNAcylation. Furthermore, 6-diazo-5-oxo-L-norleucine (DON), a GFAT inhibitor, or dapagliflozin, an SGLT2 inhibitor, avoided the inhibitory effect of HG on expression and activity of NKA associated with the decrease in O-GlcNAcylation., Conclusion: Our results show that the impairment of tubular sodium reabsorption, in the early stage of DM, is due to SGLT2-mediated HG influx in PTECs, increase in O-GlcNAcylation and reduction in NKA expression and activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The shell Nucleus Accumbens (NAcc) projects to the lateral preoptic area, which is involved in the central micturition control and receives inputs from medullary areas involved in cardiovascular control. We investigated the role of GABAergic and glutamatergic transmission in the shell NAcc on intravesical pressure (IP) and cardiovascular control. Male Wistar rats with guide cannulas implanted bilaterally in the shell NAcc 7 days prior to the experiments were anesthetized with 2% isoflurane in 100% O 2 and subjected to cannulation of the femoral artery and vein for mean arterial pressure (MAP) and heart rate recordings (HR) and infusion of drugs, respectively. The urinary bladder (UB) was cannulated for IP measurement. A Doppler flow probe was placed around the renal arterial for renal blood flow (RBF) measurement. After the baseline MAP, HR, IP and RBF recordings for 15 min, GABA or bicuculline methiodate (BMI) or L-glutamate or kynurenic acid (KYN) or saline (vehicle) were bilaterally injected into the shell NAcc and the variables were measured for 30 min. Data are as mean ± SEM and submitted to Student́s t test. GABA injections into the shell NAcc evoked a significant fall in MAP and HR and increased IP and RC compared to saline. L-glutamate in the shell NAcc increased MAP, HR and IP and reduced RC. Injections of BMI and KYN elicited no changes in the variables recorded. Therefore, the GABAergic and glutamatergic transmissions in neurons in the shell NAcc are involved in the neural pathways responsible for the central cardiovascular control and UB regulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Haemonchus contortus is the most pathogenic blood-feeding parasitic in sheep, causing anemia and consequently changes in the color of the ocular conjunctiva, from the deep red of healthy sheep to shades of pink to practically white of non-healthy sheep. In this context, the Famacha method has been created for detecting sheep unable to cope with the infection by H. contortus , through visual assessment of ocular conjunctiva coloration. Thus, the objectives of this study were (1) to extract ocular conjunctiva image features to automatically classify Famacha score and compare two classification models (multinomial logistic regression-MLR and random forest-RF) and (2) to evaluate the applicability of the best classification model on three sheep farms. The dataset consisted of 1,156 ocular conjunctiva images from 422 animals. RF model was used to segment the images, i.e., to select the pixels that belong to the ocular conjunctiva. After segmentation, the quantiles (1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 99%) of color intensity in each image channel (red, blue, and green) were determined and used as explanatory variables in the classification models, and the Famacha scores 1 (non-anemic) to 5 (severely anemic) were the target classes to be predicted (scores 1 to 5, with 162, 255, 443, 266, and 30 images, respectively). For objective 1, the performance metrics (precision and sensitivity) were obtained using MLR and RF models considering data from all farms randomly split. For objective 2, a leave-one-farm-out cross-validation technique was used to assess prediction quality across three farms (farms A, B, and C, with 726, 205, and 225 images, respectively). The RF provided the best performances in predicting anemic animals, as indicated by the high values of sensitivity for Famacha score 3 (80.9%), 4 (46.2%), and 5 (60%) compared to the MLR model. The precision of the RF was 72.7% for Famacha score 1 and 62.5% for Famacha score 2. These results indicate that is possible to successfully predict Famacha score, especially for scores 2 to 4, in sheep via image analysis and RF model using ocular conjunctiva images collected in farm conditions. As expected, model validation excluding entire farms in cross-validation presented a lower prediction quality. Nonetheless, this setup is closer to reality because the developed models are supposed to be used across farms, including new ones, and with different environments and management conditions., Competing Interests: There are no potential conflicts of interest that may affect our ability to objectively present or review the research data submitted here., (Published by Oxford University Press for the American Society of Animal Science 2023.)

Many insects feed on xylem or phloem sap of vascular plants. Although physical damage to the plant is minimal, the process of insect feeding can transmit lethal viruses and bacterial pathogens. Disparities between insect-mediated pathogen transmission efficiency have been identified among xylem sap-feeding insects; however, the mechanistic drivers of these trends are unclear. Identifying and understanding the structural factors and associated integrated functional components that may ultimately determine these disparities are critical for managing plant diseases. Here, we applied synchrotron-based X-ray microcomputed tomography to digitally reconstruct the morphology of three xylem sap-feeding insect vectors of plant pathogens: Graphocephala atropunctata (blue-green sharpshooter; Hemiptera, Cicadellidae) and Homalodisca vitripennis (glassy-winged sharpshooter; Hemiptera, Cicadellidae), and the spittlebug Philaenus spumarius (meadow spittlebug; Hemiptera, Aphrophoridae). The application of this technique revealed previously undescribed anatomical features of these organisms, such as key components of the salivary complex. The visualization of the 3D structure of the precibarial valve led to new insights into the mechanism of how this structure functions. Morphological disparities with functional implications between taxa were highlighted as well, including the morphology and volume of the cibarial dilator musculature responsible for extracting xylem sap, which has implications for force application capabilities. These morphological insights will be used to target analyses illuminating functional differences in feeding behavior., (© 2023 The Authors. Journal of Morphology published by Wiley Periodicals LLC.)

Glioblastoma (GB) is the most aggressive primary malignant brain tumor and is associated with short survival. O-GlcNAcylation is an intracellular glycosylation that regulates protein function, enzymatic activity, protein stability, and subcellular localization. Aberrant O-GlcNAcylation is related to the tumorigenesis of different tumors, and mounting evidence supports O-GlcNAc transferase (OGT) as a potential therapeutic target. Here, we used two human GB cell lines alongside primary human astrocytes as a non-tumoral control to investigate the role of O-GlcNAcylation in cell proliferation, cell cycle, autophagy, and cell death. We observed that hyper O-GlcNAcylation promoted increased cellular proliferation, independent of alterations in the cell cycle, through the activation of autophagy. On the other hand, hypo O-GlcNAcylation inhibited autophagy, promoted cell death by apoptosis, and reduced cell proliferation. In addition, the decrease in O-GlcNAcylation sensitized GB cells to the chemotherapeutic temozolomide (TMZ) without affecting human astrocytes. Combined, these results indicated a role for O-GlcNAcylation in governing cell proliferation, autophagy, cell death, and TMZ response, thereby indicating possible therapeutic implications for treating GB. These findings pave the way for further research and the development of novel treatment approaches which may contribute to improved outcomes and increased survival rates for patients facing this challenging disease.

Background: Clinical outcomes of bicuspid aortic valve (BAV) patients with ascending aortic diameters ≥50 mm who are under surveillance are poorly defined., Objectives: The purpose of this study was to assess clinical outcomes in BAV patients with ascending aorta ≥50 mm., Methods: Multicenter retrospective cohort study of BAV adults with ascending aorta diameters ≥50 mm by transthoracic echocardiography (TTE). Patients were categorized into 50 to 54 mm and ≥55 mm groups. Clinical outcomes were aortic dissection (AoD), aorta surgery, surgical mortality, and all-cause death., Results: Of 875 consecutive BAV patients (age 60 ± 13 years, 86% men, aortic diameter 51 mm [interquartile range (IQR): 50-53 mm]), 328 (37%) underwent early surgery ≤3 months from index TTE. Of the remaining 547 patients under surveillance, 496 had diameters 50 to 54 mm and 51 had diameters ≥55 mm and were collectively followed for 7.51 (IQR: 3.98-12.20) years. Of 496 patients with diameters 50 to 54 mm under surveillance, 266 (54%) underwent surgery 2.0 (IQR: 0.77-4.16) years from index TTE. AoD occurred in 9/496 (1.8%) patients for an incidence of 0.4 cases per 100 person-years, surgical mortality was 5/266 (1.9%); and ≥moderate aortic stenosis (but not aorta size) was associated with all-cause death, hazard ratio: 2.05 (95% CI: 1.32-3.20), P  = 0.001. Conversely, in 547 total patients under surveillance (including 50-54 mm and ≥55 mm), both aorta size and ≥moderate aortic stenosis were associated with all-cause death (both P  ≤ 0.027). AoD rate in patients ≥55 mm under surveillance was 5.9%., Conclusions: In BAV patients with ascending aorta 50 to 54 mm under surveillance, AoD incidence is low and the overall rates of AoD and surgical mortality are similar, suggesting clinical equivalence between surgical and surveillance strategies. Conversely, patients with aortas ≥55 mm should undergo surgery. Aortic stenosis is associated with all-cause death in these patients., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Ketamine and esketamine have both shown significant antidepressant effects in treatment-resistant depression (TRD), and conflicting evidence suggests that induced dissociation by these drugs can be a clinical predictor of esketamine/ketamine's efficacy., Methods: This study is a secondary analysis from a bi-center, randomized, controlled trial. Participants were randomly assigned 1:1 to receive an IV infusion of esketamine (.25 mg/kg) or racemic ketamine (.50 mg/kg) over 40 minutes. Dissociative symptoms were assessed using the Clinician-Administered Dissociative State Scale (CADSS) 40 minutes following the beginning of the infusion. The variation in depression scores was measured with the Montgomery-Asberg Depression Rating Scale (MADRS), which was administered before the intervention as a baseline measure and 24 hrs, 72 hrs, and 7 days following infusion., Results: Sixty-one patients were included in the analysis. Examining CADSS scores of 15 or below, for every 1-point increment in the CADSS score, there was a mean change of -0.5 (SD = 0.25; p-value 0.04) of predicted MADRS score from baseline to 24 hrs. The results for 72 hrs and 7 days following infusion were not significant. Limitations: This study was not designed to assess the relationship between ketamine or esketamine-induced dissociation and antidepressant effects as the main outcome, therefore confounding variables for this relationship were not controlled., Conclusion: We suggest a positive relationship between dissociation intensity, measured by CADSS, and antidepressant effect 24 hours after ketamine and esketamine infusion for a CADSS score of up to 15 points., Competing Interests: ALTL reports grants and personal fees from Janssen Pharmaceutical, personal fees from Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Libbs, Pfizer, Myralis Farma, Aché Laboratórios, Hypera Pharma, and Sanofi-Aventis, grants from Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, Forum Pharmaceuticals and from the following public funding programs CNPq and FAPESP. LCQ reports consulting fees from Allergan, Abbott, Cristalia, Janssen Pharmaceutical, and Lundbeck and research fees from Janssen Pharmaceutica and Fundação Baiana de Infectologia. No other conflicts of interest declared concerning the publication of this article.

Introduction: The medial preoptic area (mPOA) participates in thermoregulatory control and blood pressure modulation as shown by studies with electrical stimulation of this area or cobalt chloride injection, a non-selective synapse inhibitor. This study aimed to investigate whether angiotensin II (Ang II) and GABA could act or not in the mPOA to mediate the cardiovascular and micturition control pathways. Methods: Female Wistar rats were submitted to stereotaxic surgery for implantation of a guide cannula into the mPOA 7 days prior to the experiments. Afterwards, the animals were isoflurane- anesthetized and submitted to the catheterization of the femoral artery and vein and urinary bladder cannulation for mean arterial pressure (MAP), heart rate (HR), and intravesical pressure (IP) recordings, respectively. After the baseline MAP, HR, and IP recordings for 15 min, Ang II (0.1 nM, 1 μL), losartan (AT-1 receptor antagonist, 100 nM, 1 μL), GABA (50 mM, 1 μL) or saline (1 μL) were injected into the mPOA, and the variables were measured for additional 30 min. In a different group of rats, the AT-1 receptor, angiotensin II converting enzyme (ACE), and GABAa receptor gene expression was evaluated in mPOA samples by qPCR. The data are as mean ± SEM and submitted to One-way ANOVA (Tukey posttest) or paired Student t-test (P <0.05). Results: The injection of Ang II into the mPOA evoked a significant hypotension (-37±10 mmHg, n = 6, p = 0.024) and bradycardia (-47 ± 20 bpm, p = 0.030) compared to saline (+1 ± 1 mmHg and +6 ± 2 bpm, n = 6). A significant increase in IP was observed after Ang II injection into the mPOA (+72.25 ± 17.91%, p = 0.015 vs. -1.80 ± 2.98%, n = 6, saline). No significant changes were observed in MAP, HR and IP after the losartan injection in the mPOA compared to saline injection. Injection of GABA into the mPOA evoked a significant fall in MAP and HR (-68 ± 2 mmHg, n = 6, p < 0.0001 and -115 ± 14 bpm, n = 6, p = 0.0002 vs. -1 ± 1 mmHg and +4 ± 2 bpm, n = 6, saline), but no significant changes were observed in IP. The AT-1 receptor, ACE and GABAa receptor mRNA expression was observed in all mPOA samples. Discussion: Therefore, in female rats, Ang II mediated transmission in the mPOA is involved in the cardiovascular regulation and in the control of central micturition pathways. A phasic control dependent on AT-1 receptors in the mPOA seems to be involved in the regulation of those cardiovascular and intravesical 3 parameters. In contrast, GABAergic transmission in the mPOA participates in the pathways of cardiovascular control in anesthetized female rats, nevertheless, this neurotransmission is not involved in the micturition control., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Daiuto, de Carvalho, Vale, Dsouki, Giannocco, Cafarchio, Aronsson and Sato.)

We used spatial analysis tools to examine the epidemiological situation and spatial distribution of American tegumentary leishmaniasis in the municipality of Caratinga between 2016 and 2021. In addition, potential sandfly vectors were captured. All information used in this study was retrieved from public health archives and confirmed in the state health services databases. All cases were analyzed using Geographic Information Systems software. In addition, sandfly collections and molecular detection of Leishmania were carried out in areas with the highest number of cases. During the analyzed period, American tegumentary leishmaniasis (ATL) cases increased and remained high in the last years. The hotspots included urban areas of Caratinga city and the districts of Patrocínio of Caratinga and Sapucaia. The species Nyssomyia whitmani, Nyssomyia intermedia, and Migonemyia migonei were the most abundant species and the ITS1-polymerase chain reaction technique detected Leishmania DNA in these species. On the basis of our analyses, the urbanization of ATL in Caratinga has taken place in recent years. Because of the increase in the number of human cases and the presence of vectors, it is recommended that health authorities focus on control measures in hotspots.

The pathogen Xylella fastidiosa subsp. fastidiosa has circulated through California's vineyards since its introduction from Central America in the 1800s. This pathogen is responsible for a bacterial disease called Pierce's disease (PD) of grapevine. With no known cure, PD has had devastating effects on some vineyards. Important factors that impact disease severity and persistence include: the presence of insect vectors, grapevine cultivar, management, ecology, and winter temperatures. Removal of infected vines is critical for reducing pathogen spread but relies on accurate and rapid pathogen detection. In this study, we foster a greater understanding of disease symptom emergence by way of a 3-year field inoculation project in Napa Valley. Although PD emergence and symptom progression have been studied in greenhouse and experimental plots, there is a large knowledge gap in quantifying disease progression under commercial conditions. After inoculating 80 mature Vitis vinifera vines in April 2017, we measured bacterial populations and six symptom types at four locations within each plant throughout the subsequent three growing seasons. The main foci of the project were understanding X. fastidiosa movement through the plants, infection, overwinter curing, and symptom development. We observed greater winter recovery than expected, and shriveled grape clusters proved to be a more reliable early indication of infection than other more commonly used symptoms. Although there were differences among wine grape cultivars, this work suggests that disease progression in the field may not fit the paradigm of predominant leaf scorch and low recovery rates as neatly as has been previously believed., Competing Interests: The author(s) declare no conflict of interest.

There are significantly fewer options for the treatment of bipolar depression than major depressive disorder, with an urgent need for alternative therapies. In this pilot study, we treated six subjects with bipolar disorder types I and II (according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria) who had been in a current depressive episode for at least four weeks. Four subjects were female (66.66%), and the mean age was 45.33 (±12.32). Subjects received adjunct treatment with two arketamine intravenous infusions one week apart-0.5 mg/kg first and then 1 mg/kg. The mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 36.66, which decreased to 27.83 24h after the first infusion of 0.5 mg/kg of arketamine (p = 0.036). In respect of the 1 mg/kg dose, the mean MADRS total score before the second infusion was 32.0, which dropped to 17.66 after 24h (p < 0.001). Arketamine appears to have rapid-acting antidepressant properties, consistent with previous animal studies on major depression. All individuals tolerated both doses, exhibiting nearly absent dissociation, and no manic symptoms. To the best of our knowledge, this pilot trial is the first to test the feasibility and safety of the (R)-enantiomer of ketamine (arketamine) for bipolar depression., Competing Interests: Declaration of competing interest Dr. Quarantini reports consulting fees from Allergan, Abbott, Janssen Pharmaceuticals and Lundbeck and research fees from Janssen Pharmaceuticals. Dr. Lacerda reports grants and personal fees from Janssen Pharmaceuticals, personal fees from Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Libbs, Pfizer, Myralis Farma, Aché Laboratórios, Hypera Pharmaand Sanofi-Aventis, grants from Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, Forum Pharmaceuticals and from public programs: CNPq and FAPESP., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Rapamycin is an immunosuppressor that acts by inhibiting the serine/threonine kinase mechanistic target of rapamycin complex 1. Therapeutic use of rapamycin is limited by its adverse effects. Proteinuria is an important marker of kidney damage and a risk factor for kidney diseases progression and has been reported in patients and animal models treated with rapamycin. However, the mechanism underlying proteinuria induced by rapamycin is still an open matter. In this work, we investigated the effects of rapamycin on parameters of renal function and structure and on protein handling by proximal tubule epithelial cells (PTECs). Methods: Healthy BALB/c mice were treated with 1.5 mg/kg rapamycin by oral gavage for 1, 3, or 7 days. At the end of each treatment, the animals were kept in metabolic cages and renal function and structural parameters were analyzed. LLC-PK1 cell line was used as a model of PTECs to test specific effect of rapamycin. Results: Rapamycin treatment did not change parameters of glomerular structure and function. Conversely, there was a transient increase in 24-h proteinuria, urinary protein to creatinine ratio (UPCr), and albuminuria in the groups treated with rapamycin. In accordance with these findings, rapamycin treatment decreased albumin-fluorescein isothiocyanate uptake in the renal cortex. This effect was associated with reduced brush border expression and impaired subcellular distribution of megalin in PTECs. The effect of rapamycin seems to be specific for albumin endocytosis machinery because it did not modify renal sodium handling or (Na + +K + )ATPase activity in BALB/c mice and in the LLC-PK1 cell line. A positive Pearson correlation was found between megalin expression and albumin uptake while an inverse correlation was shown between albumin uptake and UPCr or 24-h proteinuria. Despite its effect on albumin handling in PTECs, rapamycin treatment did not induce tubular injury measured by interstitial space and collagen deposition. Conclusion: These findings suggest that proteinuria induced by rapamycin could have a tubular rather than a glomerular origin. This effect involves a specific change in protein endocytosis machinery. Our results open new perspectives on understanding the undesired effect of proteinuria generated by rapamycin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Peres, Peruchetti, Silva-Aguiar, Teixeira, Gomes, Takiya, Pinheiro and Caruso-Neves.)

COVID-19 has accounted for more than 6 million deaths worldwide. Bacillus Calmette-Guérin (BCG), the existing tuberculosis vaccine, is known to induce heterologous effects over other infections due to trained immunity and has been proposed to be a potential strategy against SARS-CoV-2 infection. In this report, we constructed a recombinant BCG (rBCG) expressing domains of the SARS-CoV-2 nucleocapsid and spike proteins (termed rBCG-ChD6), recognized as major candidates for vaccine development. We investigated whether rBCG-ChD6 immunization followed by a boost with the recombinant nucleocapsid and spike chimera (rChimera), together with alum, provided protection against SARS-CoV-2 infection in K18-hACE2 mice. A single dose of rBCG-ChD6 boosted with rChimera associated with alum elicited the highest anti-Chimera total IgG and IgG2c Ab titers with neutralizing activity against SARS-CoV-2 Wuhan strain when compared with control groups. Importantly, following SARS-CoV-2 challenge, this vaccination regimen induced IFN-γ and IL-6 production in spleen cells and reduced viral load in the lungs. In addition, no viable virus was detected in mice immunized with rBCG-ChD6 boosted with rChimera, which was associated with decreased lung pathology when compared with BCG WT-rChimera/alum or rChimera/alum control groups. Overall, our study demonstrates the potential of a prime-boost immunization system based on an rBCG expressing a chimeric protein derived from SARS-CoV-2 to protect mice against viral challenge., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Purpose: Although liver transplantation (LT) outcomes have improved significantly over the last decades, early vascular complications are still associated with elevated risks of graft failure. Doppler ultrasound (DUS) enables detection of vascular complications, provides hepatic artery Resistive Index (RI). The aim of our study was to evaluate the association of the RI parameters of DUS performed in the first post-transplant week with post-transplant outcomes., Methods: All consecutive patients undergoing a first LT between 2001 and 2019 at a single center were included. Patients were divided into two groups: RI < 0.55 and RI ≥ 0.55. Patients were also divided according to the presence or absence of hepatic artery thrombosis (HAT). Graft survival was compared between groups., Results: Overall, 338 patients were included. HAT occurred in 23 patients (6.8%), of which 7 were partial and 16, complete. Biliary complications were more common in patients with HAT (10 [43.5%]) vs. 38 [12.1%] [p < 0.001]). Graft survival was lower for patients with HAT (p = 0.047). Also, RI < 0.55 was associated with increased incidence of HAT (p < 0.001). Additionally, patients with RI < 0.55 on post-operative day 1 had decreased graft survival as compared to patients with RI > 0.55 (p = 0.041). RI on post-operative day 3 and 5 was not predictive of inferior graft outcomes., Conclusions: Intensive use of DUS in the early post-LT period offers the possibility of early diagnosis of vascular complications, guiding medical and surgical management of HAT. Additionally, according to our data, low RI (< 0.55) on the first postoperative day also is a predictor of HAT and decreased graft-survival., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Statement of Problem: How the masticatory function of complete denture wearers is influenced by the positioning and occlusion of posterior teeth or by the presence of a single mandibular implant is unclear., Purpose: The purpose of this randomized crossover clinical trial was to evaluate the masticatory efficiency of wearers of bimaxillary complete dentures and of wearers of maxillary complete denture and single implant-retained mandibular overdentures, both with bilateral balanced occlusion and lingualized occlusion., Material and Methods: Participants received 2 sets of complete dentures with interchangeable teeth in the mandibular prosthesis to allow a change in the occlusion scheme. Subsequently, 1 implant was placed in the mandibular symphysis region, and the mandibular complete dentures were converted to overdentures. The masticatory efficiency was measured by the sieve method for both occlusal schemes., Results: Repeated measures ANOVA showed no statistically significant difference in the masticatory efficiency with the 2 occlusal schemes for conventional complete dentures (P=.707) or overdentures (P=.407). When comparing the type of prosthesis, statistical differences were found for masticatory efficiency (P=.012), with improved mastication for the overdentures., Conclusions: A mandibular single implant improved the masticatory efficiency of patients with complete dentures, but the occlusal scheme did not influence this factor., (Copyright © 2021 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

While there are documented host shifts in many bacterial plant pathogens, the genetic foundation of host shifts is largely unknown. Xylella fastidiosa is a bacterial pathogen found in over 600 host plant species. Two parallel host shifts occurred-in Brazil and Italy-in which X. fastidiosa adapted to infect olive trees, whereas related strains infected coffee. Using 10 novel whole-genome sequences from an olive-infecting population in Brazil, we investigated whether these olive-infecting strains diverged from closely related coffee-infecting strains. Several single-nucleotide polymorphisms, many derived from recombination events, and gene gain and loss events separated olive-infecting strains from coffee-infecting strains in this clade. The olive-specific variation suggests that this event was a host jump with genetic isolation between coffee- and olive-infecting X. fastidiosa populations. Next, we investigated the hypothesis of genetic convergence in the host shift from coffee to olive in both populations (Brazil and Italy). Each clade had multiple mutations and gene gain and loss events unique to olive, yet no overlap between clades. Using a genome-wide association study technique, we did not find any plausible candidates for convergence. Overall, this work suggests that the two populations adapted to infect olive trees through independent genetic solutions., (© 2023 The Authors. Molecular Plant Pathology published by British Society for Plant Pathology and John Wiley & Sons Ltd.)

Background: Racemic ketamine is a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with the latter regarded as the main isomer for antidepressant effects. However, preclinical data and one open-label human trial suggest arketamine might exert a more potent and longer-lasting antidepressant effect with fewer side effects. We aimed to explore the feasibility of a randomized controlled trial of arketamine for treatment-resistant depression (TRD) and to assess its efficacy and safety compared to placebo., Methods: This is a, randomized, double-blind, crossover, pilot trial (n = 10). All participants received saline and arketamine (0.5 mg/kg) with a one-week interval. Treatment effects were analyzed with a linear mixed effects (LME) model., Results: Our analysis suggested the presence of a carryover effect, so the main efficacy analysis was limited to the first week, which demonstrated a main effect of time (p = 0.038) but not for treatment (p = 0.40) or their interaction (p = 0.95). This indicates that depression improved over time, but without significant difference between arketamine and placebo. Analyzing the two weeks together, findings were the same. Dissociation and other adverse events were minimal., Limitations: This was a pilot study with a small sample and underpowered., Conclusions: Arketamine was not superior to placebo for TRD but demonstrated to be extremely safe. Our findings reinforce the importance of continuing studies with this drug, with better powered clinical trials, perhaps considering a parallel design with higher or flexible doses and repeated administrations., Competing Interests: Conflict of interest Dr. Lacerda reports grants and personal fees from Janssen Pharmaceutical, Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Libbs, Pfizer, Myralis Farma, Aché Laboratórios, Hypera Pharma, Sanofi-Aventis, Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, and Forum Pharmaceuticals. Dr. Sanacora, in the last 12 months, has provided consulting services to Ancora, Aptinyx, Axsome Therapeutics, Biohaven Pharmaceuticals, Bristol-Myers Squibb, Clexio Biosciences, Denovo Biopharma, EMA Wellness, Engrail, Gilgamesh, Freedom Biosciences, Intra-Cellular Therapies, Janssen, miCure Therapeutics, Merck, Navitor Pharmaceuticals, Neurocrine, Novartis, Noven Pharmaceuticals, Perception Neuroscience, Praxis, Sage Pharmaceuticals, Seelos Pharmaceuticals, and XW Labs. He has received funds for contracted research from Janssen Pharmaceuticals, Merck, and Usona Institute. He holds equity in Biohaven Pharmaceuticals and has received royalties paid from patent licenses with Biohaven Pharmaceuticals. His employer, Yale University, has a financial relationship with Janssen Pharmaceuticals and may receive financial benefits from this relationship. Other authors have no conflicts of interest to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Homologous recombination plays a key function in the evolution of bacterial genomes. Within Xylella fastidiosa, an emerging plant pathogen with increasing host and geographic ranges, it has been suggested that homologous recombination facilitates host switching, speciation, and the development of virulence. We used 340 whole-genome sequences to study the relationship between inter- and intrasubspecific homologous recombination, random mutation, and natural selection across individual X. fastidiosa genes. Individual gene orthologs were identified and aligned, and a maximum likelihood (ML) gene tree was generated. Each gene alignment and tree pair were then used to calculate gene-wide and branch-specific r/m values (relative effect of recombination to mutation), gene-wide and branch-site nonsynonymous over synonymous substitution rates (d N /d S values; episodic selection), and branch length (as a proxy for mutation rate). The relationships between these variables were evaluated at the global level (i.e., for all genes among and within a subspecies), among specific functional classes (i.e., COGs), and between pangenome components (i.e., accessory versus core genes). Our analysis showed that r/m varied widely among genes as well as across X. fastidiosa subspecies. While r/m and d N /d S values were positively correlated in some instances (e.g., core genes in X. fastidiosa subsp. fastidiosa and both core and accessory genes in X. fastidiosa subsp. multiplex ), low correlation coefficients suggested no clear biological significance. Overall, our results indicate that, in addition to its adaptive role in certain genes, homologous recombination acts as a homogenizing and a neutral force across phylogenetic clades, gene functional groups, and pangenome components. IMPORTANCE There is ample evidence that homologous recombination occurs frequently in the economically important plant pathogen Xylella fastidiosa. Homologous recombination has been known to occur among sympatric subspecies and is associated with host-switching events and virulence-linked genes. As a consequence, is it generally assumed that recombinant events in X. fastidiosa are adaptive. This mindset influences expectations of how homologous recombination acts as an evolutionary force as well as how management strategies for X. fastidiosa diseases are determined. Yet, homologous recombination plays roles beyond that of a source for diversification and adaptation. Homologous recombination can act as a DNA repair mechanism, as a means to facilitate nucleotide compositional change, as a homogenization mechanism within populations, or even as a neutral force. Here, we provide a first assessment of long-held beliefs regarding the general role of recombination in adaptation for X. fastidiosa. We evaluate gene-specific variations in homologous recombination rate across three X. fastidiosa subspecies and its relationship to other evolutionary forces (e.g., natural selection, mutation, etc.). These data were used to assess the role of homologous recombination in X. fastidiosa evolution., Competing Interests: The authors declare no conflict of interest.

Purpose: To evaluate arterial stiffness, a predictor of vascular damage was assessed by means of pulse wave velocity (PWV) in patients with chronic obstructive pulmonary disease (COPD) and comorbid obstructive sleep apnea (OSA), namely overlap syndrome (OS)., Methods: Consecutive stable patients with COPD were evaluated for OSA by means of overnight polysomnography in the laboratory. A clinical assessment was performed according to a strict protocol, including two COPD questionnaires: the COPD assessment test and the modified Medical Research Council scale. COPD severity was graded according to the guidelines of the Global Initiative for Chronic Obstructive Lung Disease. Arterial stiffness was assessed by means of PWV, using a standard technique., Results: Of 102 patients with COPD, 51 had associated OSA. The OS group had more men than the COPD group (73% vs. 47%, respectively; p < 0.01). Both groups had similar ages (66.2 ± 9.2 years vs. 69.6 ± 10.7, p = 0.09) and airflow limitation (p = 0.37). Hypertension was found in 22% of COPD patients, as opposed to 17% patients in the OS group (p = 0.29). High PWV values were present in 42% of the patients. Patients with COPD and OS had the same PWV values (9.8 vs. 10.5 m/s, p = 0.34). There were no differences in central blood pressure, peripheral blood pressure, and augmentation index between the two groups (p > 0.05)., Conclusion: High PWV values were frequently observed in patients with COPD. However, there was no difference in PWV between patients with OS and those with COPD alone., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

We examine the association between the Covid-19 pandemic and and access to basic needs, and how households respond using various coping strategies in the context of Nigeria. We use data from the Covid-19 National Longitudinal Phone Surveys (Covid-19 NLPS-2020) conducted during the Covid-19 lockdown. Our findings reveal that the Covid-19 pandemic is associated with households' exposure to shocks such as illness or injury, disruption of farming, job losses, non-farm business closure, and increase in price of food items and farming inputs. These negative shocks have severe consequences on access to basic needs of households, and the outcomes are heterogeneous across gender of household head and rural-urban residence. Households adopt a number of coping strategies, both formal and informal to mitigate the effects of the shocks on access to basic needs. The findings of this paper lend credence to the growing evidence on need to support households exposed to negative shocks and the role of formal coping mechanisms for households in developing countries., (© European Association of Development Research and Training Institutes (EADI) 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Studying structural variants that can control complex traits is relevant for dairy cattle production, especially for animals that are tolerant to breeding conditions in the tropics, such as the Dairy Gir cattle. This study identified and characterized high confidence copy number variation regions (CNVR) in the Gir breed genome. A total of 38 animals were whole-genome sequenced, and 566 individuals were genotyped with a high-density SNP panel, among which 36 animals had both sequencing and SNP genotyping data available. Two sets of high confidence CNVR were established: one based on common CNV identified in the studied population (CNVR&#95;POP), and another with CNV identified in sires with both sequence and SNP genotyping data available (CNVR&#95;ANI). We found 10 CNVR&#95;POP and 45 CNVR&#95;ANI, which covered 1.05 Mb and 4.4 Mb of the bovine genome, respectively. Merging these CNV sets for functional analysis resulted in 48 unique high confidence CNVR. The overlapping genes were previously related to embryonic mortality, environmental adaptation, evolutionary process, immune response, longevity, mammary gland, resistance to gastrointestinal parasites, and stimuli recognition, among others. Our results contribute to a better understanding of the Gir breed genome. Moreover, the CNV identified in this study can potentially affect genes related to complex traits, such as production, health, and reproduction., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Braga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Subclinical acute kidney injury (subAKI) is characterized by tubule-interstitial injury without significant changes in glomerular function. SubAKI is associated with the pathogenesis and progression of acute and chronic kidney diseases. Currently, therapeutic strategies to treat subAKI are limited. The use of gold nanoparticles (AuNPs) has shown promising benefits in different models of diseases. However, their possible effects on subAKI are still unknown. Here, we investigated the effects of AuNPs on a mouse model of subAKI. Animals with subAKI showed increased functional and histopathologic markers of tubular injury. There were no changes in glomerular function and structure. The animals with subAKI also presented an inflammatory profile demonstrated by activation of Th1 and Th17 cells in the renal cortex. This phenotype was associated with decreased megalin-mediated albumin endocytosis and expression of proximal tubular megalin. AuNP treatment prevented tubule-interstitial injury induced by subAKI. This effect was associated with a shift to an anti-inflammatory Th2 response. Furthermore, AuNP treatment preserved megalin-mediated albumin endocytosis in vivo and in vitro. AuNPs were not nephrotoxic in healthy mice. These results suggest that AuNPs have a protective effect in the tubule-interstitial injury observed in subAKI, highlighting a promising strategy as a future antiproteinuric treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Diabetic kidney disease (DKD) is characterized by progressive impairment of kidney function. It has been postulated that tubule-interstitial injury, associated with tubular albuminuria, precedes glomerular damage in the early stage of DKD. Here, we wanted to determine if the development of tubule-interstitial injury at the early stage of DKD implies modulation of megalin-mediated protein reabsorption in proximal tubule epithelial cells (PTECs) by SGLT2-dependent high glucose influx. Rats with streptozotocin (STZ)-induced diabetes were treated or not with dapagliflozin (DAPA) for 8 weeks. Four experimental groups were generated: (1) CONT, control; (2) DAPA, rats treated with DAPA; (3) STZ, diabetic rats; (4) STZ + DAPA, diabetic rats treated with DAPA. No changes in glomerular structure and function were observed. The STZ group presented proteinuria and albuminuria associated with an increase in the fractional excretion of proteins. A positive correlation between glycemia and proteinuria was found. These phenomena were linked to a decrease in luminal and total megalin expression and, consequently, in albumin reabsorption in PTECs. We also observed tubule-interstitial injury characterized by an increase in urinary tubular injury biomarkers and changes in tubular histomorphometry parameters. In addition, inverse correlations were found between cortical albumin uptake and tubule-interstitial injury or glycemia. All these modifications were attenuated in the STZ + DAPA group. These results suggest that SGLT2-dependent high glucose influx into PTECs promotes a harmful effect on the PTECs, leading to the development of tubular albuminuria and tubule-interstitial injury preceding glomerular damage. These results expand current knowledge on the renoprotective effects of gliflozins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Trypanosoma brucei is the causative agent of African trypanosomiasis, a deadly disease that affects humans and cattle. There are very few drugs to treat it, and there is evidence of mounting resistance, raising the need for new drug development. Here, we report the presence of a phosphoinositide phospholipase C (TbPI-PLC-like), containing an X and a PDZ domain, that is similar to the previously characterized TbPI-PLC1. TbPI-PLC-like only possesses the X catalytic domain and does not have the EF-hand, Y, and C2 domains, having instead a PDZ domain. Recombinant TbPI-PLC-like does not hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and does not modulate TbPI-PLC1 activity in vitro. TbPI-PLC-like shows a plasma membrane and intracellular localization in permeabilized cells and a surface localization in non-permeabilized cells. Surprisingly, knockdown of TbPI-PLC-like expression by RNAi significantly affected proliferation of both procyclic and bloodstream trypomastigotes. This is in contrast with the lack of effect of downregulation of expression of TbPI-PLC1 .