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Macrophages are the main cells present in the synovial membrane. They play an important role in the development and progression of osteoarthritis (OA). After the establishment of the disease macrophages mostly adopt a pro-inflammatory secretory phenotype (OA phenotype) further inducing cartilage degradation. Indomethacin (IND) is a non-steroidal anti-inflammatory drug (NSAID) able to inhibit the synthesis of prostaglandins mediated by both cyclooxygenase isoforms depicting a potent anti-inflammatory capacity. However, the lack of specificity and short half-like of free drugs within the joint cavity limits its utility in controlling inflammation after intra-articular administration. This study aims at developing IND loaded glycosylated nanostructured lipid carriers (NLCs) to selectively target macrophages and promote their reprogramming to an anti-inflammatory phenotype. This approach focused on the local administration of the NLCs, offers a promising therapeutic strategy for treating OA by modulating the inflammatory environment within the joint. NLCs will be designed by combining experimental and in silico docking analyses, and thoroughly characterized to obtain drug delivery systems with high stability and suitable physicochemical properties. The proposed mannose-functionalized systems exhibited adequate particle sizes (≈ 70 nm) and positive surface charges (> 20 mV) to be efficiently retained in the joint cavity. Moreover, the developed NLCs demonstrated effective and specific uptake by OA-like macrophages leading to a significant decrease in the secretion of the pro-inflammatory cytokines IL-6, IL-8 and TNF-α similarly to the free drug. Therefore, these systems effectively reprogrammed OA-associated macrophages to adopt a more regenerative phenotype, offering a promising strategy for managing inflammation in OA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Patricia Diaz-Rodriguez reports financial support was provided by Spanish Ministry of Science and Innovation. Mariana Landin reports financial support was provided by Xunta de Galicia. If there are other authors, they 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Brown adipocytes are defined based on a distinct morphology and genetic signature that includes, amongst others, the expression of the Purinergic 2 Receptor X5 (P2RX5). However, the role of P2RX5 in brown adipocyte and brown adipose tissue function is poorly characterized. In the present study, we conducted a metabolic characterization of P2RX5 knockout male mice; next, we characterized this purinergic pathway in a cell-autonomous context in brown adipocytes. We then tested the role of the P2RX5 receptor agonism in metabolic responses in vivo in conditions of minimal adaptive thermogenesis requirements. Our data show that loss of P2RX5 causes reduced brown adipocyte differentiation in vitro, and browning in vivo. Lastly, we unravel a previously unappreciated role for P2RX5 agonism to exert an anti-obesity effect in the presence of enhanced brown adipose tissue recruitment in male mice housed at thermoneutrality. Altogether, our data support a role for P2RX5 in mediating brown adipocyte differentiation and function that could be further targeted for benefits in the context of adipose tissue pathology and metabolic diseases.

Introduction: Primary bladder neck obstruction (BNO) occurs when the bladder neck fails to open during voiding, causing urinary symptoms despite no anatomic obstruction. The cause of BNO is unclear but may involve neurogenic dysregulation related to the sympathic nervous system such as upper motor neuron lesion or peripheral autonomic neuropathy (small fiber neuropathy (SFN)). Another etiology can incuded increased sympathetic tone secondary to anxiety or stress conditons. Botulinum toxin A (BoNT-A) to the bladder neck has been used in our practice to treat women with BNO who failed conventional therapies (alpha blockers, relaxation strategies). This is the first report of patient-reported outcomes after BoNT-A treatment in women with pelvic pain and BNO., Materials and Methods: We included female patients with pelvic pain and BNO who received BoNT-A to the bladder neck between January 2022 and March 2023, and mailed self-reported outcome questionnaires. The primary outcome was the Global Response Assessment (GRA); secondary outcomes included pain scores on the Visual Analogue Scale (VAS) and symptom checklists. BNO was diagnosed using Nitti Criteria (high bladder pressure, low flow in bladder neck on video urodynamics), supplemented by additional criteria (e.g., high voiding pressure, prolonged attempts, Valsalva effort, and cystoscopic evidence or symptoms related to BNO). Urodynamic studies followed International Continence Society standards. Additionally, due to BNO's association with SFN, patient history of biopsy-confirmed SFN was recorded., Results: Our inclusion criteria was satisfied among 18 patietns, with 17 completing the questionnaire. Out of those, 14 patients (77%) reported improvement on the GRA, with an average VAS of 8.3 ("Very Helpful"). The most commonly improved symptoms were feeling of incomplete emptying, difficulty starting stream, urethral burning, pain with urination, and pelvic pain. Postoperative symptom flares were reported in six patients for an average of 16 days. All six patients with biopsy-confirmed SFN showed significant improvement (VAS 8.7). Total of 14 patients (77%) indicated they would repeat the procedure., Conclusions: BoNT-A to the bladder neck significantly improved pelvic pain and refractory hesitancy in women with bladder neck obstruction, especially in those with small fiber neuropathy. Symptom flares are common, but did not reduce interest in repeated treatments, and scheduling injections before symptom recurrence may mitigate these flares., (© 2024 Wiley Periodicals LLC.)

Aims: The study aims to examine the outcome of replacement of prandial insulin with once-weekly subcutaneous semaglutide in people with type 2 diabetes reasonably controlled on multiple daily insulin injections (MDI)., Materials and Methods: This single-centre, randomised, open-label trial enrolled a statistically predetermined sample of 60 adults with HbA1c ≤7.5% (58 mmol/mol) receiving MDI, with a total daily dose (TDD) ≤120 units/day. Participants were assigned 2:1 to subcutaneous semaglutide 1.0 mg plus insulin degludec, or to continue MDI. The primary outcome was percentage of subjects maintaining HbA1c ≤7.5% (58 mmol/mol) at Week 26., Results: At Week 26, 90% of semaglutide and 75% of MDI subjects maintained HbA 1c  ≤7.5% (≤58 mmol/mol) (p = 0.18). Mean changes (95% CI) in HbA 1c , weight and percentage body weight for semaglutide versus MDI, respectively, were -0.5% (-0.7, -0.3) versus 0.0% (-0.3, 0.3; p = 0.009); -8.9 kg (-9.9, -7.8) versus 1.5 kg (-0.1, 3.1; p < 0.001); and -8.6% (-9.6, -7.6) versus 1.4% (0.0, 2.8; p < 0.001). Insulin TDD decreased 56.0% (-62.3, -49.7) with semaglutide and increased 6.7% (-2.5, 16.0) with MDI (p < 0.001). Among semaglutide subjects, 58% reduced insulin TDD > 50%, 97.5% stopped prandial insulin and 45% lost >10% body weight. Participant treatment satisfaction scores trended higher with semaglutide. Hypoglycaemia frequency was similar between groups., Conclusions: In people with type 2 diabetes well controlled (HbA 1c  ≤7.5% [≤58 mmol/mol]) on MDI ≤120 units/day, replacing multiple daily injections of prandial insulin with once-weekly subcutaneous semaglutide can maintain and even improve HbA 1c , lower body weight and lessen the burden of management., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Introduction and Objectives: The occurrence of a difficult airway during intubation is a critical event in anaesthesia. Despite the usefulness of clinical predictors, difficult intubation frequently arises unexpectedly. The aim of this study was to determine the utility of airway ultrasound in detecting these patients., Materials and Methods: This was a case-control study. The patients in the case group were identified from the registry of patients with reports of difficult laryngoscopy (Cormack III and IV). The controls were selected from among patients classed as Cormack I who underwent surgery under general anaesthesia. Fifty patients (25 cases and 25 controls) participated in the study. All patients underwent ultrasound to obtain 3 measurements: distance from the skin to the hyoid bone, distance from the skin to the epiglottis, and distance from the skin to the vocal cords., Results: A skin-to-hyoid bone distance greater than 9.8 mm (50% of the sample) generated an odds ratio of 5.46 (p = 0.005); a skin-to-epiglottis distance greater than 21.3 mm (50% of the sample) generated an odds ratio of 6.62 (p = 0.002). There was no significant difference in the skin-to-vocal cords distance., Conclusions: Ultrasound has proven to be a useful tool for predicting difficult laryngoscopy. Despite the low sensitivity of clinical predictors, they appear to improve the detection of patients with difficult laryngoscopy when integrated into predictive models alongside ultrasound values., (Copyright © 2024 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

Many ancient cultures used musical tools for social and ritual procedures, with the Aztec skull whistle being a unique exemplar from postclassic Mesoamerica. Skull whistles can produce softer hiss-like but also aversive and scream-like sounds that were potentially meaningful either for sacrificial practices, mythological symbolism, or intimidating warfare of the Aztecs. However, solid psychoacoustic evidence for any theory is missing, especially how human listeners cognitively and affectively respond to skull whistle sounds. Using psychoacoustic listening and classification experiments, we show that skull whistle sounds are predominantly perceived as aversive and scary and as having a hybrid natural-artificial origin. Skull whistle sounds attract mental attention by affectively mimicking other aversive and startling sounds produced by nature and technology. They were psychoacoustically classified as a hybrid mix of being voice- and scream-like but also originating from technical mechanisms. Using human neuroimaging, we furthermore found that skull whistle sounds received a specific decoding of the affective significance in the neural auditory system of human listeners, accompanied by higher-order auditory cognition and symbolic evaluations in fronto-insular-parietal brain systems. Skull whistles thus seem unique sound tools with specific psycho-affective effects on listeners, and Aztec communities might have capitalized on the scary and scream-like nature of skull whistles., Competing Interests: Competing interest The authors declare no competing interests., (© 2024. The Author(s).)

The global spread of multi-drug-resistant (MDR) bacteria is rapidly increasing due to antibiotic overuse, posing a major public health threat and causing millions of deaths annually. The present study explored the potential of nanocarriers for delivering novel and alternative antibacterial agents using nanotechnology-based approaches to address the challenge of MDR bacteria. The purpose was to enhance the solubility, stability, and targeted delivery of berberine (BER) and its synthetic derivative NR16 using Styrene- co -Maleic Acid (SMA) nanoparticles. Characterization of the nanoparticles, including dynamic light scattering (DLS) analysis, TEM, and UV/Vis absorption spectroscopy, confirmed their suitability and high stability for passive drug delivery. Antibacterial and antifungal activities were evaluated against a panel of pathogens, revealing significant inhibitory effects on Gram-positive strains; particularly BER, SMA-BER, and NR16 were active against MRSA, MSSA, VR, and VS E. faecalis , and S. epidermidis . Additionally, SMA-BER and SMA-NR16 showed promising activity against biofilm formation of S. epidermidis ; while the two free drugs contributed to S. epidermidis biofilm disruption activity. Hemolysis tests and in vitro studies on human embryonic kidney cells (HEK-293) confirmed the safety profiles of the nanoparticles and free drugs. Overall, this research highlighted the potential of nanotechnology in developing effective antibacterial agents with reduced toxicity, addressing the growing threat of MDR bacterial infections., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background and Objective: The depth of the prostate-specific antigen (PSA) decline after androgen receptor pathway inhibitor (ARPI) treatment combined with androgen deprivation therapy for patients with metastatic hormone-sensitive prostate cancer (mHSPC) may affect prognosis. The primary objective in our study was the correlation between the PSA response at 3 mo and radiologic progression-free survival (rPFS) at 24 mo. Three groups were defined according to the PSA decline: complete response (PSA ≤0.02 ng/ml), partial response (PSA >0.02 and ≤0.2 ng/ml), and incomplete response (PSA >0.2 ng/ml). Secondary objectives were correlation between the PSA response at 3 mo and overall survival, and the development of a model predicting complete PSA response., Methods: We conducted a retrospective multicenter study of patients with mHSPC treated with apalutamide from May 2018 to September 2023 registered in the Real-World Evidence APA registry across 20 centers., Key Findings and Limitations: We included 633 patients with mHSPC. The median age at diagnosis was 68 yr (interquartile range [IQR] 63-75) and median PSA was 16 ng/ml (IQR 7.5-64). Some 63% of the short had low-volume disease, 51% had de novo disease, 48% had recurrent disease. At 3 mo, 27% had a complete response, 42% a partial response, and 31% an incomplete response, with corresponding rRFS rates at 24 mo of 92%, 86%, and 63%. According to the predictive model, a complete PSA response at 3 mo was associated with the use of next-generation imaging and PSA <50 ng/ml at diagnosis. Study limitations include heterogeneity among the groups and variations in data quality and assessment methods., Conclusions and Clinical Implications: Patients with a complete PSA response after 3 mo of apalutamide treatment face a very low risk of progression within 2 yr. Conversely, nearly 50% of patients with an incomplete PSA response will experience disease progression., Patient Summary: For patients with metastatic prostate cancer that is still responsive to hormone therapy, a complete response after treatment with a drug called apalutamide is associated with a very low risk of progression within 2 years. However, nearly half of patients with an incomplete response to apalutamide will experience progression of their cancer., (© 2024 The Author(s).)

LIN28, a highly conserved RNA-binding protein that acts as a posttranscriptional modulator, plays a vital role in the regulation of T-cell development, reprogramming, and immune activity in infectious diseases and T-cell-based immunotherapies. LIN28 inhibit the expression of let-7 miRNAs, the most prevalent family of miRNAs in lymphocytes. Recently it has been suggested that let-7 enhances murine anti-tumor immune responses. Here, we investigated the impact of LIN28 upregulation on human T cell functions, focusing on its influence on CAR T cell therapy. LIN28 lentiviral transduction of human T cells led to a stable expression of LIN28 that significantly downregulated the let-7 miRNA family without affecting cell viability or expansion potential. LIN28 overexpression maintained human T cell phenotype markers and functionality but impaired the antitumoral cytotoxicity of NKG2D-CAR T cells both in vitro and in vivo . These findings highlight the intricate relationship between LIN28/ let-7 axis and human T cell functionality, including in CAR T cell therapy., 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 Garcia-Rodriguez, Hidalgo, Rodriguez-Milla, Somovilla-Crespo and Garcia-Castro.)

Ozone (O₃), a potent oxidant, can penetrate the body through breathing, generating reactive oxygen species (ROS) and triggering inflammatory processes. Oxidative stress, an imbalance between the production of ROS and the body's antioxidant capacity, plays a crucial role in the pathophysiology of various neurodegenerative diseases. This phenomenon can negatively impact the Central Nervous System (CNS), inducing structural and functional alterations that contribute to the development of neurological pathologies. This review examines how O₃-induced oxidative stress affects the nervous system by analyzing existing literature on the involved molecular mechanisms and potential antioxidant systems to mitigate its effects. Through a comprehensive review of experimental studies, our objective is to shed light on the interaction between O₃ and the nervous system, as well as its signaling pathways and altered genes, providing a foundation for future research in this field. Several studies have demonstrated that prolonged exposure to O₃ leads to increased expression of reactive oxygen species, causing alterations in the blood-brain barrier and damage to astrocytes and microglia. These effects can lead to an increase in the production of proinflammatory cytokines, neurotoxins, and genes, exacerbating neuronal damage and accelerating the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and other neurological disorders. The results of this review suggest that exposure to O₃ may induce oxidative damage to the nervous system, which could have significant implications for public health., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Wildlife abundance and movement are strongly impacted by landscape heterogeneity, especially in cities which are among the world's most heterogeneous landscapes. Nonetheless, current global land cover maps, which are used as a basis for large-scale spatial ecological modeling, represent urban areas as a single, homogeneous, class. This often requires urban ecologists to rely on geographic resources from local governments, which are not comparable between cities and are not available in underserved countries, limiting the spatial scale at which urban conservation issues can be tackled. The recent expansion of community-based geographic databases, for example, OpenStreetMap (OSM), represents an opportunity for ecologists to generate large-scale maps geared toward their specific research needs. However, computational differences in language and format, and the high diversity of information within, limit the access to these data. We provide a framework, using R, to extract geographic features from the OSM database, classify, and integrate them into global land cover maps. The framework includes an exhaustive list of OSM features describing urban and peri-urban landscapes and is validated by quantifying the completeness of the OSM features characterized, and the accuracy of its final output in 34 cities in North America. We portray its application as the basis for generating landscape variables for ecological analysis by using the OSM-enhanced map to generate an urbanization index, and subsequently analyze the spatial occupancy of six mammals throughout Chicago, Illinois, USA. The OSM features characterized had high completeness values for impervious land cover classes (50%-100%). The final output, the OSM-enhance map, provided an 89% accurate representation of the landscape at 30m resolution. The OSM-derived urbanization index outperformed other global spatial data layers in the spatial occupancy analysis and concurred with previously seen local response trends, whereby lagomorphs and squirrels responded positively to urbanization, while skunks, raccoons, opossums, and deer responded negatively. This study provides a roadmap for ecologists to leverage the fine resolution of open-source geographic databases and apply it to spatial modeling by generating research-specific landscape variables. As our occupancy results show, using context-specific maps can improve modeling outputs and reduce uncertainty, especially when trying to understand anthropogenic impacts on wildlife populations., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

Background and Objective: Decipher is a tissue-based genomic classifier (GC) developed and validated in the post-radical prostatectomy (RP) setting as a predictor of metastasis. We conducted a prospective randomized controlled cluster-crossover trial assessing the use of Decipher to determine its impact on adjuvant treatment after RP., Methods: Eligible patients had undergone RP within 9 mo of enrollment, had pT3-4 disease and/or positive surgical margins, and prostate-specific antigen <0.1 ng/ml. Centers were randomized to a sequence of 3-mo periods of either GC-informed care or usual care (UC). Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) recurrence risk scores were provided to treating physicians and patients in all periods., Key Findings and Limitations: Impact of GC test results on adjuvant treatment were compared with UC alone. Longitudinal patient-reported urinary and sexual function was assessed. A total of 175 patients were enrolled in 27 periods with GC and 163 in 28 periods with UC. At 18 mo after RP, an average patient in the GC arm received adjuvant treatment 9.7% of the time compared with 8.7% for an average individual in the UC arm (0.99% mean difference, 95% confidence interval [CI] -7.6%, 9.6%, p = 0.8). While controlling for CAPRA-S score, higher GC scores tended to result in an increased likelihood of adjuvant treatment that was not statistically significant (odds ratio [OR] = 1.35 per 0.1 increase in GC score, 95% CI 0.98-1.85, p = 0.066). Using the GC risk groups, reflecting clinical use, a high GC risk was associated with significantly higher odds of receiving adjuvant treatment (OR = 6.9, 95% CI 1.8, 26, p = 0.005) compared with a low GC score, adjusted for CAPRA-S score. There were no differences in patient-reported urinary and sexual function between the study arms. As oncologic outcomes are immature, the present data cannot address whether GC testing provides any cancer control benefit., Conclusions and Clinical Implications: GC testing impacts adjuvant therapy administration when viewed through the risk categories presented in the patient report; however, these data do not provide specific support for GC testing in the adjuvant treatment setting., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: There is an ongoing national shortage in the vascular surgery (VS) workforce. To increase interest in the specialty, the Society for Vascular Surgery (SVS) Resident and Student Outreach Committee (RSOC) developed a dedicated general surgery (GS) resident and medical student (MS) program at the Vascular Annual Meeting (VAM) and invested in a scholarship program to help reduce attendee expenses. This study assesses the program's effectiveness, correlating recipient feedback with the likelihood of matching into a VS training program., Methods: Records related to the SVS VAM GS resident and MS program from 2013 to 2023 were reviewed, focusing on attendee evaluations of the program. The program included a simulation session from 2013 to 2019. VS training program match rates among scholarship recipients were determined. The annual average match rate in VS was used to divide the survey responses into two groups: below average (BA) and above average (AA) match rate groups. Survey responses were based on a 5-point Likert scale and allowed for comments. Responses were divided into high value, strongly favoring the activity (scores 4-5), and low value (scores 1-3) categories. The survey responses from the group of years with AA match rates were compared with the group of years with BA rates., Results: The SVS awarded 1040 GS resident and MS travel scholarships over the 10 years assessed. Overall, applicants had a 43% success rate in receiving a scholarship. During the study period, the annual number of applicants increased, whereas the number of scholarships and match success rates significantly decreased. The average match rate into VS among scholarship recipients was 50.2%. The survey response rate was 33%. During AA match rate years, evaluations for simulation allotted time and lectures were significantly more likely to be high value compared with BA years. Simulation content and the residency fair consistently had the most favorable evaluations (>90% high value), and overall, the program had a consistently positive impact on recipients' interest in VS (>90% high value). Trainees in the AA group were significantly more likely to provide positive comments (73% vs 55%; P < .001). Numerous recipients commented on the need for a dedicated space to interact with faculty and mentors and highlighted simulation as the standout aspect of the program., Conclusions: The SVS VAM RSOC program is positively correlated with attendee interest in VS, with approximately 50% of scholarship recipients matching into the field. The quality of the program and the number of scholarships correlate with VS match rates. Additional investments in similar programs could help close the workforce gap., Competing Interests: Disclosures C.I.O.C. has a patent for U.S.S.N. 10,524,891 and is a consultant for enVVeno Medical Corporation., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

In the present study, the feasibility to achieve localized induction heating and debonding of multi-material composite structures is assessed in testing coupons prepared by Automated Fiber Placement (AFP) and extrusion-based additive manufacturing (AM) technologies. Nano-compounds of Polyether-ketone-ketone (PEKK) with iron oxide nanoparticles acting as electromagnetic susceptors have been processed in a parallel co-rotating twin-screw extruder to produce filament feedstock for extrusion-based AM. The integration of nanocomposite interlayers as discrete debonding zones (DZ) by AFP-AM manufacturing has been investigated for two types of sandwich-structured laminate composites, i.e., laminate-DZ-laminate panels (Type I) and laminate-DZ-AM gyroid structures (Type II). Specimens were exposed to an alternating magnetic field generated by a radio frequency generator and a flat spiral copper induction coil, and induction heating parameters (frequency, power, heating time, sample standoff distance from coil) have been investigated in correlation with real-time thermal imaging to define the debonding process window without compromising laminate quality. For the optimized process parameters, i.e., 2-3 kW generator power and 20-25 mm standoff distance, corresponding to magnetic field intensities in the range of 3-5 kA m -1 , specimens were effectively heated above PEKK melting temperature, exhibiting high heating rates within the range of 5.3-9.4 °C/s (Type I) and 8.0-17.5 °C/s (Type II). The results demonstrated that localized induction heating successfully facilitated debonding, leading to full unzipping of the debonding zones in both laminate structures. Further insight on PEKK nanocomposites debonding performance was provided by thermal, morphological characterization and non-destructive inspection via X-ray micro-computed tomography at different processing stages. The developed framework aims to contribute to the development of rapid, on-demand joining, repair and disassembly technologies for thermoplastic composites, towards more efficient maintenance, repair and overhaul operations in the aviation sector and beyond.

A study of resonant structures in B^{+}→D^{*+}D^{-}K^{+} and B^{+}→D^{*-}D^{+}K^{+} decays is performed, using proton-proton collision data at center-of-mass energies of sqrt[s]=7, 8, and 13 TeV recorded by the LHCb experiment, corresponding to an integrated luminosity of 9  fb^{-1}. A simultaneous amplitude fit is performed to the two channels with contributions from resonances decaying to D^{*-}D^{+} and D^{*+}D^{-} states linked by C parity. This procedure allows the C parities of resonances in the D^{*±}D^{∓} mass spectra to be determined. Four charmonium or charmoniumlike states are observed decaying into D^{*±}D^{∓}: η&#95;{c}(3945), h&#95;{c}(4000), χ&#95;{c1}(4010), and h&#95;{c}(4300), with quantum numbers J^{PC} equal to 0^{-+}, 1^{+-}, 1^{++}, and 1^{+-}, respectively. At least three of these states have not been observed previously. In addition, the existence of the T&#95;{c[over ¯]s[over ¯]0}^{*}(2870)^{0} and T&#95;{c[over ¯]s[over ¯]1}^{*}(2900)^{0} resonances in the D^{-}K^{+} mass spectrum, already observed in the B^{+}→D^{+}D^{-}K^{+} decay, is confirmed in a different production channel.

Objective: To determine the impact of chronic dental disease on the nasolacrimal duct of chinchillas using contrast CT dacryocystorhinography., Animals Studied: Two 12-year-old female chinchillas with uni- or bilateral ocular discharge and a history of chronic, moderate (Chinchilla 1, one-year) or severe (Chinchilla 2, three-years) dental disease., Procedures: Contrast CT dacryocystorhinography was performed to identify abnormalities in the nasolacrimal duct and dentition, and to correlate those changes., Results: Chinchilla 1 had a focal soft tissue attenuating expansion of the maxillary bone rostral to the first left premolar interpreted as possible abscessation causing deviation of the nasolacrimal duct over its dorsomedial margin. The right nasolacrimal duct appeared normal. Chinchilla 2 had periapical abscessation of a retained subgingival left maxillary incisor fragment which extended into the nasal cavity causing focal narrowing and distal dilation of the left nasolacrimal duct. Complete contrast infusion of the right nasolacrimal duct could not be completed on Chinchilla 2. A focal area of superficial corneal fibrosis ipsilateral to the obstructed nasolacrimal duct was also identified in Chinchilla 2. Treatment consisted of occlusal adjustments to correct the coronal elongation, systemic antibiotics (metronidazole and either marbofloxacin or azithromycin), and topical tear replacement therapy and diclofenac as needed. Ocular discharge decreased in both chinchillas but did not resolve long-term in either animal., Conclusions: Chronic dental disease including periapical abscessation in chinchillas can obstruct the nasolacrimal duct, leading to impaired tear drainage. Management of dental disease is crucial to maintain patency of the nasolacrimal duct., (© 2024 The Author(s). Veterinary Ophthalmology published by Wiley Periodicals LLC on behalf of American College of Veterinary Ophthalmologists.)

Human brain ontogeny is characterized by a considerably prolonged neotenic development of cortical neurons and circuits. Neoteny is thought to be essential for the acquisition of advanced cognitive functions, which are typically altered in intellectual disability (ID) and autism spectrum disorders (ASDs). Human neuronal neoteny could be disrupted in some forms of ID and/or ASDs, but this has never been tested. Here, we use xenotransplantation of human cortical neurons into the mouse brain to model SYNGAP1 haploinsufficiency, one of the most prevalent genetic causes of ID/ASDs. We find that SYNGAP1-deficient human neurons display strong acceleration of morphological and functional synaptic formation and maturation alongside disrupted synaptic plasticity. At the circuit level, SYNGAP1-haploinsufficient neurons display precocious acquisition of responsiveness to visual stimulation months ahead of time. Our findings indicate that SYNGAP1 is required cell autonomously for human neuronal neoteny, providing novel links between human-specific developmental mechanisms and ID/ASDs., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cuprous copper [Cu(I)] is an essential cofactor for enzymes that support many fundamental cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly reliant on mitochondrial production of ATP, with many neurodegenerative diseases, including Parkinson's disease, associated with diminished mitochondrial function. The gene MBLAC1 encodes a ribonuclease that targets pre-mRNA of replication-dependent histones, proteins recently found in yeast to reduce Cu(II) to Cu(I), and when mutated disrupt ATP production, elevates oxidative stress, and severely impacts cell growth. Whether this process supports neuronal and/or systemic physiology in higher eukaryotes is unknown. Previously, we identified swip-10 , the putative Caenorhabditis elegans ortholog of MBLAC1 , establishing a role for glial swip-10 in limiting dopamine (DA) neuron excitability and sustaining DA neuron viability. Here, we provide evidence from computational modeling that SWIP-10 protein structure mirrors that of MBLAC1 and locates a loss of function coding mutation at a site expected to disrupt histone RNA hydrolysis. Moreover, we find through genetic, biochemical, and pharmacological studies that deletion of swip-10 in worms negatively impacts systemic Cu(I) levels, leading to deficits in mitochondrial respiration and ATP production, increased oxidative stress, and neurodegeneration. These phenotypes can be offset in swip-10 mutants by the Cu(I) enhancing molecule elesclomol and through glial expression of wildtype swip-10 . Together, these studies reveal a glial-expressed pathway that supports systemic mitochondrial function and neuronal health via regulation of Cu(I) homeostasis, a mechanism that may lend itself to therapeutic strategies to treat devastating neurodegenerative diseases., Competing Interests: Competing interests statement:The authors declare no competing interest.

Significant efforts are currently being made to improve the quality of life of the older adult population. These efforts focus on aspects such as health, social interaction, and mental health. One of the approaches that has shown positive results in several studies is the application of game-based systems. These systems are not only used for entertainment, but also as tools for learning and promoting positive feelings. They are a means to overcome loneliness and isolation, as well as to improve health and provide support in daily life. However, it is important to note that, while these experiences are gradually being introduced to the older adult population, they are often designed with a younger audience in mind who are assumed to be more technologically proficient. This supposition can make older adults initially feel intimidated when interacting with this type of technology, which limits their ability to fully utilize and enjoy these technological solutions. Therefore, the purpose of this article is to apply a game experience and fun evaluation process oriented toward the older adult population based on the playability theory of human-computer interaction in virtual reality game experiences. This is expected to offer highly rewarding and pleasurable experiences, which will improve engagement with the older population and promote active and healthy aging.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent kidney genetic disorder, producing structural abnormalities and impaired function. This research investigates its evolution on mouse models, utilizing a combination of histology imaging, Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) to evaluate its progression thoroughly. ADPKD has been induced in mice via PKD2 gene knockout, followed by image acquisition at different stages. Histology data provides two-dimensional details, like the cystic area ratio, whereas CT and MRI facilitate three-dimensional temporal monitoring. Our approach allows to quantify the affected tissue at different disease stages through multiple quantitative metrics. A pivotal point is shown at approximately ten weeks after induction, marked by a swift acceleration in disease advancement, and leading to a notable increase in cyst formation. This multimodal strategy augments our comprehension of ADPKD dynamics and suggests the possibility of employing higher-resolution imaging in the future for more accurate volumetric analyses., (© 2024. The Author(s).)

A measurement of time-dependent CP violation in D^{0}→π^{+}π^{-}π^{0} decays using a pp collision data sample collected by the LHCb experiment in 2012 and from 2015 to 2018, corresponding to an integrated luminosity of 7.7  fb^{-1}, is presented. The initial flavor of each D^{0} candidate is determined from the charge of the pion produced in the D^{*}(2010)^{+}→D^{0}π^{+} decay. The decay D^{0}→K^{-}π^{+}π^{0} is used as a control channel to validate the measurement procedure. The gradient of the time-dependent CP asymmetry ΔY in D^{0}→π^{+}π^{-}π^{0} decays is measured to be ΔY=(-1.3±6.3±2.4)×10^{-4}, where the first uncertainty is statistical and the second is systematic, which is compatible with CP conservation.

Background: Psychedelic Public Health is an emerging discipline uniting the practices of public health with the potential benefits of psychedelics to reduce harm and promote health, wellness, and equity at community and population levels. Little is known regarding the current state of psychedelic public health despite rising psychedelic usage, evidence of its health efficacy, opening policy environments, and concerns regarding equity and potential harms., Methods: To characterize the current state of psychedelic public health, this survey reviewed relevant webpages from 228 universities housing accredited Schools and Programs in Public Health (SPPHs) and 59 Psychedelic Research Centers (PRCs) in the US and globally. The scan corresponded to the Prisma 2020 checklist, identifying URLs through keyword searches by Beautiful Soup python package and Google search engine web application. Measures were coded through webpage text analysis., Findings: Fewer than 10% (9.6%) of SPPHs engaged with psychedelics (2.6% substantially), while half (52.6%) of universities engaged (28.1% substantially). Among PRCs, only 10% indicated a collaboration with SPPHs, and fewer than 3% of PRC personnel held public health degrees. PRCs were preponderantly affiliated with medical schools. Although Indigeneity significantly contributes to Western therapeutic psychedelic protocols, only approximately one-quarter of active universities, SPPHs, or PRCs visibly addressed Indigeneity and only one PRC included Indigenous leadership. 92% of PRCs were led or co-led by people characterized as White-European and 88% by men. Only 20-43% of SPPHs, universities, and PRCs visibly addressed social determinants of health., Conclusions: Public health schools, which train, study, and advise the future of public health, showed limited involvement in the growing psychedelic field, signifying a gap in psychedelic science and practice. The absence of public health's population-level approaches signifies a missed opportunity to maximize benefits and protect against potential harms of psychedelics at community and population levels., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The nematode Caenorhabditis elegans is well known for its ability to support forward genetic screens to identify molecules involved in neuronal viability and signaling. The proteins involved in C. elegans dopamine (DA) regulation are highly conserved across evolution, with prior work demonstrating that the model can serve as an efficient platform to identify novel genes involved in disease-associated processes. To identify novel players in DA signaling, we took advantage of a recently developed library of pre-sequenced mutant nematodes arising from the million mutation project (MMP) to identify strains that display the DA-dependent swimming-induced-paralysis phenotype (Swip). Our screen identified novel mutations in the dopamine transporter encoding gene dat-1, whose loss was previously used to identify the Swip phenotype, as well as multiple genes with previously unknown connections to DA signaling. Here, we present our isolation and characterization of one of these genes, bbs-1, previously linked to the function of primary cilia in worms and higher organisms, including humans, and where loss-of-function mutations result in a human disorder known as Bardet-Biedl syndrome. Our studies of C. elegans BBS-1 protein, as well as other proteins that are known to be assembled into a higher order complex (the BBSome) reveal that functional or structural disruption of this complex leads to exaggerated C. elegans DA signaling to produce Swip via a cell-autonomous mechanism. We provide evidence that not only does the proper function of cilia in C. elegans DA neurons support normal swimming behavior, but also that bbs-1 maintains normal levels of DAT-1 trafficking or function via a RHO-1 and SWIP-13/MAPK-15 dependent pathway where mutants may contribute to Swip independent of altered ciliary function. Together, these studies demonstrate novel contributors to DA neuron function in the worm and demonstrate the utility and efficiency of forward genetic screens using the MMP library., (© 2024 International Society for Neurochemistry.)

Background: The epidemic of obesity and associated cardiovascular morbidity continues to grow, attracting public attention and healthcare resources. However, the impact of malnutrition and being underweight continues to be overshadowed by obesity, especially in patients with peripheral arterial disease (PAD). This study assesses the characteristics and outcomes of patients with low body mass index (BMI ≤ 18.5) compared to patients with nonobese BMI undergoing peripheral vascular interventions (PVI)., Methods: A retrospective analysis of patients undergoing PVI due to PAD registered in the Vascular Quality Initiative database. Patients were categorized into underweight (BMI ≤ 18.5) and nonobese BMI (BMI = 18.5-30). Patients in both groups were matched 3:1 for baseline demographic characteristics, comorbidities, medications, and indications. Kaplan-Meier analysis was done for long-term outcomes., Results: A total of 337,926 patients underwent PVI, of whom 12,935 (4%) were underweight, 215,728 (64%) were nonobese, and 109,263 (32%) were obese. Underweight patients were more likely to be older, female, smokers, with chronic obstructive pulmonary disorder, and more likely to present with chronic limb-threatening ischemia than nonobese patients. After propensity matching, there were 18,047 nonobese patients and 6,031 underweight patients. There were no significant differences in matched characteristics. Perioperatively, underweight patients were more likely to require a longer hospital length of stay. Underweight patients had statistically significantly higher 30-day mortality compared to patients with nonobese BMI (3% vs. 1.6%, P < 0.001) and a higher rate of thrombotic complications. As for long-term outcomes, underweight patients had a higher rate of reintervention (20% vs. 18%, P < 0.001) and major adverse limb events (27% vs. 22%, P < 0.001). The 4-year rate of amputation-free survival was significantly lower in underweight patients (70% vs. 82%, P < 0.001), and the 2-year freedom from major amputation (90% vs. 94%, P < 0.001) showed similar trends with worse outcomes in patients who were underweight., Conclusions: Underweight patients with PAD are disproportionally more likely to be African American, females, and smokers and suffer worse outcomes after PVI than PAD patients with nonobese BMI. When possible, increased scrutiny and optimization of nutrition and other factors contributing to low BMI should be addressed prior to PVI., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Schizophrenia is a chronic mental illness characterized by delusions, hallucinations, and important functional and social disability. Interventions labeled as 'transitional' add to care plans made during the hospital stay in preparation for discharge. They also include interventions developed after discharge to support people with serious mental illness as they make the transition from the hospital to the community. Transitional discharge interventions may anticipate the future needs of the patient after discharge by co-ordinating the different levels of the health system that can effectively guarantee continuity of care in the community. This occurs through the provision of therapeutic relationships which give a safety net throughout the discharge and community reintegration processes to improve the general condition of users, level of functioning, use of health resources, and satisfaction with care., Objectives: To assess the effects of transitional discharge interventions for people with schizophrenia., Search Methods: On 7 December 2022, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, MEDLINE, Embase, PubMed, CINAHL, ClinicalTrials.gov, ISRCTN, PsycINFO, and WHO ICTRP., Selection Criteria: Randomized controlled trials (RCTs) evaluating the effects of transitional discharge interventions in people with schizophrenia and schizophrenia-related disorders. Eligible interventions included three key elements: predischarge planning, co-ordination of care and follow-up, and postdischarge support., Data Collection and Analysis: We used standard Cochrane methods. Outcomes of this review included global state (relapse), service use (hospitalization), general functioning, satisfaction with care, adverse effects/events, quality of life, and direct costs. For binary outcomes, we calculated risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous outcomes, we calculated the mean difference (MD) or standardized mean difference (SMD) and their 95% CIs. We used GRADE to assess certainty of evidence., Main Results: We found 12 studies with 1748 participants comparing transitional discharge interventions to usual care. All were parallel-group RCTs. No studies assessed global state (relapse) or reported data about adverse events/effects. All studies had a high risk of bias, mainly due to serious concerns about allocation concealment, deviations from intended interventions, measurement of the outcomes, and missing outcome data. Transitional discharge interventions may make little to no difference in service use (hospitalization) at short- and long-term follow-ups, but the evidence is very uncertain (RR 1.18, 95% CI 0.55 to 2.50; I 2 = 54%; 4 studies, 462 participants; very low-certainty evidence). Transitional discharge intervention may increase the levels of functioning after discharge (clinically important change in general functioning) (SMD 0.95, 95% CI -0.06 to 1.97; I² = 95%; 4 studies, 437 participants; very low-certainty evidence) and may increase the proportion of participants who are satisfied with the intervention (clinically important change in satisfaction) (RR 1.96, 95% CI 1.37 to 2.80; 1 study, 76 participants; very low-certainty evidence), but for both outcomes the evidence is very uncertain. Transitional discharge intervention may make little to no difference in quality of life compared to treatment as usual (SMD 0.24, 95% CI -0.30 to 0.78; I² = 90%; 4 studies, 748 participants; very low-certainty evidence), but we are very uncertain. For direct costs, one study with 124 participants did not report full details and thus the results were inconclusive., Authors' Conclusions: There is currently no clear evidence for or against implementing transitional discharge interventions for people with schizophrenia. Transitional discharge interventions may improve patient satisfaction and functionality, but this evidence is also very uncertain. For future research, it is important to improve the quality of the conduct and reporting of these trials, including using validated tools for measuring their outcomes., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

In the summer of 2023, within the Alentejo region (Portugal), a new occurrence of a plant disease of strawberry (Fragaria × ananassa) cv. 'Monterey' was observed in a Spring commercial planting. Symptoms consisted of foliar wilting, drying of older leaves, deformed and highly chlorotic leaflets, crown discoloration, plant stunting, and in some cases death. Several outbreak foci, covering nearly half a hectare, were observed within the affected farm, with almost 80% of the plants showing symptoms. Four samples,of 6 plants, were collected from 4 locations within the field. Petiole sections (1 cm) were rinsed with 0.1% Tween 20, submersed in 70% EtOH for 20 s followed by 60 s in 1% NaOCL, and then placed on Komada's medium (Komada, 1975). After incubation at room temperature in the dark for a week, white-colored fluffy mycelia grew profusely from the petioles of all samples. Colony morphology and non-septate, ellipsoidal microconidia (5.7-12.4×2.5-4.3 μm) borne on monophialides, exhibited a resemblance to Fusarium oxysporum (Leslie and Summerell, 2006). Ten single strains were obtained from different plants by single hyphal tip isolation. For molecular confirmation, a portion of the translation elongation factor 1-alpha (EF1α) was amplified by PCR using EF1/EF2 primers (O'Donnell et al., 1998). Additionally, the RNA polymerase subunit RPB2 was amplified as two contiguous fragments via primers and protocols described by O'Donnell et al., 2021. Amplicons were sequenced (GenBank Accession Nos. PP426617 - 426626, PQ058494 - 058513). Using Fusarium-ID and Fusarioid-ID databases, EF1α and RPB2 sequences were found to be more than 99% identical to published F. oxysporum type isolates and Fusarium sp. isolates in the F. oxysporum species complex (Crous et al., 2021; Wang et al., 2022). A specific F. oxysporum f. sp. fragariae (Fof) qPCR assay (Burkhardt et al., 2019) was used to determine if these isolates could be Fof race 1. A Fof race 1 isolate (MAFF305558), negative controls, and water controls were included. All ten isolates and the Fof race 1 control were positive (Ct < 30), while other Fusarium spp. used as negative controls and the water controls did not amplify. Two isolates (F.200 and F.202) and MAFF305558 (positive control) were included in a pathogenicity test on two strawberry cultivars, 'Monterey' (susceptible to race 1) and 'Fronteras' (resistant to race 1) (Dilla-Ermita et al., 2023). Each isolate was included in two independent trials. In each trial, 5 plants per cultivar were inoculated by dipping roots for 10 min in 5 × 106 conidia/mL of 0.1% water agar (WA) or in sterile 0.1% WA for the negative control plants. Each plant was then planted in a pot filled with peat. Pots were placed randomly in random positions in a growth chamber at 28/20°C and 12h photoperiod. After 8 - 10 weeks, the control plants and 'Fronteras' plants remained healthy, while the inoculated plants cv. 'Monterey' were severely wilted and/or dead. Fusarium oxysporum was re-isolated from all symptomatic plants. Recovered isolates were confirmed to be the same as the inoculated ones using the Fof-qPCR, including the same controls as above. This is the first report of Fof race 1 in the Iberian Peninsula. Given that the land was not previously used for strawberry, it is highly probable that the pathogen was introduced with the planting material originated from a Spanish nursery. In conclusion, it is imperative to implement more severe control measures in nurseries to avoid the spread of this race.

Oncolytic viruses often face challenges in achieving optimal antitumor immunity as standalone therapies. The penton base RGD-integrin interactions play a significant role in wild-type adenovirus-induced innate immune responses. To modify these responses, we present ISC301, a novel oncolytic adenovirus engineered by deleting the natural RGD motifs in the penton base while incorporating artificial RGD motifs in the fiber knobs. ISC301 demonstrated comparable in vitro infectivity, cytotoxic effects, and signaling profiles across various cell types to its parental ICOVIR-5, which retains the penton base RGD motif. In immunodeficient and immunocompetent mouse models, ISC301 exhibited similar in vivo antitumor efficacy to ICOVIR-5. However, ISC301 induced higher intratumoral inflammation through NF-κB activation, leading to increased levels of tumor-infiltrating leukocytes and higher proportion of cytotoxic CD8 + T cells. In addition, ISC301 elicits a heightened pro-inflammatory response in peripheral blood. Importantly, when combined with CAR T cell therapy, ISC301 exhibited superior antitumor efficacy, surpassing monotherapy outcomes. These findings emphasize the impact of adenoviral modifications on antitumor immune responses. The deletion of penton base RGD motifs enhances ISC301's pro-inflammatory profile and boosts CAR T cell therapy efficacy. This study enhances understanding of oncolytic virus engineering strategies, positioning ISC301 as a promising candidate for combined immunotherapeutic approaches in cancer treatment., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Introduction: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis., Methods: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes., Results: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function., Discussion: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID., Highlights: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Assembly of NADPH oxidase 2 (NOX2) proteins in neutrophils plays an essential role in controlling microbial infections by producing high levels of reactive oxygen species (ROS). In contrast, the role of the Hv1 voltage-gated proton channel that is required for sustained NOX2 activity is less well characterized. We examined the role of Hv1 in a murine model of blinding Pseudomonas aeruginosa corneal infection and found that in contrast to C57BL/6 mice, Hvcn1 -/- mice exhibit an impaired ability to kill bacteria and regulate disease severity. In vitro , we used a novel Hv1 Inhibitor Flexible (HIF) to block ROS production by human and murine neutrophils and found that HIF inhibits ROS production in a dose-dependent manner following stimulation with PMA or infection with P. aeruginosa . Collectively, these findings demonstrate an important role for Hv1 on controlling bacterial growth in a clinically relevant bacterial infection model., Competing Interests: Competing interests The authors declare no conflicts of interest.

In this paper, the effect of doping and nanostructuring on the electrostatic potential across the electrochemical interface between a transition metal oxide and a water electrolyte is investigated by means of the Poisson-Boltzmann model. For spherical nanoparticles and nanorods, compact expressions for the limiting potentials at which the space charge layer includes the whole semiconductor are reported. We provide a quantitative analysis of the distribution of the potential drop between the solid and the liquid and show that the relative importance changes with doping. It is usually assumed that high doping improves charge dynamics in the semiconductor but reduces the width of the space charge layer. However, nanostructuring counterbalances the latter negative effect; we show quantitatively that in highly doped nanoparticles the space charge layer can occupy a similar volume fraction as in low-doped microparticles. Moreover, as shown by some recent experiments, under conditions of high doping the electric fields in the Helmholtz layer can be as high as 100 mV/Å, comparable to electric fields inducing freezing in water. This work provides a systematic quantitative framework for understanding the effects of doping and nanostructuring on electrochemical interfaces, and suggests that it is necessary to better characterize the interface at the atomistic level.

Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer's disease. Gaining insight into the molecular mechanisms underlying this vulnerability will help reveal genes and pathways at play during incipient stages of the disease. Here, we use a data-driven functional genomics approach to model ECII neurons in silico and identify the proto-oncogene DEK as a regulator of tau pathology. We show that epigenetic changes caused by Dek silencing alter activity-induced transcription, with major effects on neuronal excitability. This is accompanied by the gradual accumulation of tau in the somatodendritic compartment of mouse ECII neurons in vivo, reactivity of surrounding microglia, and microglia-mediated neuron loss. These features are all characteristic of early Alzheimer's disease. The existence of a cell-autonomous mechanism linking Alzheimer's disease pathogenic mechanisms in the precise neuron type where the disease starts provides unique evidence that synaptic homeostasis dysregulation is of central importance in the onset of tau pathology in Alzheimer's disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Ibogaine is a potent atypical psychedelic that has gained considerable attention due to its antiaddictive and antidepressant properties in preclinical and clinical studies. Previous research from our group showed that ibogaine suppresses sleep and produces an altered wakefulness state, which resembles natural REM sleep. However, after systemic administration, ibogaine is rapidly metabolized to noribogaine, which also shows antiaddictive effects but with a distinct pharmacological profile, making this drug a promising therapeutic candidate. Therefore, we still ignore whether the sleep/wake alterations depend on ibogaine or its principal metabolite noribogaine. To answer this question, we conducted polysomnographic recordings in rats following the administration of pure noribogaine. Our results show that noribogaine promotes wakefulness while reducing slow-wave sleep and blocking REM sleep, similar to our previous results reported for ibogaine administration. Thus, we shed new evidence on the mechanisms by which iboga alkaloids work in the brain., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Alzheimer's disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of cognitive deterioration and neurodegeneration remain unclear, leading to a lack of effective strategies to prevent dementia. Recent evidence highlights the role of neuroinflammation, particularly involving microglia, in Alzheimer's disease onset and progression. Characterizing the initial phase of Alzheimer's disease can lead to the discovery of new biomarkers and therapeutic targets, facilitating timely interventions for effective treatments. We used the App NL-G-F knock-in mouse model, which resembles the amyloid pathology and neuroinflammatory characteristics of Alzheimer's disease, to investigate the transition from a pre-plaque to an early plaque stage with a combined functional and molecular approach. Our experiments show a progressive decrease in the power of cognition-relevant hippocampal gamma oscillations during the early stage of amyloid pathology, together with a modification of fast-spiking interneuron intrinsic properties and postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes in synaptic function-associated pathways. Concurrently, homeostasis- and inflammatory-related microglia signature genes were downregulated. Moreover, we found a decrease in Iba1-positive microglia in the hippocampus that correlates with plaque aggregation and neuronal dysfunction. Collectively, these findings support the hypothesis that microglia play a protective role during the early stages of amyloid pathology by preventing plaque aggregation, supporting neuronal homeostasis, and overall preserving the oscillatory network's functionality. These results suggest that the early alteration of microglia dynamics could be a pivotal event in the progression of Alzheimer's disease, potentially triggering plaque deposition, impairment of fast-spiking interneurons, and the breakdown of the oscillatory circuitry in the hippocampus., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

One of the main concerns in oligonucleotide-based therapeutics is achieving a successful cell targeting while avoiding drug degradation and clearance. Nanoparticulated drug delivery systems have emerged as a way of overcoming these issues. Among them, membrane-coated nanoparticles are of increasing relevance mainly due to their enhanced cellular uptake, immune evasion and biocompatibility. In this study, we designed and elaborated a simple and highly tuneable biomimetic drug delivery nanosystem based on a polymeric core surrounded by extracellular vesicles (EVs)-derived membranes. This strategy should allow the nanosystems to benefit from the properties conferred by the membrane proteins present in EVs membrane, key paracrine mediators. The developed systems were able to successfully encapsulate the required oligonucleotides. Also, their characterisation through already well standardised methods (dynamic light scattering, transmission electron microscopy and nanoparticle tracking analysis) and by fluorescence cross-correlation spectroscopy (FCCS) showed the desired core-shell structure. The cellular uptake using different cell types further confirmed the coating though an enhancement in cell internalisation of the developed biomimetic nanoparticles. This study brings up new possibilities for GapmeR delivery as it might be a base for the development of new delivery systems for gene therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Patricia Diaz-Rodriguez reports financial support was provided by Spain Ministry of Science and Innovation. Erik Briffault reports financial support was provided by Canary Islands Agency for Research, Innovation and Information Society. Rebeca Martinez-Borrajo reports a relationship with IACOBUS program that includes: funding grants., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The SafeBoosC-III trial investigated the effect of cerebral oximetry-guided treatment in the first 72 h after birth on mortality and severe brain injury diagnosed by cranial ultrasound in extremely preterm infants (EPIs). This ancillary study evaluated the effect of cerebral oximetry on global brain injury as assessed by magnetic resonance imaging (MRI) at term equivalent age (TEA)., Methods: MRI scans were obtained between 36 and 44.9 weeks PMA. The Kidokoro score was independently evaluated by two blinded assessors. The intervention effect was assessed using the nonparametric Wilcoxon rank sum test for median difference and 95% Hodges-Lehmann (HL) confidence intervals (CIs). The intraclass correlation coefficient (ICC) was used to assess the agreement between the assessors., Results: A total of 210 patients from 8 centers were included, of whom 121 underwent MRI at TEA (75.6% of alive patients): 57 in the cerebral oximetry group and 64 in the usual care group. There was an excellent correlation between the assessors for the Kidokoro score (ICC agreement: 0.93, 95% CI: 0.91-0.95). The results showed no significant differences between the cerebral oximetry group (median 2, interquartile range [IQR]: 1-4) and the usual care group (median 3, IQR: 1-4; median difference -1 to 0, 95% HLCI: -1 to 0; p value 0.1196)., Conclusions: In EPI, the use of cerebral oximetry-guided treatment did not lead to significant alterations in brain injury, as determined by MRI at TEA. The strong correlation between the assessors highlights the potential of the Kidokoro score in multicenter trials., (© 2024 S. Karger AG, Basel.)

In recent years, there has been a surge in the development of methods for cell segmentation and tracking, with initiatives like the Cell Tracking Challenge driving progress in the field. Most studies focus on regular cell population videos in which cells are segmented and followed, and parental relationships annotated. However, DNA damage induced by genotoxic drugs or ionizing radiation produces additional abnormal events since it leads to behaviors like abnormal cell divisions (resulting in a number of daughters different from two) and cell death. With this in mind, we developed an automatic mitosis classifier to categorize small mitosis image sequences centered around one cell as "Normal" or "Abnormal." These mitosis sequences were extracted from videos of cell populations exposed to varying levels of radiation that affect the cell cycle's development. We explored several deep-learning architectures and found that a network with a ResNet50 backbone and including a Long Short-Term Memory (LSTM) layer produced the best results (mean F1-score: 0.93 ± 0.06). In the future, we plan to integrate this classifier with cell segmentation and tracking to build phylogenetic trees of the population after genomic stress., (© 2024. The Author(s).)

The LHCb Collaboration measures production of the exotic hadron χ&#95;{c1}(3872) in proton-nucleus collisions for the first time. Comparison with the charmonium state ψ(2S) suggests that the exotic χ&#95;{c1}(3872) experiences different dynamics in the nuclear medium than conventional hadrons, and comparison with data from proton-proton collisions indicates that the presence of the nucleus may modify χ&#95;{c1}(3872) production rates. This is the first measurement of the nuclear modification factor of an exotic hadron.

Background: Cilostazol is used for the treatment of intermittent claudication. The impact of cilostazol on the outcomes of peripheral vascular interventions (PVIs) remains controversial. This study assesses the use and impact of cilostazol on patients undergoing PVI for peripheral arterial disease (PAD)., Methods: The Vascular Quality Initiative (VQI) database files for PVI were reviewed. Patients with PAD who underwent PVI for chronic limb threatening-ischemia or claudication were included and divided based on the use of cilostazol preoperatively. After propensity matching for patient demographics and comorbidities, the short-term and long-term outcomes of the 2 groups (preoperative cilostazol use versus no preoperative cilostazol use) were compared. The Kaplan-Meier method was used to determine outcomes., Results: A total of 245,309 patients underwent PVI procedures and 6.6% (N = 16,366) were on cilostazol prior to intervention. Patients that received cilostazol were more likely to be male (62% vs 60%; P < 0.001), White (77% vs. 75%; P < 0.001), and smokers (83% vs. 77%; P < 0.001). They were less likely to have diabetes mellitus (50% vs. 56%; P < 0.001) and congestive heart failure (14% vs. 23%; P < 0.001). Patient on cilostazol were more likely to be treated for claudication (63% vs. 40%, P < 0.001), undergo prior lower extremity revascularization (55% vs. 51%, P < 0.001) and less likely to have undergone prior minor and major amputation (10% vs. 19%; P < 0.001) compared with patients who did not receive cilostazol. After 3:1 propensity matching, there were 50,265 patients included in the analysis with no differences in baseline characteristics. Patients on cilostazol were less likely to develop renal complications and more likely to be discharged home. Patients on cilostazol had significantly lower rates of long-term mortality (11.5% vs. 13.4%, P < 0.001 and major amputation (4.0% vs. 4.7%, P = 0.022). However, there were no significant differences in rates of reintervention, major adverse limb events, or patency after PVI. Amputation-free survival rates were significantly higher for patients on cilostazol, after 4 years of follow up (89% vs. 87%, P = 0.03)., Conclusions: Cilostazol is underutilized in the VQI database and seems to be associated with improved amputation-free survival. Cilostazol therapy should be considered in all patients with PAD who can tolerate it prior to PVI., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Bowel bladder dysfunction (BBD) is common in children. Risk factors for BBD include age, gender, obesity, and behavioral issues such as ADHD. We investigated the modified Swedish Bowel-Bladder questionnaire as a sensitive indicator of BBD in healthy children., Objectives: We tested the usefulness of the Swedish Bowel-Bladder Questionnaire (BBQ) as an indicator of BBD in children not complaining of bowel/bladder dysfunction at the time of their visit to a pediatric urologist. Our secondary aim was to identify correlations between BBQ scores and risk factors such as gender, BMI, and ADHD., Study Design: All families in our Pediatric Urology practice with patients >30 months old who were reportedly toilet trained were provided the Swedish BBQ. Total score as well as sub-scores for storage, emptying, and constipation were prospectively collected. Presenting diagnosis, gender, BMI, and ADHD history were collected. BBQ scores for patients with voiding dysfunction were compared to controls: a) those with genital problems (e.g. hydrocele/undescended testes), b) those with CAKUT (congenital anomalies of the kidneys and urinary tract). BBQ scores were analyzed as a continuous variable vs the potential risk factors (ADHD, obesity, age, and gender) using univariable/multivariable regression analysis., Results: The median BBQ score for the 328 control patients (95 CAKUT and 233 genital) was 2.25 with an IQR: 1 to 6. In contrast, the median BBQ was higher for those with possible voiding dysfunction; n = 282; 9 with an IQR: 5 to 15). Total BBQ score exceeded 6 in 16% (52/328) of control patients. On multivariable analysis, age-adjusted total BBQ scores increased with ADHD in our controls (p = 0.03) but were unaffected by gender or BMI. On multivariable analysis of the voiding dysfunction group, total BBQ scores similarly decreased with age (p < 0.001) and increased with ADHD (p < 0.001) and were affected by gender (p = 0.024). BMI percentile had no significant effect in either cohort., Discussion and Conclusion: The Swedish BBQ was used in a U.S population and demonstrated trends towards increased voiding dysfunction associated with younger age, female gender, and ADHD. We learned that voiding dysfunction in children with ADHD is not associated with constipation and improves over time. Additionally, 16% of children with genital or urinary abnormalities and no voiding complaints have noticeable BBD uncovered by the BBQ. Hence, we conclude that the Swedish BBQ is a sensitive indicator of BBD even in children not complaining of those problems., Competing Interests: Conflict of interest None., (Copyright © 2024 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Receiving a neurodegenerative disease (NDD) diagnosis, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis, is devastating, particularly given the limited options for treatment. Advances in genetic technologies have allowed for efficient modeling of NDDs in animals and brought hope for new disease-modifying medications. The complexity of the mammalian brain and the costs and time needed to identify and develop therapeutic leads limits progress. Modeling NDDs in invertebrates, such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, offers orders of magnitude increases in speed of genetic analysis and manipulation, and can be pursued at substantially reduced cost, providing an important, platform complement and inform research with mammalian NDD models. In this review, we describe how our efforts to exploit C. elegans for the study of neural signaling and health led to the discovery of a paralytic phenotype (swimming-induced paralysis) associated with altered dopamine signaling and, surprisingly, to the discovery of a novel gene and pathway whose dysfunction in glial cells triggers neurodegeneration. Research to date on swip-10 and its putative mammalian ortholog MBLAC1, suggests that a tandem analysis will offer insights into NDD mechanisms and insights into novel, disease-modifying therapeutics., (© 2023 Wiley Periodicals LLC.)

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder. Worldwide, its prevalence is ~2% and its etiology is mostly unknown. Identifying biological factors contributing to OCD will elucidate underlying mechanisms and might contribute to improved treatment outcomes. Genomic studies of OCD are beginning to reveal long-sought risk loci, but >95% of the cases currently in analysis are of homogenous European ancestry. If not addressed, this Eurocentric bias will result in OCD genomic findings being more accurate for individuals of European ancestry than other ancestries, thereby contributing to health disparities in potential future applications of genomics. In this study protocol paper, we describe the Latin American Trans-ancestry INitiative for OCD genomics (LATINO, https://www.latinostudy.org). LATINO is a new network of investigators from across Latin America, the United States, and Canada who have begun to collect DNA and clinical data from 5000 richly phenotyped OCD cases of Latin American ancestry in a culturally sensitive and ethical manner. In this project, we will utilize trans-ancestry genomic analyses to accelerate the identification of OCD risk loci, fine-map putative causal variants, and improve the performance of polygenic risk scores in diverse populations. We will also capitalize on rich clinical data to examine the genetics of treatment response, biologically plausible OCD subtypes, and symptom dimensions. Additionally, LATINO will help elucidate the diversity of the clinical presentations of OCD across cultures through various trainings developed and offered in collaboration with Latin American investigators. We believe this study will advance the important goal of global mental health discovery and equity., (© 2023 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

The electrode-electrolyte interface, and in particular the nature of the cation, has considerable effects on the activity and product selectivity of the electrochemical reduction of CO 2 . Therefore, to improve the electrocatalysis of this challenging reaction, it is paramount to ascertain whether cation effects on adsorbed intermediates are systematic. Here, DFT calculations are used to show that the effects of K + , Na + , and Mg 2+ , on single carbon CO 2 reduction intermediates can either be stabilizing or destabilizing depending on the metal and the adsorbate. Because systematic trends are observed, cation effects can be accurately predicted in simple terms for a wide variety of metals, cations and adsorbed species. These results are then applied to the reduction of CO 2 to CO on four different catalytic surfaces (Au, Ag, Cu, Pd) and activation of weak-binding metals is consistently observed by virtue of the stabilization of the key intermediate *COOH., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Retinal pigment epithelial cells (RPECs) are a type of retinal cells that structurally and physiologically support photoreceptors. However, hyperglycemia has been shown to play a critical role in the progression of diabetic retinopathy (DR), which is one of the leading causes of vision impairment. In the diabetic eye, the high glucose environment damages RPECs via the induction of oxidative stress, leading to the release of excess reactive oxygen species (ROS) and triggering apoptosis. In this study, we aim to investigate the antioxidant mechanism of Vitamin C in reducing hyperglycemia-induced stress and whether this mechanism can preserve the function of RPECs., Methods and Results: ARPE-19 cells were treated with high glucose in the presence or absence of Vitamin C. Cell viability was measured by MTT assay. Cleaved poly ADP-ribose polymerase (PARP) was used to identify apoptosis in the cells. ROS were detected by the DCFH-DA reaction. The accumulation of sorbitol in the aldose reductase (AR) polyol pathway was determined using the sorbitol detection assay. Primary mouse RPECs were isolated from adult mice and identified by Rpe65 expression. The mitochondrial damage was measured by mitochondrial membrane depolarization. Our results showed that high glucose conditions reduce cell viability in RPECs while Vitamin C can restore cell viability, compared to the vehicle treatment. We also demonstrated that Vitamin C reduces hyperglycemia-induced ROS production and prevents cell apoptosis in RPECs in an AR-independent pathway., Conclusions: These results suggest that Vitamin C is not only a nutritional necessity but also an adjuvant that can be combined with AR inhibitors for alleviating hyperglycemic stress in RPECs., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Nanostructured lipid carriers (NLCs) hold significant promise as drug delivery systems (DDS) owing to their small size and efficient drug-loading capabilities. Surface functionalization of NLCs can facilitate interaction with specific cell receptors, enabling targeted cell delivery. Mannosylation has emerged as a valuable tool for increasing the ability of nanoparticles to be recognized and internalized by macrophages. Nevertheless, the design and development of functionalized NLC is a complex task that entails the optimization of numerous variables and steps, making the process challenging and time-consuming. Moreover, no previous studies have been focused on evaluating the functionalization efficiency. In this work, hybrid Artificial Intelligence technologies are used to help in the design of mannosylated drug loaded NLCs. Artificial neural networks combined with fuzzy logic or genetic algorithms were employed to understand the particle formation processes and optimize the combinations of variables for the different steps in the functionalization process. Mannose was chemically modified to allow, for the first time, functionalization efficiency quantification and optimization. The proposed sequential methodology has enabled the design of a robust procedure for obtaining stable mannosylated NLCs with a uniform particle size distribution, small particle size (< 100 nm), and a substantial positive zeta potential (> 20mV). The incorporation of mannose on the surfaces of these DDS following the established protocols achieved > 85% of functionalization efficiency. This high effectiveness should enhance NLC recognition and internalization by macrophages, thereby facilitating the treatment of chronic inflammatory diseases., (© 2024. The Author(s).)

Background: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes., Methods: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses., Findings: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort., Interpretation: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine., Funding: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128)., Competing Interests: Declaration of interests PF, SLE and members of 23andMe Research Team are employees of 23andMe, Inc., and hold stock or stock options in 23andMe. ASH has filed for a provisional Patent entitled “Methods of Treatments for Multi-Drug or Broad Addiction Liability”, University patent application T-020489. ASH reports consulting fees from Psychiatric Genomics Consortium Suicide working group, speaker fees from Jackson Laboratories and a grant from National Institute on Alcoholism and Alcohol Abuse (NIAAA K01 AA030083-01). CK received a new investigator award from TRDRP and consulting fees and stock options from CARI Health, Inc. JG is paid for editorial work for the journal ‘Complex Psychiatry’ and is named as an inventor on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists” filed January 24, 2018 and issued on January 26, 2021 as U.S. Patent No. 10,900,082. AP received consulting fees from universities and companies and holds a biomedical patent (related to inhibitions of the gene Glo1), both unrelated to this work. SSR received consulting fees from the Externalizing Consortium as well as a Royal Society Alcoholism Early Career Award honoraria. EA reports consulting fees from PGC-PTSD and LATINO consortium. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Imaging techniques in anatomy have developed rapidly over the last decades through the emergence of various 3D scanning systems. Depending on the dissection level, non-contact or tactile contact methods can be applied on the targeted structure. The aim of this study was to assess the inter and intra-observer reproducibility of an ArUco-based localisation stylus, that is, a manual technique on a hand-held stylus. Ten fresh-frozen, unembalmed adult arms were used to digitalise the glenoid cartilage related to the glenohumeral joint and the contour of the clavicle cartilage related to the acromioclavicular joint. Three operators performed consecutive digitalisations of each cartilage contour using an ArUco-based localisation stylus recorded by a single monocular camera. The shape of each cartilage was defined by nine shape parameters. Intra-observer repeatability and inter-observer reproducibility were computed using an intra-class correlation (ICC) for each of these parameters. Overall, 35.2 ± 2.4 s and 26.6 ± 10.2 s were required by each examiner to digitalise the contour of a glenoid and acromioclavicular cartilage, respectively. For most parameters, good-to-excellent agreements were observed concerning intra-observer (ICC ranging between 0.81 and 1.00) and inter-observer (ICC ranging between 0.75 and 0.99) reproducibility. To conclude, through a fast and versatile process, the use of an ArUco-based localisation stylus can be a reliable low-cost alternative to conventional imaging methods to digitalise shoulder cartilage contours., (© 2024 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)