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The main aim of the current investigation was to evaluate the relationships between metabolic parameters, acute-phase proteins, and the outcome of treatment of Staphylococcus aureus subclinical mastitis in dairy cows. Serum metabolic parameters and milk haptoglobin were measured in two groups: S. aureus subclinical mastitis cows with successful treatment (n = 26) and S. aureus subclinical mastitis cows with unsuccessful treatment (n = 26). Significantly higher serum aspartate aminotransferase (AST), alkaline phosphatase (ALP), and LDL cholesterol concentrations were seen in subclinical mastitis cows with unsuccessful treatment compared to subclinical mastitis cows with successful treatment (p < 0.05). On the other hand, subclinical mastitis cows with successful treatment demonstrated higher serum iron and copper concentrations than the other group (p < 0.05). Comparison of measured variables before treatment revealed that cows suffering from subclinical mastitis with higher values of serum LDL cholesterol, ALP, and AST did not respond to antibiotic treatment and subclinical mastitis was persisted in the second examination, whereas subclinical mastitis cows with successful treatment demonstrated higher serum copper and iron concentrations (p < 0.05). The findings of the current investigation suggested that there was a relationship between the treatment outcome of S. aureus subclinical mastitis and trace element concentrations and liver health status. Furthermore, the present study provided cutoff values for serum LDL cholesterol, AST, ALP, iron, and copper, which would help predict the treatment outcome in cows with S. aureus subclinical mastitis., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Attributing the sources of legacy contamination, including brines, is important to determine remediation options and to allocate responsibility. To make sound remediation decisions, it is necessary to distinguish subsurface sources, such as leaking oil and gas ("O&G") wells or natural upward fluid migrations, from surface releases. While chemical signatures of surface and subsurface releases may be similar, they are expected to imprint specific dissolved noble gas signatures, caused by the accumulation of terrigenic noble gases in subsurface leaks or re-equilibration of noble gases following surface releases. We demonstrate that only a historic surface release influenced the dissolved noble gas signature of groundwater in monitoring wells contaminated with brine near an abandoned O&G well, rather than subsurface leakage from the well. Elevated brine concentrations were associated with lower terrigenic helium concentrations, indicating re-equilibration with atmospheric helium at the surface during the release. Geophysical surveying indicating elevated salinity in surficial soils upgradient of the wells further supported the interpretation of the noble gas data. Eliminating the possibility that subsurface leakage was the source of the plume was critical to selecting the proper remedial action at the site, which otherwise may have included an unnecessary and costly well re-abandonment. This study demonstrates the use of noble gas analysis to compare potential sources of brine contamination in groundwater and to exclude subsurface leakage as a potential source in an oilfield., (© 2024 The Authors. Groundwater published by Wiley Periodicals LLC on behalf of National Ground Water Association.)

This study examines the potential for aquifer storage and recovery (ASR) in the brackish portion of the Edwards aquifer in New Braunfels, Texas. Successful ASR relies on understanding hydraulic properties, aquifer heterogeneity, water geochemistry, and geochemical processes during operations. The research aims to investigate the chemistries of native groundwater and injectant during ASR operation, estimate the hydraulic properties of the aquifer layers, and assess the recovery rate for the recovered groundwater meeting the total dissolved solids (TDS) threshold. The study found that native groundwater is of Na-Cl facies due to halite dissolution and a possible basinal brine migration associated with the zone of greatest fault displacement. High sulfate ions in background native groundwater result from sulfate-bearing minerals' dissolution in the Kainer and Person Formations. The injectant water is of Ca-Mg-HCO 3 facies due to the carbonate-rich composition of the aquifer host matrix and interaction with the Guadalupe River riverbed. During ASR operations, mixing controlled the shift in hydrochemical facies from Na-Cl to Ca-Mg-HCO 3 .The study also suggests a possible connection between Kainer and Person Formations and preferential pathways in the targeted storage zone aquifer. The estimated conductivity values also indicate dominant horizontal flow via possible fracture pathways in both the Person and Kainer Formation storage zones. Recovery of groundwater meeting the TDS of 1000 mg/L requires a recovery rate of 0.03 m 3 /s for 60 days after 40-day storage. This research emphasizes that understanding the hydrogeological conditions and geochemical processes is critical to ASR feasibility in brackish carbonate multi-aquifer fractured systems., (© 2023 The Authors. Groundwater published by Wiley Periodicals LLC on behalf of National Ground Water Association.)

Gonadotropin inhibitory hormone (GnIH) is essential for regulating the reproduction of mammals and inhibiting testicular activities in mice. This study aimed to explore the mechanism of GnIH on spermatogenesis and steroidogenesis by acting through the hypothalamus-pituitary-testis axis of mice. Mice were subcutaneously injected with different doses of GnIH (1 μg/150 μL, 3 μg/150 μL, 6 μg/150 μL, 150 μL saline, twice daily) for 11 days. Subsequently, luteinizing hormone (LH), testosterone (T), and inhibin B (INH B) levels of peripheral blood were determined, and the expression of GnRH synthesis-related genes (GnRH-1, Kiss-1, NPY) and gonadotropin synthesis-related genes (FSH β, LH β, GnRH receptor) in the hypothalamus and pituitary gland were respectively detected. Additionally, the expression of steroidogenesis-related genes/proteins (P450scc, StAR and 3β-HSD) and spermatogenesis-related proteins/genes including LH receptor (LHR), androgen receptor (AR), heat shock factor-2 (HSF-2) and INH B were analyzed using western blot and q-PCR. Results showed that GnIH treatment significantly reduced the concentration of LH in the peripheral blood. Further analysis revealed that GnIH treatment markedly reduced the expression of GnRHImRNA and Kiss-1 mRNA in the hypothalamus, and mRNA levels of FSH β, LH β, and GnRHR genes in the pituitary. We also observed that GnIH treatment significantly decreased T levels and expression of the P450scc, StAR, and 3β-HSD proteins in the testis. Furthermore, GnIH treatment down-regulated LHR, AR proteins, and HSF-2 gene in the testis. Importantly, the INH B concentration of and INH βb mRNA levels significantly declined following GnIH treatment. Additionally, GnIH treatment may induce germ cell apoptosis in the testis of mice. In conclusion, GnIH may suppress spermatogenesis and steroidogenesis by acting through the hypothalamus-pituitary-testis axis in mice., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

YbeX of Escherichia coli, a member of the CorC protein family, is encoded in the same operon with ribosome-associated proteins YbeY and YbeZ. Here, we report the involvement of YbeX in ribosomal metabolism. The ΔybeX cells accumulate distinct 16S rRNA degradation intermediates in the 30S particles and the 70S ribosomes. E. coli lacking ybeX has a lengthened lag phase upon outgrowth from the stationary phase. This growth phenotype is heterogeneous at the individual cell level and especially prominent under low extracellular magnesium levels. The ΔybeX strain is sensitive to elevated growth temperatures and to several ribosome-targeting antibiotics that have in common the ability to induce the cold shock response in E. coli. Although generally milder, the phenotypes of the ΔybeX mutant overlap with those caused by ybeY deletion. A genetic screen revealed partial compensation of the ΔybeX growth phenotype by the overexpression of YbeY. These findings indicate an interconnectedness among the ybeZYX operon genes, highlighting their roles in ribosomal assembly and/or degradation., (© 2024 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and Friedrich ataxia are all incurable neurodegenerative diseases defined by the continuous progressive loss of distinct neuronal subtypes. Despite their rising prevalence among the world's ageing population, fewer advances have been made in the concurrent massive efforts to develop newer drugs. Recently, there has been a shift in research focus towards the discovery of new therapeutic agents for neurodegenerative diseases. In this review, we have summarized the recently developed therapies and their status in the management of neurodegenerative diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) is a complex neurological disorder that results in cognitive decline. The incidence rates of AD have been increasing, particularly among individuals 60 years of age or older. In June 2021, the US FDA approved aducanumab, the first humanized monoclonal antibody, as a potential therapeutic option for AD. Clinical trials have shown this drug to effectively target the accumulation of Aβ (beta-amyloid) plaques in the brain, and its effectiveness is dependent on the dosage and duration of treatment. Additionally, aducanumab has been associated with improvements in cognitive function. Biogen, the pharmaceutical company responsible for developing and marketing aducanumab, has positioned it as a potential breakthrough for treating cerebral damage in AD. However, the drug has raised concerns due to its high cost, limitations, and potential side effects. AD is a progressive neurological condition that affects memory, cognitive function, and behaviour. It significantly impacts the quality of life of patients and caregivers and strains healthcare systems. Ongoing research focuses on developing disease-modifying therapies that can halt or slow down AD progression. The pathogenesis of AD involves various molecular cascades and signaling pathways. However, the formation of extracellular amyloid plaques is considered a critical mechanism driving the development and progression of the disease. Aducanumab, as a monoclonal antibody, has shown promising results in inhibiting amyloid plaque formation, which is the primary pathological feature of AD. This review explores the signaling pathways and molecular mechanisms through which aducanumab effectively prevents disease pathogenesis in AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The treatment of metastatic castration-resistant prostate cancer (mCRPC) in the actual world currently presents difficulties. In light of this, it is crucial to investigate high-risk factors for the progression of advanced prostate cancer and to identify methods for delaying the onset of CRPC., Aims: This study aimed to explore the high-risk factors that impact the progression of prostate cancer and emphasize the significance of precise diagnosis and treatment based on etiological classification in the clinical management of castration-resistant prostate cancer., Methods: A retrospective analysis was conducted on 277 newly diagnosed cases of PCa treated with endocrine therapy. A follow-up was done on prostate-specific antigen (PSA) levels and testosterone. Additionally, a prospective analysis was performed on the clinical data of 60 patients with CRPC. Following the principle of "4W1H", 30 patients were included in the precision treatment group for a second biopsy and related tests, while another 30 patients were included in the conventional treatment group. The therapeutic effect and prognosis of the two groups were observed., Results: Distant metastasis (HR = 1.879, 95% CI: 1.311 ~ 2.694, P = 0.001), PSA nadir > 0.2 ng/mL (HR = 1.843, 95% CI: 1.338 ~ 2.540, P = 0.001), testosterone nadir > 20 ng/dL (HR = 1.403, 95% CI: 1.035 ~ 1.904, P = 0.029), and time to testosterone nadir > 6 months (HR = 1.919, 95% CI: 1.364 ~ 2.701, P = 0.001) were risk factors for the progression to CRPC. Patients in the CRPC group were treated with precision therapy and conventional therapy based on their molecular subtyping. The precision treatment group showed a significantly prolonged median PSA progression-free survival compared to the conventional treatment group (16.0 months vs. 13.0 months, P=0.025). The median radiographic progression-free survival was also significantly extended in the precision treatment group compared to the conventional treatment group (21.0 months vs. 16.0 months, P=0.042)., Conclusion: Patients with prostate cancer diagnosed with distant metastasis at initial presentation require early intervention. Close monitoring of PSA and serum testosterone changes is necessary during the process of endocrine therapy. After entering the CRPC stage, the etiological classification precision treatment can improve the therapeutic effect and improve the prognosis of patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: The use of open-source automated insulin delivery systems (OS-AIDs), for the management of type 1 diabetes (T1D), has increased over recent years in all age groups. Real-life data has demonstrated the safety and efficacy of these systems, however, studies in the pediatric population remain limited. In this study, we aimed to examine the effect of transition to an OS-AIDs on glycemic parameters, and on several aspects related to quality of life. In addition, we aimed to characterize the socioeconomic position of families who chose this treatment modality, assess their motivations to do so, and evaluate treatment satisfaction., Methods: In this multi-center observational real-life study from the AWeSoMe Group, we compared glycemic parameters of 52 individuals with T1D (56% males, mean diabetes duration 4.2 ± 3.9 years), from the last clinic visit prior to OS-AIDs initiation to the most recent clinic visit while using the system. Socioeconomic position (SEP) index was retrieved from the Israel Central Bureau of Statistics. Caregivers completed questionnaires assessing reasons for system initiation and treatment satisfaction., Results: Mean age at OS-AIDs initiation was 11.2 ± 4 years, range 3.3-20.7 years with a median usage duration of 11.1 months (range 3-45.7). Mean SEP Index was 1.033 ± 0.956 (value range: -2.797 to 2.590). Time in range (TIR) of 70 to 180 mg/dl increased from 69.0 ± 11.9 to 75.5 ± 11.7%, (P < 0.001), and HbA1c decreased from 6.9 ± 0.7 to 6.4 ± 0.6%, (P < 0.001). Time in tight range (TITR) of 70 to 140 mg/dl increased from 49.7 ± 12.9 to 58.8 ± 10.8% (P < 0.001). No episodes of severe hypoglycemia or DKA were reported. Reduction in diabetes burden and sleep quality improvement were the main reasons for OS-AID initiation., Conclusions: In our cohort of youth with T1D, the transition to an OS-AID resulted in greater TIR and less severe hypoglycemia regardless of age, diabetes duration or SEP, which was found to be above average. The overall improvement in glycemic parameters in our study population with excellent baseline glycemic control, provides additional evidence of beneficence and efficacy of OS-AIDs in the pediatric population., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The wounding-responsive KED gene, named for its coding for a lysine (K), glutamic acid (E), and aspartic acid (D)-rich protein, is widely present among land plants. However, little is known about its regulation or function. In this study, we found that transcription of the tomato (Solanum lycopersicum) KED gene, SlKED, was rapidly and transiently elevated by wounding or ethephon treatment. Compared to the wild-type plants, the CRISPR/Cas9-mediated SlKED knockout plants did not exhibit altered expression patterns for genes involved in hormone biosynthesis or stress signaling, suggesting a lack of pleiotropic effect on other stress-responsive genes. Conversely, jasmonic acid did not appear to directly regulate SlKED expression. Wounded leaves of the KED-lacking plants exhibited higher binding of Evans blue dye than the wild-type, indicating a possible role for KED in healing damaged tissues. The SlKED knockout plants showed a similar dietary effect as the wild-type on the larval growth of tobacco hornworm. But a higher frequency of larval mandible (mouth) movement was recorded during the first 2 minutes of feeding on the wounded KED-lacking SlKED knockout plants than on the wounded KED-producing wild-type plants, probably reflecting an initial differential response by the feeding larvae to the SlKED knockout plants. Our findings suggest that SlKED may be an ethylene-mediated early responder to mechanical stress in tomato, acting downstream of the wound stress response pathways. Although its possible involvement in response to other biotic and abiotic stresses is still unclear, we propose that SlKED may play a role in plant's rapid, short-term, early wounding responses, such as in cellular damage healing., (© 2023 Scandinavian Plant Physiology Society.)

The early attainment of puberty in heifers is essential for the profitability of the cow-calf farm. This study aimed to evaluate the impact of juvenile average daily gain (ADG) and sire's expected progeny difference (EPD) on puberty of crossbred beef heifers. Sixty Angus × Nellore heifers early weaned (age = 102 ± 4.3 d; initial BW = 103 ± 4.7 kg) were used in a 2 × 2 factorial arrangement. The factor 1 was the sire's EPD for scrotal circumference, in which heifers born from sires with positive EPD were considered precocious (P), and heifers born from sires with negative EPD were considered non-precocious (NP). The factor 2 was the high (HG; ADG = 0.9 kg; ad libitum) and medium ADG (MG; ADG = 0.7 kg) from 3 rd to 7 th month of age (1 st phase). After 1 st phase until puberty, all heifers were fed ad libitum (2 nd phase). Statistical analysis was performed by SAS. There was an interaction between factors for DMI in the 1 st phase (P = 0.02), which PHG heifers had higher DMI than NPHG. There was no effect on puberty rate, BW, age and BCS at puberty comparing HG vs. MG. However, favorable sires' EPD for scrotal circumference induced a higher proportion of puberty (P 87% vs. NP 59%) at 15 months of age. Thus, the ADG in juvenile age did not affect puberty rate, but sires with positive EPD increased puberty rate of Angus × Nellore heifers in heifers fed a high gain diet., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Chloroplast pre-ribosomal RNA (rRNA) undergoes maturation, which is critical for ribosome assembly. While the central and auxiliary factors in rRNA maturation have been elucidated in bacteria, their mode of action remains largely unexplored in chloroplasts. We now reveal chloroplast-specific factors involved in 16S rRNA maturation, Arabidopsis thaliana orthologs of bacterial RsmD methyltransferase (AtRsmD) and ribosome maturation factor RimM (AtRimM). A forward genetic screen aimed to find suppressors of the Arabidopsis yellow variegated 2 (var2) mutant defective in photosystem II quality control found a causal nonsense mutation in AtRsmD. The substantially impaired 16S rRNA maturation and translation due to the mutation rescued the leaf variegation phenotype by lowering the levels of chloroplast-encoded proteins, including photosystem II core proteins, in var2. The subsequent co-immunoprecipitation coupled with mass spectrometry analyses and bimolecular fluorescence complementation assay found that AtRsmD interacts with AtRimM. Consistent with their interaction, loss of AtRimM also considerably impairs 16S rRNA maturation with decelerated m 2 G915 modification in 16S rRNA catalyzed by AtRsmD. The atrimM mutation also rescued var2 mutant phenotypes, corroborating the functional interplay between AtRsmD and AtRimM towards modification and maturation of 16S rRNA and chloroplast proteostasis. The maturation and post-transcriptional modifications of rRNA are critical to assembling ribosomes responsible for protein translation. Here, we revealed that the cooperative regulation of 16S rRNA m 2 G915 modifications by AtRsmD methyltransferase and ribosome assembly factor AtRimM contributes to 16S rRNA maturation, ribosome assembly, and proteostasis in chloroplasts., (© 2023 Society for Experimental Biology and John Wiley & Sons Ltd.)

Introduction: Once-daily and once-weekly injectable glucagon-like peptide-1 receptor agonist therapies (GLP-1 RAs) are established in obesity and type 2 diabetes mellitus (T2DM). In T2DM, both once-daily and once-weekly insulin are expected to be available. This study elicited utilities associated with these treatment regimens from members of the general public in the UK, Canada, and China, to quantify administration-related disutility of more-frequent injectable treatment, and allow economic modelling., Methods: Two anchor states (no pharmacological treatment), and seven treatment states (daily oral tablet and generic injectable regimens of variable frequency), with identical outcomes were tested A broadly representative sample of the general public in each country participated (excluding individuals with diabetes or pharmacologically treated obesity). An adapted Measurement and Valuation of Health protocol was administered 1:1 in web-enabled interviews by trained moderators: visual analogue scale (VAS) as a "warm-up", and time trade-off (TTO) using a 20-year time horizon for utility elicitation., Results: A total of 310 individuals participated. The average disutility of once-daily versus once-weekly GLP-1 RA was - 0.048 in obesity and - 0.033 in T2DM; the corresponding average disutility for insulin was - 0.064. Disutilities were substantially greater in China, relative to UK and Canada., Discussion: Within obesity and T2DM, more-frequent treatment health states had lower utility. Scores by VAS also followed a logical order. The generated utility values are suitable for use in modelling injectable therapy regimens in obesity and T2DM, due to the use of generic descriptions and assumption of equal efficacy. Future research could examine the reasons for greater administration-related disutility in China., (© 2022. The Author(s).)

The formation of sensory organs is an important developmental and evolutionary question. In the context of regenerative medicine also, it is important to know as accurately as possible how sensory organs form. The formation of ears, eyes or nose stems presumably from tissue thickenings called placodes Graham and Shimeld (J Anat 222(1):32-40, 2013), Horie et al. (Nature 560:228-232, 2018) which become these organs after processes termed inductions. However, the origin of the placodes, the mechanism of induction and the overall face organization are not understood. Recently, it has been suggested that there is a physical principle to face organization. Indeed, it has been shown that there exists a pattern of rings and rays in the early blastula which defines the position of face landmarks, especially the ears and eyes Fleury et al. (Second order division in sectors as a prepattern for sensory organs in vertebrate development, 2021), Fleury and Abourachid (Eu Phys J E 45:31, 2022). Tensions in the sectors defined by the intersections of the said rings and rays create the actual face features. I report here that a similar situation exists for the nose. This explains the robustness of face formation in the chordates phylum. By studying nasal pit formation in the chicken embryo by time-lapse (T-L) video microscopy, I show that the nasal placode originates in a narrow sector deformed by tension forces following the biaxial pattern of rings and rays mentioned above. Cells align in the pattern and exert organized forces. Further contractions of the pattern contribute to inducing the nasal pit. The observation of the early pre-pattern of lines which locks the facial features explains readily a number of facts regarding sensory organs. Especially the existence of a lacrimal canal between the eye and the nose Lefevre and Freitag (Semin Ophthalmo l 27(5-6):175-86, 2012), or of a slit connecting the nose to the mouth, the correlation between nose, mouth and eye morphogenesis Dubourg et al. (J Rare Dis 2(8), 2007), the presence of shallow valleys on the nasal and optic vesicles, the medio-lateral asymmetry of nostrils with often a bent slit Liu et al. (PLoS ONE 12: e0181928, 2017), the uneven number of nostrils in many fish Cox (J R Soc Interf 5(23):575-593, 2008) and possibly the transition between agnatha and gnathostomes Gai and Zhu (Chinese Sci Bull 57(31), 2012): all appear under this light, geometrically straightforward. The nasal pit forms in a sector of tissue which was present on the blastodic (early embryonic stage), and which is projected onto the nasal vesicle during neurulation. The nasal pit forms along a hairpin of tissue. The top part of the hairpin forms the nares, and the bottom part a groove often visible in many animals., (© 2022. The Author(s).)

Antibiotic resistance gene pollution in the environment has been identified as a potential contributor to the global issue of antibiotic resistance prevalence, creating a need to identify and characterize environmental reservoirs for antibiotic resistance genes. Because many polluted environments have been shown to contain elevated levels of antibiotic resistance genes, agriculturally based pesticide bioremediation systems called 'biobeds' could serve as environmental reservoirs for antibiotic resistance genes, although this has never been extensively explored. Metagenomic and metatranscriptomic analyses of an on-farm biobed system sampled before and after a season of pesticide use demonstrated that in situ pesticide applications applied to biobeds can enrich for multidrug, sulphonamide, aminoglycoside and beta-lactam resistance genes. Additionally, this study demonstrated an enrichment for genes associated with gene mobilization, such as genes involved in horizontal gene transfer and plasmid mobility, as well as transposons and integrases., (© 2022 The Society for Applied Microbiology.)

We describe the structural analysis of two Anticalin® proteins that tightly bind A β 40 , a peptide involved in the pathophysiology of Alzheimer's disease. These anticalins, US7 and H1GA, were engineered on the basis of the human lipocalin 2, thus yielding compact single-domain binding proteins as an alternative to antibodies. Albeit selected under different conditions and mutually deviating in 13 amino acid positions within the binding pocket (of 17 mutated residues in total), both crystallised anticalins recognize the same epitope in the middle of the β -amyloid peptide. In the two complexes with the A β 40 peptide, its central part comprising residues Lys P16 to Lys P28 shows well defined electron density whereas the flanking regions appear structurally disordered. The compact zigzag-bend conformation which is seen in both structures may indicate a role during conversion of the soluble monomeric form into pathogenic A β state(s) and, thus, explain the aggregation-inhibiting effect of the anticalins. In contrast to solanezumab, which targets the same A β region in a different conformation, the anticalin H1GA does not show cross-reactivity with sequence-related human plasma proteins. Consequently, anticalins offer promising reagents to prevent oligomerization of A β peptides to neurotoxic species in vivo and their small size may enable new routes for brain delivery., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

This review considers antiviral nucleoside analog drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS-CoV or SARS-CoV-2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro "host" cell mutagenicity of its active principle, β-d-N4-hydroxycytidine, we have reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, that is, ribavirin, favipiravir, and 5-(2-chloroethyl)-2'-deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human genotoxicity data and follow-up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG-A and error corrected next generation sequencing (duplex sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis., (© 2022 Environmental Mutagen Society.)

Literature shows that mental healthcare workers in Ghana face incessant fear of patient violence that compromise safe care delivery. However, the nature, scale, perceived causes, and consequences of these assaults and how they shape risk perceptions have received limited empirical attention, hence the need for this study. The study employed sequential explanatory mixed methods where questionnaire administration preceded and informed the design of an interview guide used for in-depth interviews with health workers in referral psychiatric hospitals. Descriptive statistics and multivariate logistic regressions were used to analyze the quantitative data. Qualitative data were transcribed and analyzed thematically. Findings showed that physical and non-physical violent assaults and risk perceptions of the hospitals were statistically and significantly associated with females (P < 0.01), nurses (P < 0.01), other clinical cadre (P < 0.01), and those with low job tenure (P < 0.05). About 57% and 71% of the sample reported experiencing physical and non-physical assaults, respectively. Major and minor injuries and psychosocial problems were frequent sequelae following physical violent assaults. As a result, 80% of the participants perceived the hospitals environment to be unsafe to provide care. Violent assaults compromises safety and care delivery efforts suggesting the need for systematic interventions to minimize mental healthcare workers exposure to patient violence., (© 2021 John Wiley & Sons Australia, Ltd.)

Purpose: Flash glucose monitoring (FGM) in patients with type 1 diabetes (DM1) provides glucometric data that allow assessing glycemic control beyond HbA1c. The objective of this study was to evaluate metabolic control and use of FGM in a cohort of the pediatric and adult population with DM1., Material and Methods: A cross-sectional study of patients with DM1 and FGM. Data on the use of the system and metabolic control were evaluated, carrying out a comparative study between different age ranges, ≤12 years; 13-19 years, 20-25 years, and ≥26 years., Results: One hundred and ninety-five patients have included: 35.9% children and adolescents (≤19 years), 42.6% female, 26.2% in treatment with an insulin pump. Mean age was 28.5 ± 15.9 years, mean duration of diabetes 13.7 ± 11.0 years, and mean HbA1c 7.1 ± 0.9% (54 ± 6 mmol/l). Average daily FGM scans were 11.1 ± 6.7. Mean glucose was 162 ± 35 mg/dl, mean standard deviation (SD) 66.1 ± 20.4 mg/dl, mean coefficient of variation 41.4 ± 7.9%, mean time in range (TIR) 58.8 ± 17.0%, mean time above range 33.7 ± 17.6% and mean time below range 7.5 ± 5.8%. The pediatric group showed higher TIR, lower HbA1c, lower glycemic variability, lower mean glucose, and higher use of the device than the adult population. In the entire cohort, the device scans showed a negative quadratic correlation with HbA1c, mean glucose, SD, and age and a positive quadratic correlation with TIR., Conclusions: Children under 12 years showed the best metabolic control and the most frequent use of the device. Metabolic control deteriorates with age. The greater number of device scans was in correlation with better metabolic control in all age groups.

Inorganic nanoparticles (NPs) represent promising examples of engineered nanomaterials, providing interesting biomedical solutions in several fields, like therapeutics and diagnostics. Despite the extensive number of investigations motivated by their remarkable potential for nanomedicinal applications, the interactions of NPs with biological interfaces are still poorly understood. The effect of NPs on living organisms is mediated by biological barriers, such as the cell plasma membrane, whose lateral heterogeneity is thought to play a prominent role in NPs adsorption and uptake pathways. In particular, biological membranes feature the presence of rafts, that is segregated lipid micro and/or nanodomains in the so-called liquid ordered phase (L o ), immiscible with the surrounding liquid disordered phase (L d ). Rafts are involved in various biological functions and act as sites for the selective adsorption of materials on the membrane. Indeed, the thickness mismatch present along their boundaries generates energetically favourable conditions for the adsorption of NPs. Despite its clear implications in NPs internalisation processes and cytotoxicity, a direct proof of the selective adsorption of NPs along the rafts' boundaries is still missing to date. Here we use multicomponent supported lipid bilayers (SLBs) as reliable synthetic models, reproducing the nanometric lateral heterogeneity of cell membranes. After being characterised by atomic force microscopy (AFM) and neutron reflectivity (NR), multidomain SLBs are challenged by prototypical inorganic nanoparticles, that is citrated gold nanoparticles (AuNPs), under simplified and highly controlled conditions. By exploiting AFM, we demonstrate that AuNPs preferentially target lipid phase boundaries as adsorption sites. The herein reported study consolidates and extends the fundamental knowledge on NPs-membrane interactions, which constitute a key aspect to consider when designing NPs-related biomedical applications. LAY DESCRIPTION: Inorganic nanoparticles (NPs) represent promising examples of engineered nanomaterials, offering interesting biomedical solutions in multiple fields like therapeutics and diagnostics. Despite being extensively investigated due to their remarkable potential for nanomedicinal applications, the interaction of NPs with biological systems is in several cases still poorly understood. The interaction of NPs with living organisms is mediated by biological barriers, such as the cell plasma membrane. Supported lipid bilayers (SLBs) represent suitable synthetic membrane models for studying the physicochemical properties of natural interfaces and their interaction with inorganic nanomaterials under simplified and controlled conditions. Recently, multicomponent SLBs were developed in order to mimic the lateral heterogeneity of most biological membranes. In particular, biological membranes feature the presence of rafts, that is segregated lipid micro and/or nanodomains, enriched in cholesterol, sphingomyelin, saturated glycerophospholipids and glycosphingolipids: these lipids segregate in the so-called liquid-ordered phase (L o ), characterised by a high molecular packing degree, which promotes the phase separation from the surrounding liquid-crystalline (disordered, L d ) phase, where the intermolecular mobility is increased. Rafts are thought to participate in the formation and targeting of nano-sized biogenic lipid vesicles and are also actively involved in multiple membrane processes. Indeed, L o -L d phase boundaries represent high energy areas, providing active sites for the preferential adsorption of external material. The selective adsorption of NPs along the phase boundaries of rafted membranes has been theorised and indirectly probed by different research groups; however, a direct proof of this phenomenon is still missing to date. We herein exploit atomic force microscopy (AFM) to directly visualise the preferential adsorption of gold nanoparticles (AuNPs) along the phase boundaries of multicomponent SLBs (previously characterised by neutron reflectivity), obtained from synthetic vesicles containing both an L d and an L o phase. The quantitative localisation and morphometry of AuNPs adsorbed on the SLB reveal important information on their interaction with the lipid matrix and directly prove the already theorised differential NPs-lipid interaction at the phase boundaries. The presented results could help the development of future NP-based applications, involving NPs adsorption on membranes with nanoscale phase segregations., (© 2020 Royal Microscopical Society.)

Procarbazine (PCZ) and N-propyl-N-nitrosourea (PNU) are rodent mutagens and carcinogens. Both induce GPI-anchored marker-deficient mutant-phenotype red blood cells (RBCs) in the flow cytometry-based rat RBC Pig-a assay. In the present study, we traced the origin of the RBC mutant phenotype by analyzing Pig-a mutations in the precursors of RBCs, bone marrow erythroid cells (BMEs). Rats were exposed to a total of 450 mg/kg PCZ hydrochloride or 300 mg/kg PNU, and bone marrow was collected 2, 7, and 10 weeks later. Using a flow cell sorter, we isolated CD59-deficient mutant-phenotype BMEs from PCZ- and PNU-treated rats and examined their endogenous X-linked Pig-a gene by next generation sequencing. Pig-a mutations consistent with the properties of PCZ and PNU were found in sorted mutant-phenotype BMEs. PCZ induced mainly A > T transversions with the mutated A on the nontranscribed strand of the Pig-a gene, while PNU induced mainly T > A transversions with the mutated T on the nontranscribed strand. The treatment-induced mutations were distributed across the protein coding sequence of the Pig-a gene. The causal relationship between BMEs and RBCs and the agent-specific mutational spectra in CD59-deicient BMEs indicate that the rat RBC Pig-a assay, scoring CD59-deficient mutant-phenotype RBCs in peripheral blood, detects Pig-a gene mutation., (© 2020 Wiley Periodicals LLC.)

Acute graft-versus-host disease (GVHD) remains a major complication after allogeneic haematopoietic stem cell transplantation (allo-HSCT). The emergence of different immuno-prophylaxis strategies, such as post-transplant cyclophosphamide or anti-thymocyteglobulin has reduced the incidence of acute GVHD in recent years. The biology of the acute GVHD we observe in the clinic may change due to the use of novel immuno-stimulatory agents, including immune checkpoint inhibitors or anti-neoplastic immune-modifiers, like lenalidomide, given before or after allo-HSCT. Here we discuss the recent advances in our understanding of acute GVHD with a focus on early events of the disease, including tissue damaging factors, innate immune cells, costimulatory pathways, immune cell signalling, immuno-regulatory cell types, biomarkers of GVHD and regenerative approaches. New insight in the pathogenesis of acute GVHD has revealed the role of pro-inflammatory intracellular signalling, defects in intestinal tissue regeneration and anti-bacterial defence, as well as a reduced diversity of the microbiome, which will be the basis for the development of novel therapies., (© 2019 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Managed aquifer recharge is an effective strategy for urban stormwater management. Chemical ions are normally retained in stormwater and groundwater and may accelerate clogging during the recharge process. However, the effect of water chemistry on physical clogging has not previously been investigated. In this study, we investigated the hydrogeochemical mechanism of saturated porous media clogging in a series of column experiments. The column was packed with river sand and added suspensions of kaolinite particles. Calcium chloride and sodium chloride are used as representative ions to study chemical effects. We found that an increase in ionic strength resulted in retention of kaolinite solids in the column, with a breakthrough peak of C/C 0 value of 1 to 0.2. The corresponding hydraulic conductivity decreased with increased solids clogging. Divalent cations were also found to have a greater influence on kaolinite particle clogging than monovalent cations. The enhanced hydrochemical-related clogging was caused by kaolinite solids flocculating and increasing the deposition rate coefficient by 1 to 2 times in high ionic strength conditions. Three clogging mechanisms of kaolinite solids are proposed: surface filtration, inner blocking, and attachment. This study further deepens the understanding of the mechanisms of solids clogging during aquifer recharge and demonstrates the significance of ionic strength on recharge clogging risk assessments., (© 2019, National Ground Water Association.)

The nucleolus is a dynamically changing organelle that is central to a number of important cellular functions. Not only is it important for ribosome biogenesis, but it also reacts to stress by instigating a nucleolar stress response and is further involved in regulating the cell cycle. Several studies report nucleolar dysfunction in Alzheimer's disease (AD). Studies have reported a decrease in both total nucleolar volume and transcriptional activity of the nucleolar organizing regions. Ribosomes appear to be targeted by oxidation and reduced protein translation has been reported. In addition, several nucleolar proteins are dysregulated and some of these appear to be implicated in classical AD pathology. Some studies also suggest that the nucleolar stress response may be activated in AD, albeit this latter research is rather limited and requires further investigation. The purpose of this review is to draw the connections of all these studies together and signify that there are clear changes in the nucleolus and the ribosomes in AD. The nucleolus is therefore an organelle that requires more attention than previously given in relation to understanding the biological mechanisms underlying the disease., (©2019 Walter de Gruyter GmbH, Berlin/Boston.)

Over the last six decades, voltage-gated sodium (Na v ) channels have attracted a great deal of scientific and pharmaceutical interest, driving fundamental advances in both biology and technology. The structure and physiological function of these channels have been extensively studied; clinical and genetic data have uncovered their implication in diseases such as epilepsy, arrhythmias, and pain, bringing them into focus as current and future drug targets. While different techniques have been established to record the activity of Na v channels, proper determination of their properties still presents serious challenges, depending upon the experimental conditions and the desired subtype of channel to be characterized. The aim of this unit is to review the characteristics of Na v channels, their properties, the cells in which they can be studied, and the currently available techniques. Topics covered include the determination of Na v -channel biophysical properties as well as the use of toxins to discriminate between subtypes using electrophysiological or optical methods. Perspectives on the development of high-throughput screening assays with their advantages and limitations are also discussed to allow a better understanding of the challenges encountered in voltage-gated sodium channel preclinical drug discovery. © 2016 by John Wiley & Sons, Inc., (Copyright © 2016 John Wiley & Sons, Inc.)

Abstract  In the past 5 years advances in the management of wounds in dogs and cats have included the development of materials and techniques used to enhance the healing of both open and closed wounds. New topical and locally injected medications as well as new bandaging materials have been evaluated. The use of omental flaps to enhance wound healing has been found to be promising. Ultrasonography has been found useful in assessing wound tissues to guide treatment. Because tension is a major factor in dealing with wound closure, skin expanders, skin stretchers, presutures and adjustable horizontal mattress sutures have been described as means of overcoming tension. Recently completed research projects at the Scott-Ritchey Research Center studied the woundhealing effects of fibrin sealants, topical bovine collagen, omega-3 fatty acid-enriched diets and magnetic field therapy. Projects underway are evaluating the healing effects of a new biological tissue adhesive, a macrophage stimulant and a thromboxane synthestase inhibitor. Parameters for evaluating wound healing have included histopathology, tensiometry, planimetry, laser Doppler image scanning, biochemistry and immunohistochemistry. Resumen  En los últimos 5 años, algunos de los avances en la curación de heridas en perros y gatos ha incluido el desarrollo de materiales y técnicas utilizados para mejorar la curación tanto de heridas cerradas como abiertas. Se han evaluado nuevas medicaciones tópicas y sistémicas asi como nuevos marteriales de vendaje. El us0 de injertos omentales para estimular la curación de heridas ha mostrado resultados prometedores. La ecografia es un método éutil en la valoración de los tejidos lesionados para guiar el tratamiento. Debido a que la tensión es un factor importante en el caso de cerramiento de heridas, se describen como métodos de evitar la tensión productos como expansores cutáneos, estiradores cutáneos, presuturas y suturas cutáneas horizontales acolchonadas ajustables. Algunos proyectos de investigación recientemente finalizados en el Centro de Investigación Scott-Ritchey estudiaron los efectos sobre la curación de heridas de selladores de fibrina, colágeno tópico bovino, dietas enriquecidas con ácido graso omega-3 y terapia de campo magnético. Otros proyectos en realización están evaluando los efectos curativos de un nuevo adhesivo tisular biológico, un estimulante de macrófagos y un inhibidor de la tromboxano-sintetasa. Los parámetros para evaluar la curación de herida han incluido la histopatología, la tensiometría, la planimetría, el scanner por imágen doppler laser, bioquímica e inmunohistoquímica. [Swaim, S.F. Advances in wound healing in small animal practice: current status and lines of development (Avances en la curcion de heridas en pequeños animales: estado actual y lineas de desarrollo). Veterinary Dermatology 1997; 8: 249-257] Zusammenfassung  In den letzten 5 Jahren wurden Fortschritte in der Wundversorgung bei Hund und Katze unter anderem durch die Entwicklung von Materialien und Techniken erzielt, die zur besseren Heilung von offenen und geschlossenen Wunden verwendet werden. Neue lokale und systemische Medikamente sowie neue Verbandsmaterialien wurden untersucht. Die Verwendung von Omentumlappen zur Verbesserung der Wundheilung scheint vielversprechend zu sein. Ultraschalluntersuchungen waren von Nutzen, um Wundgewebe zu beurteilen und die Behandlung zu lenken. Spannung ist ein wesentlicher Faktor im Wundverschluss, Hautexpander, Hautdehner, vorbereitende Nähte und regulierbare, horizontale Matratzennähte wurden zur Überwindung der Wundspannung beschrieben. Kürzlich fertiggestellte Forschungsprojekte am Scott-Ritchie Research Center erforschten die Effekte von Fibrindichtungsmitteln, lokalem bovinen Kollagen, Futtermitteln mit Omega-3 Fettsäurenzusatz und Magnetfeldtherapie. Gegenwärtige Forschungsprojekte bewerten die Heilungseffekte eines neuen, biologischen Gewebehaftmittels, eines Makrophagenstimulans und eines Thromboxansynthetasehemmers. Parameter zur Bewertung der Wundheilung waren Histopathologie, Tensiometrie, Planimetrie, Laser Doppler, physiologische Chemie und Immunhistochemie. [Swaim, S.F. Advances in wound healing in small animal practice: current status and lines of development (Fortschritte bei der Wundheilung in der Kleintierpraxis: Derzeitiger Stand und Entwicklung). Veterinary Dermatology 1997; 8: 249-257] Résumé  Durant les 5 dernières années, le progrés dans le traitement des plaies chez les chiens et les chats ont inclus le développement de matériaux et de techniques utilisés pour augmenter la cicatrisation des plaies ouvertes et fermées. De nouvelles médications topiques et systémiques ainsi que de nouveaux matériaux de bandages ont étéévalués. L'utilisation de lambeaux d'éplipon s'est révélée prometteuse dans l'amélioration de la cicatrisation des plaies. L'ultrasonographie s'est montrée utile dans le traitement de guidance de l'évaluation des plaies tissulaires. La tension étant un facteur major lors de la fermeture de plaies, expansseurs cutanés, étireurs cutanés et surjets de matelassier ajustables ont tous été décrits comme moyens permettant de vaincre la tension. Récemment des projets de recherche achevés au Scott-Ritchey Research Center ont étudiés les effets des joints de fibrine, du collagène bovin topique, des régimes enrichis en acides gras omega-3 et de la thérapies de champs magnétiques sur la cicatrisation des plaies. Les projets mis en route sont l'évaluation des effets sur la cicatrisation d'un nouvel adhésif tissulaire biologique, d'un stimulant de macrophages et d'un nouvel inhibiteur de la thromboxane synthase. Les paramètres intervenant dans l'évaluation de la cicatrisation des plaies ont inclus l'histopathologie, la tensiométrie, la planimétrie, le laser Doppler, l'imagerie, la biochimie et l'immunohistochimie. [Swaim, S.F. Advances in wound healing in small animal practice: current status and lines of development (Progres de la cicatrisation en pratique des petits animaux: etat actuel et lignes de developpement). Veterinary Dermatology 1997; 8: 249-257].