Sex and hormonal status influence the anxiolytic-like effect of oxytocin in mice.

Anxiety and depression are highly prevalent psychiatric disorders, affecting approximately 18% of the United States population. Evidence indicates that central oxytocin mediates social cognition, social bonding, and social anxiety. Although it is well-established that oxytocin ameliorates social deficits, less is known about the therapeutic effects of oxytocin in non-social contexts. We hypothesized that positive effects of oxytocin in social contexts are attributable to intrinsic effects of oxytocin on neural systems that are related to emotion regulation. The present study investigated the effect of intracerebroventricular (ICV) oxytocin administration (i.e., central action) on anxiety- and depression-like behavior in C57Bl/6J mice using non-social tests. Male and female mice received an ICV infusion of vehicle or oxytocin (100, 200, or 500 ng), then were tested in the elevated zero maze (for anxiety-like behavior) and the tail suspension test (for depression-like behavior). Oxytocin dose-dependently increased open zone occupancy and entries in the elevated zero maze and reduced immobility duration in the tail suspension test in both sexes. Oxytocin decreased anxiety and depression-like behavior in male and female mice. The observed effect of oxytocin on anxiolytic-like behavior appeared to be driven by the males. Given the smaller anxiolytic-like effect of oxytocin in the female mice and the established interaction between oxytocin and reproductive hormones (estrogen and progesterone), we also explored whether oxytocin sensitivity in females varies across estrous cycle phases and in ovariectomized females that were or were not supplemented with estrogen or progesterone. Oxytocin reduced anxiety-like behavior in female mice in proestrus/estrus, ovariectomized females (supplemented or not with estrogen or progesterone), but not females in metestrus/diestrus. Additionally, oxytocin reduced depression-like behavior in all groups tested with slight differences across the various hormonal statuses. These results suggest that the effect of oxytocin in depression- and anxiety-like behavior in mice can be influenced by sex and hormonal status.

Changing Faces: Factors Associated with the Intention to Pursue Plastic Surgery and Practice in Underserved Areas.

Improving the number of plastic and reconstructive surgeons who provide care to patients in underserved communities is critical to achieving health equity. We aimed to identify factors associated with graduating medical students' intentions to pursue plastic surgery and practice in underserved areas. Methods: De-identified data for US medical school graduates were obtained from the Association of American Medical Colleges for students who matriculated in academic years 2007-2008 and 2011-2012. Data collected included self-reported demographic and future practice intentions. Multivariate analysis was conducted to determine indicators of students' interest in plastic surgery, and their intention to practice in underserved areas. Results: Of the 57,307 graduating US medical students in our cohort who completed the Graduation Questionnaire, 532 (0.9%) reported an intention to pursue plastic surgery. Hispanic [adjusted odds ratio (aOR): 1.45; 95% confidence interval (95% CI), 1.07-1.98] and multiracial (aOR: 1.59; 95% CI, 1.03-2.45) students were more likely to pursue plastic surgery compared with other surgical specialties. Among students interested in plastic surgery, compared with non-Hispanic White students, Black (aOR: 6.15; 95% CI, 1.96-19.26) students were more likely to report intention to practice in underserved areas. Students with community-engagement experiences were more likely to report intention to practice in underserved areas. Conclusions: Diversity among medical trainees pursuing plastic and reconstructive surgery is critical for maintaining and expanding plastic surgery services rendered in underserved areas. These findings suggest that student demographics and experiences with community-engagement experiences are positive indicators of practicing in underserved communities.

Plastome phylogenomics reveals an early Pliocene North- and Central America colonization by long-distance dispersal from South America of a highly diverse bromeliad lineage.

Understanding the spatial and temporal frameworks of species diversification is fundamental in evolutionary biology. Assessing the geographic origin and dispersal history of highly diverse lineages of rapid diversification can be hindered by the lack of appropriately sampled, resolved, and strongly supported phylogenetic contexts. The use of currently available cost-efficient sequencing strategies allows for the generation of a substantial amount of sequence data for dense taxonomic samplings, which together with well-curated geographic information and biogeographic models allow us to formally test the mode and tempo of dispersal events occurring in quick succession. Here, we assess the spatial and temporal frameworks for the origin and dispersal history of the expanded clade K, a highly diverse Tillandsia subgenus Tillandsia (Bromeliaceae, Poales) lineage hypothesized to have undergone a rapid radiation across the Neotropics. We assembled full plastomes from Hyb-Seq data for a dense taxon sampling of the expanded clade K plus a careful selection of outgroup species and used them to estimate a time- calibrated phylogenetic framework. This dated phylogenetic hypothesis was then used to perform biogeographic model tests and ancestral area reconstructions based on a comprehensive compilation of geographic information. The expanded clade K colonized North and Central America, specifically the Mexican transition zone and the Mesoamerican dominion, by long-distance dispersal from South America at least 4.86 Mya, when most of the Mexican highlands were already formed. Several dispersal events occurred subsequently northward to the southern Nearctic region, eastward to the Caribbean, and southward to the Pacific dominion during the last 2.8 Mya, a period characterized by pronounced climate fluctuations, derived from glacial-interglacial climate oscillations, and substantial volcanic activity, mainly in the Trans-Mexican Volcanic Belt. Our taxon sampling design allowed us to calibrate for the first time several nodes, not only within the expanded clade K focal group but also in other Tillandsioideae lineages. We expect that this dated phylogenetic framework will facilitate future macroevolutionary studies and provide reference age estimates to perform secondary calibrations for other Tillandsioideae lineages.

New detection method of SARS-CoV-2 antibodies toward a point-of-care biosensor.

The outbreak of COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is regarded as the most severe of the documented coronavirus pandemics. The measurement and monitoring of SARS-CoV-2 antibody levels by serological tests are relevant for a better epidemiological and clinical understanding of COVID-19. The aim of this work was to design a method called the SARS-CoV-2 antibody detection method (SARS-CoV-2 AbDM) for fluorescence immunodetection of anti-SARS-CoV-2 IgG and IgM on both plate and microfluidic chip. For this purpose, a system with magnetic beads that immobilize the antigen (S protein and RBD) on its surface was used to determine the presence and quantity of antibodies in a sample in a single reaction. The SARS-CoV-2 AbDM led to several advantages in the performance of the tests, such as reduced cost, possibility of performing isolated or multiple samples, potential of multiplex detection, and capacity to detect whole blood samples without losing resolution. In addition, due to the microfluidic chip in conjunction with the motorized actuated platform, the time, sample quantity, and operator intervention during the process were reduced. All these advantages suggest that the SARS-CoV-2 AbDM has the potential to be developed as a PoC that can be used as a tool for seroprevalence monitoring, allowing a better understanding of the epidemiological and clinical characteristics of COVID-19 and contributing to more effective and ethical decision-making in strategies to fight against the COVID-19 pandemic.

Lupus enteritis: A 10-year experience in a single Latin American center.

OBJECTIVE: The objective is to compare the clinical and laboratory characteristics of systemic lupus erythematosus (SLE) patients with and without lupus enteritis (LE) and to identify the factors associated with the occurrence of LE. METHODS: We performed a retrospective, case-control study in hospitalized patients with SLE who were admitted to our tertiary hospital between January 2012 and December 2021. Sixteen LE patients (cases) were matched (1:3 ratio) for sex and birth year with 48 non-LE patients (controls). Univariable and multivariable logistic regression analyses were used to identify the variables associated with LE. RESULTS: Of 2,479 SLE patients who were admitted to our hospital as inpatients, 16 (0.65%) were diagnosed as having LE. All patients, cases and controls, were of Mestizo ethnicity. SLE was diagnosed simultaneously with the first episode of LE in 10 (62.5%) patients. The median time from SLE diagnosis to the first episode of LE was 7 (IQR 0-78) months. LE patients had a shorter median disease duration [7 (0-78) vs 34 (9.5-79) months], and a significantly longer hospital stay (28.3 ± 15.8 vs 6.5 ± 7.9 days, p < 0.001) than non-LE patients. Most LE patients (93.8%) had concomitant lupus nephritis. LE patients had higher SLEDAI-2K scores than those without LE (20.5 ± 9.4 vs 9.8 ± 10.4, p < 0.001). By multivariable analysis, a higher SLEDAI-2K score (OR 1.10, 95% CI 1.02-1.18; p = 0.015) was independently associated with LE occurrence after adjusting for cutaneous involvement, lymphocyte count, serum creatinine, and serum complement C4. Recurrence was observed in two patients (12.5%), both with a bowel wall thickening > 8 mm. The two patients with large intestine-dominant LE developed intestinal pseudo-obstruction. No patient had life-threatening complications (intestinal hemorrhage, infarction, or perforation), and there were no deaths induced directly by LE itself. CONCLUSION: In patients of Mestizo ethnicity, LE occurs during the early course of SLE, frequently is one of the presenting manifestations of SLE, and in most cases, it presents with concomitant lupus nephritis. Higher levels of disease activity at diagnosis were independently associated with LE occurrence and when recurrences occur, they do so in the context of severe wall thickness.

The Rise and Rise of Lupus.

Despite how difficult the early diagnosis of systemic lupus erythematosus (SLE) is, which is mainly due to the heterogeneity and non-specificity of its clinical manifestations, SLE is currently being diagnosed more frequently than in past decades. In fact, there has been an increase in the incidence and prevalence of SLE over the last four decades; this can be explained by a number of reasons including a better knowledge of the pathogenesis of the disease which allows its earlier diagnosis, the rising ethnic and racial diversity of the world population, the use of the 2019 EULAR/ACR criteria that allows classifying patients earlier, and improvements in survival over the last decades, which results in an increase in the prevalent cases of SLE. In this article, we will also review the genetic, environmental, and lifestyle factors, that are reported to increase the risk of developing SLE and how preventive strategies through a clinical care pathway may prevent or delay the development of SLE and improve these patients' outcomes.

Isolation by resistance explains genetic diversity in the Arremon brushfinches of northern Mesoamerica.

Genetic differentiation between and within natural populations is the result of the joint effects of neutral and adaptative processes. In addition, the spatial arrangement of the landscape promotes connectivity or creates barriers to gene flow, directly affecting speciation processes. In this study, we carried out a landscape genomics analysis using NextRAD data from a montane forest specialist bird complex, the Mesoamerican Chestnut-capped/Green-striped Brushfinch of the genus Arremon. Specifically, we examined population genomic structure using different assignment methods and genomic differentiation and diversity, and we tested alternative genetic isolation hypotheses at the individual level (e.g., isolation by barrier, IBB; isolation by environment, IBE; isolation by resistance, IBR). We found well-delimited genomic structuring (K = 5) across Mesoamerican montane forests in the studied group. Individual-level genetic distances among major montane ranges were mainly explained by IBR hypotheses in this sedentary Neotropical taxon. Our results uncover genetic distances/differentiation and patterns of gene flow in allopatric species that support the role of tropical mountains as spatial landscape drivers of biodiversity. IBR clearly supports a pattern of conserved niche-tracking of suitable habitat conditions and topographic complexity throughout glacial-interglacial dynamics.

Relevance of non-criteria antiphospholipid antibodies titers among patients with antiphospholipid syndrome and patients with systemic lupus erythematosus.

BACKGROUND: There is an increasing interest in the study of non-criteria antiphospholipid antibodies (aPL) including antibodies targeting domain 1 of the B2 glycoprotein 1 (anti-D1 B2GP1) and antibodies anti phosphatidylserine/ prothrombin (PS/PT). OBJECTIVES: Our aim was to analyze a panel of conventional and non-criteria aPL in a cohort of patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS), to describe if there are differences in aPL titers among groups, to evaluate clinical associations including risk of recurrent events of novel aPL. METHODS: Observational study that evaluated at baseline antibodies against anti-D1 B2GP1 and anti PS/PT. Anti-D1 B2GP1 antibodies were tested using a chemiluminescent immunoassay. IgG and IgM anti PS/PT, aCL and anti B2GP1 by ELISA techniques. Therefore, patients were followed in order to identify new thrombotic events. RESULTS: 133 patients with SLE and 23 with primary APS patients were included. Main APS manifestations were DVT (27%), obstetric morbidity (22%) and arterial thrombosis (10.1%). IgM anti PS/PT antibodies levels were (20.6 - 127) vs 21.9 (11.2 - 39.2) U/ml, p<0.001 in primary APS vs SLE with APS, respectively. Anti-D1 B2GP1, IgG and IgM anti PS/PT were associated with thrombotic and non-thrombotic manifestations. During follow-up, IgG B2GP1 were related with a significant cumulative risk of thrombosis. CONCLUSIONS: We found significant differences in serum titers of non-criteria aPL among patients with primary APS vs SLE with APS. Whether non-criteria aPL antibodies titers are useful to differentiate patients with primary and secondary APS requires further analysis in other populations.

Importancia de los títulos de anticuerpos antifosfolípidos no criterio entre pacientes con síndrome antifosfolípido primario y pacientes con lupus eritematoso sistémico / Relevance of non-criteria antiphospholipid antibodies titers among patients with antiphospholipid syndrome and patients with systemic lupus erythematosus

Antecedentes: Hay un interés creciente en el estudio de los anticuerpos antifosfolípidos (aPL) no criterio, incluyendo anticuerpos contra el dominio 1 de la B2 glicoproteína 1 (anti-D1 B2GP1) y anticuerpos antifosfatidilserina/protrombina (PS/PT). Objetivos: Nuestro objetivo fue analizar un panel de aPL convencionales y no criterio en una cohorte de pacientes con lupus eritematoso sistémico (LES) y síndrome antifosfolípido primario (SAF), para describir si hay diferencias en los títulos de aPL entre los grupos, y evaluar asociaciones clínicas incluyendo el riesgo de eventos recurrentes con aPL novedosos. Metodología: Estudio observacional que evaluó los anticuerpos anti-D1 B2GP1 y anti-PS/PT de manera basal. Los anticuerpos anti-D1 B2GP1 se evaluaron a través de inmunoanálisis por quimioluminiscencia. Los anticuerpos anti-PS/PT, anticardiolipinas (aCL) y anti-B2GP1 fueron evaluados por técnicas de ELISA. Finalmente, los pacientes fueron seguidos en el tiempo para identificar nuevos eventos trombóticos. Resultados: Se incluyeron 133 pacientes con LES y 23 pacientes con SAF primario. Las principales manifestaciones de SAF fueron TVP (27%), morbilidad obstétrica (22%) y trombosis arterial (10,1%). Los títulos de anticuerpos anti-PS/PT IgM fueron 46,5 (20,6-127) vs. 21,9 (11,2-39,2) U/ml, p<0,001, en pacientes con SAF primario vs. LES con SAF secundario, respectivamente. Los anti-D1 B2GP1, anti-PS/PT IgG e IgM se asociaron con manifestaciones trombóticas y no trombóticas. Durante el seguimiento, los anticuerpos IgG B2GP1 se relacionaron con un riesgo acumulativo significativo de trombosis. Conclusiones: Se encontraron diferencias estadísticamente significativas en títulos séricos de aPL no criterio en pacientes con SAF primario vs. pacientes con LES y SAF secundario. Si los títulos de aPL no criterio son útiles para diferenciar entre SAF primario y SAF secundario, se requieren más análisis en otras poblaciones para poder confirmar si los títulos de aPL no criterio.

Background: There is an increasing interest in the study of non-criteria antiphospholipid antibodies (aPL) including antibodies targeting domain 1 of the B2 glycoprotein 1 (anti-D1 B2GP1) and antibodies anti phosphatidylserine/ prothrombin (PS/PT). Objectives: Our aim was to analyze a panel of conventional and non-criteria aPL in a cohort of patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS), to describe if there are differences in aPL titers among groups, to evaluate clinical associations including risk of recurrent events of novel aPL. Methods: Observational study that evaluated at baseline antibodies against anti-D1 B2GP1 and anti PS/PT. Anti-D1 B2GP1 antibodies were tested using a chemiluminescent immunoassay. IgG and IgM anti PS/PT, aCL and anti B2GP1 by ELISA techniques. Therefore, patients were followed in order to identify new thrombotic events. Results: 133 patients with SLE and 23 with primary APS patients were included. Main APS manifestations were DVT (27%), obstetric morbidity (22%) and arterial thrombosis (10.1%). IgM anti PS/PT antibodies levels were (20.6 - 127) vs 21.9 (11.2 - 39.2) U/ml, p<0.001 in primary APS vs SLE with APS, respectively. Anti-D1 B2GP1, IgG and IgM anti PS/PT were associated with thrombotic and non-thrombotic manifestations. During follow-up, IgG B2GP1 were related with a significant cumulative risk of thrombosis. Conclusions: We found significant differences in serum titers of non-criteria aPL among patients with primary APS vs SLE with APS. Whether non-criteria aPL antibodies titers are useful to differentiate patients with primary and secondary APS requires further analysis in other populations.(AU)

Overproduce and select, or determine optimal molecular descriptor subset via configuration space optimization? Application to the prediction of ecotoxicological endpoints.

Predicting the likely biological activity (or property) of compounds is a fundamental and challenging task in the drug discovery process. Current computational methodologies aim to improve their predictive accuracies by using deep learning (DL) approaches. However, non-DL based approaches for small- and medium-sized chemical datasets have demonstrated to be most suitable for. In this approach, an initial universe of molecular descriptors (MDs) is first calculated, then different feature selection algorithms are applied, and finally, one or several predictive models are built. Herein we demonstrate that this traditional approach may miss relevant information by assuming that the initial universe of MDs codifies all relevant aspects for the respective learning task. We argue that this limitation is mainly because of the constrained intervals of the parameters used in the algorithms that compute MDs, parameters that define the Descriptor Configuration Space (DCS). We propose to relax these constraints in an open CDS approach, so that a larger universe of MDs can be initially considered. We model the generation of MDs as a multicriteria optimization problem and tackle it with a variant of the standard genetic algorithm. As a novel component, the fitness function is computed by aggregating four criteria via the Choquet integral. Experimental results show that the proposed approach generates a meaningful DCS by improving state-of-the-art approaches in most of the benchmarking chemical datasets accounted for.

Embedded-AMP: A Multi-Thread Computational Method for the Systematic Identification of Antimicrobial Peptides Embedded in Proteome Sequences.

Antimicrobial peptides (AMPs) have gained the attention of the research community for being an alternative to conventional antimicrobials to fight antibiotic resistance and for displaying other pharmacologically relevant activities, such as cell penetration, autophagy induction, immunomodulation, among others. The identification of AMPs had been accomplished by combining computational and experimental approaches and have been mostly restricted to self-contained peptides despite accumulated evidence indicating AMPs may be found embedded within proteins, the functions of which are not necessarily associated with antimicrobials. To address this limitation, we propose a machine-learning (ML)-based pipeline to identify AMPs that are embedded in proteomes. Our method performs an in-silico digestion of every protein in the proteome to generate unique k-mers of different lengths, computes a set of molecular descriptors for each k-mer, and performs an antimicrobial activity prediction. To show the efficiency of the method we used the shrimp proteome, and the pipeline analyzed all k-mers between 10 and 60 amino acids in length to predict all AMPs in less than 20 min. As an application example we predicted AMPs in different rodents (common cuy, common rat, and naked mole rat) with different reported longevities and found a relation between species longevity and the number of predicted AMPs. The analysis shows as the longevity of the species is higher, the number of predicted AMPs is also higher. The pipeline is available as a web service.

Primary and secondary focal choroidal excavation morphologic phenotypes, associated ocular disorders and prognostic implications.

AIMS: To characterise and classify the morphological, clinical and tomographic characteristics of focal choroidal excavation (FCE) lesions to determine their prognostic implications. METHODS: 36 eyes with FCE (32 patients) underwent multimodal imaging, including spectral domain optical coherence tomography and fundus autofluorescence. FCE lesions were classified into three subtypes: (1) type 1: myopic (central choroidal thickness: <100 µm), (2) type 2: suspected congenital (central choroidal thickness: 100-200 µm, without associated chorioretinal pathology) and (3) type 3: secondary or acquired (central choroidal thickness: >200 µm, with associated chorioretinal pathology). RESULTS: 80.6% of eyes were followed longitudinally (26.8±18.8 months). There were 9 type 1 FCEs (myopic), 8 type 2 FCEs (U-shaped, congenital) and 19 type 3 FCEs (V-shaped, secondary). Type 2 FCEs trended towards larger maximum widths (p=0.0563). Type 3 FCEs were associated with central serous chorioretinopathy or pachyvessels (47.4%), but were also seen in pattern dystrophy, geographic atrophy, inactive choroiditis, torpedo maculopathy and adult-onset vitelliform dystrophy. Choroidal neovascular membranes (CNVMs) were more prevalent in type 3 FCE (41.2% compared with 11.1% for type 1 FCE, p=0.251, and 0% for type 2 FCE, p=0.043). CONCLUSIONS: The FCE types, stratified by central choroidal thickness, demonstrated distinct morphological characteristics and associated findings. The classification scheme held prognostic implications as type 3 FCE with V shapes were associated with other chorioretinal conditions and were more likely to develop CNVM.

Incidence and visual outcomes of acute endophthalmitis post intravitreal injection of anti-vascular endothelial growth factors in a single referral center.

BACKGROUND: To describe the incidence and factors predicting visual outcome in patients with infectious endophthalmitis following intravitreal anti-VEGF injection. METHODS: Retrospective, single-site, cohort study. Patients with acute endophthalmitis within 6 weeks of intravitreal anti-VEGF injection who were referred to our practice after inciting injection or were injected by us between January 2010 and July 2017 were included. All patients received intravitreal antibiotics with either vitreous/anterior chamber tap (TAP) or pars plana vitrectomy. Visual outcomes pre/post treatment, baseline variables (age, gender, ocular disease) and cultures results were studied. RESULTS: Seventy eyes of 69 patients were included. Presenting VA was the strongest factor associated with final visual outcome after adjusting for other variables including culture status and baseline VA (p = .0002). Cultures were positive in 62.8% of eyes and were associated with worse visual outcome (p = .0087). Growth of Streptococcus or microorganisms other than coagulase negative Staphylococci (CNS) was also associated with worse prognosis, regardless of baseline and presenting VA (p = .0002). The crude incidence of post-injection endophthalmitis was 0.028% in our practice (40 eyes in 143,628 injections) during the study time. No significant difference was found between pre-filled bevacizumab versus ranibizumab or aflibercept drawn from a vial. CONCLUSIONS: In a large, single center, retrospective study, the incidence of acute endophthalmitis post anti-VEGF injection was relatively low. Worse visual acuity at presentation of endophthalmitis and growth of Streptococcus or organisms other than CNS were associated with the worst visual outcomes.

Handcrafted versus non-handcrafted (self-supervised) features for the classification of antimicrobial peptides: complementary or redundant?

Antimicrobial peptides (AMPs) have received a great deal of attention given their potential to become a plausible option to fight multi-drug resistant bacteria as well as other pathogens. Quantitative sequence-activity models (QSAMs) have been helpful to discover new AMPs because they allow to explore a large universe of peptide sequences and help reduce the number of wet lab experiments. A main aspect in the building of QSAMs based on shallow learning is to determine an optimal set of protein descriptors (features) required to discriminate between sequences with different antimicrobial activities. These features are generally handcrafted from peptide sequence datasets that are labeled with specific antimicrobial activities. However, recent developments have shown that unsupervised approaches can be used to determine features that outperform human-engineered (handcrafted) features. Thus, knowing which of these two approaches contribute to a better classification of AMPs, it is a fundamental question in order to design more accurate models. Here, we present a systematic and rigorous study to compare both types of features. Experimental outcomes show that non-handcrafted features lead to achieve better performances than handcrafted features. However, the experiments also prove that an improvement in performance is achieved when both types of features are merged. A relevance analysis reveals that non-handcrafted features have higher information content than handcrafted features, while an interaction-based importance analysis reveals that handcrafted features are more important. These findings suggest that there is complementarity between both types of features. Comparisons regarding state-of-the-art deep models show that shallow models yield better performances both when fed with non-handcrafted features alone and when fed with non-handcrafted and handcrafted features together.

Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies.

Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a sweet solution without alcohol, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity score-matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD.

Effect of the variation in the extracellular concentration of l-arginine in the physiology of Leishmania (Viannia) braziliensis and its susceptibility to some antileishmanial drugs.

The knowledge about amino acid metabolism in trypanosomatids is a valuable source of new therapeutic targets. l-arginine is an essential amino acid for Leishmania parasites, and it participates in the synthesis of polyamines, a group of essential nutrients used for nucleic acids, proteins biosynthesis, and redox modulation necessary for proliferation. In the present study, we evaluated the effect of changes in the availability of this amino acid on promastigotes and intracellular amastigotes on U937 macrophages and showed that the absence of l-arginine in culture medium negatively influences the growth and infectivity of Leishmania (Viannia) braziliensis, causing a decrease in the percentage of the infected cells and parasite load tested through light microscopy. In addition, the absence of l-arginine resulted in the parasite's inability to regulate its reactive oxygen species (ROS) production, which persisted for up to 24 h by flow cytometry following the probe H2DCF-DA dye. Moreover, the differentiation of promastigote to amastigote in axenic culture was more significant at low concentrations of l-arginine suggesting that this depletion induces a stress environment to increase this transformation under axenic conditions. No association was established between the availability of l-arginine and the effectiveness of antileishmanial drugs. All these results confirm the importance of l-arginine in L. braziliensis life cycle vital processes, such as its replication and infectivity, as documented in other Leishmania species. Based on these results, we proposed that the l-arginine uptake/metabolism route is possible in exploring new antileishmanial drugs.

Genetic Diversity and Population Structure of Jubaea chilensis, an Endemic and Monotype Gender from Chile, Based on SNP Markers.

Jubaea chilensis (Molina) Baill., also named Chilean palm, is an endemic species found in the coastal area of Mediterranean sclerophyllous forest in Chile. It has a highly restricted and fragmented distribution along the coast, being under intense exploitation and anthropogenic impact. Based on 1038 SNP markers, we evaluated the genetic diversity and population structure among six J. chilensis natural groups encompassing 96% of the species distribution. We observed low levels of genetic diversity, a deficit of heterozygotes (mean HE = 0.024; HO = 0.014), and high levels of inbreeding (mean FIS = 0.424). The fixation index (FST) and Nei's genetic distance pairwise comparisons indicated low to moderate structuring among populations. There was no evidence of isolation by distance (r = -0.214, p = 0.799). In the cluster analysis, we observed a closer relationship among Culimo, Cocalán, and Candelaria populations. Migration rates among populations were low, except for some populations with moderate values. The K value that best represented the spatial distribution of genetic diversity was ∆K = 3. Habitat fragmentation, deterioration of the sclerophyllous forest, lack of long-distance dispersers, and a natural regeneration deficit may have driven inbreeding and low levels of genetic diversity in the palm groves of J. chilensis. Although extant populations are not at imminent risk of extinction, the rate of inbreeding could increase and migration could decrease if the effects of climate change and human impact become more acute.

Addressing health disparities as a function of ethnicity in systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) is an autoimmune disorder with significant health disparities, as it disproportionately and more severely affects vulnerable and disadvantaged population groups in the United States and around the world, that is, women, ethnic minorities, individuals living in poverty, less educated, and lacking medical insurance. Both, genetic and non-genetic factors, contribute to these disparities. To overcome these health disparities and reduce poor outcomes among disadvantaged SLE populations, interventions on non-genetic amendable factors, especially on social health determinants, are necessary.

Do deep learning models make a difference in the identification of antimicrobial peptides?

In the last few decades, antimicrobial peptides (AMPs) have been explored as an alternative to classical antibiotics, which in turn motivated the development of machine learning models to predict antimicrobial activities in peptides. The first generation of these predictors was filled with what is now known as shallow learning-based models. These models require the computation and selection of molecular descriptors to characterize each peptide sequence and train the models. The second generation, known as deep learning-based models, which no longer requires the explicit computation and selection of those descriptors, started to be used in the prediction task of AMPs just four years ago. The superior performance claimed by deep models regarding shallow models has created a prevalent inertia to using deep learning to identify AMPs. However, methodological flaws and/or modeling biases in the building of deep models do not support such superiority. Here, we analyze the main pitfalls that led to establish biased conclusions on the leading performance of deep models. Also, we analyze whether deep models truly contribute to achieve better predictions than shallow models by performing fair studies on different state-of-the-art benchmarking datasets. The experiments reveal that deep models do not outperform shallow models in the classification of AMPs, and that both types of models codify similar chemical information since their predictions are highly similar. Thus, according to the currently available datasets, we conclude that the use of deep learning could not be the most suitable approach to develop models to identify AMPs, mainly because shallow models achieve comparable-to-superior performances and are simpler (Ockham's razor principle). Even so, we suggest the use of deep learning only when its capabilities lead to obtaining significantly better performance gains worth the additional computational cost.

Transcriptomic analysis of patients with clinical suspicion of maturity-onset diabetes of the young (MODY) with a negative genetic diagnosis.

BACKGROUND: Diagnosis of mature-onset diabetes of the young (MODY), a non-autoimmune monogenic form of diabetes mellitus, is confirmed by genetic testing. However, a positive genetic diagnosis is achieved in only around 50% of patients with clinical characteristics of this disease. RESULTS: We evaluated the diagnostic utility of transcriptomic analysis in patients with clinical suspicion of MODY but a negative genetic diagnosis. Using Nanostring nCounter technology, we conducted transcriptomic analysis of 19 MODY-associated genes in peripheral blood samples from 19 patients and 8 healthy controls. Normalized gene expression was compared between patients and controls and correlated with each patient's biochemical and clinical variables. Z-scores were calculated to identify significant changes in gene expression in patients versus controls. Only 7 of the genes analyzed were detected in peripheral blood. HADH expression was significantly lower in patients versus controls. Among patients with suspected MODY, GLIS3 expression was higher in obese versus normal-weight patients, and in patients aged < 25 versus > 25 years at diabetes onset. Significant alteration with respect to controls of any gene was observed in 57.9% of patients. CONCLUSIONS: Although blood does not seem to be a suitable sample for transcriptomic analysis of patients with suspected MODY, in our study, we detected expression alterations in some of the genes studied in almost 58% of patients. That opens the door for future studies that can clarify the molecular cause of the clinic of these patients and thus be able to maintain a more specific follow-up and treatment in each case.