A nonadaptive explanation for macroevolutionary patterns in the evolution of complex multicellularity.

"Complex multicellularity," conventionally defined as large organisms with many specialized cell types, has evolved five times independently in eukaryotes, but never within prokaryotes. A number of hypotheses have been proposed to explain this phenomenon, most of which posit that eukaryotes evolved key traits (e.g., dynamic cytoskeletons, alternative mechanisms of gene regulation, or subcellular compartments) which were a necessary prerequisite for the evolution of complex multicellularity. Here, we propose an alternative, nonadaptive hypothesis for this broad macroevolutionary pattern. By binning cells into groups with finite genetic bottlenecks between generations, the evolution of multicellularity greatly reduces the effective population size (Ne) of cellular populations, increasing the role of genetic drift in evolutionary change. While both prokaryotes and eukaryotes experience this phenomenon, they have opposite responses to drift: eukaryotes tend to undergo genomic expansion, providing additional raw genetic material for subsequent multicellular innovation, while prokaryotes generally face genomic erosion. Taken together, we hypothesize that these idiosyncratic lineage-specific evolutionary dynamics play a fundamental role in the long-term divergent evolution of complex multicellularity across the tree of life.

Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Breaking down silos: The Gastroenterology Immunology Neuroscience (GIN) Discovery Program - a new model for research.

The Gastroenterology Immunology Neuroscience (GIN) Discovery Program represents a new model for research that overcomes the limitations imposed by traditional "research silos" in science. By uniting these three fields, the GIN Program aims to enhance the understanding and treatment of chronic conditions through a system-wide perspective focusing on the gut-immune-brain axis. Key initiatives include monthly interdisciplinary seminars, an annual symposium, and GINnovate, a commercialization and entrepreneurship event. Additionally, the program offers a seed grant competition for early and mid-career researchers, promoting advancements in gut-immune-brain axis research through the power of collaboration. The GIN Program in a short period of time has facilitated the formation of a vibrant community, captivating attention from both national and international institutions. This effort to break down barriers in research aims to inspire similar models that prioritize open communication, mutual respect and a commitment to impactful science.

Comparison of Digitally Delivered Gut-Directed Hypnotherapy Program With an Active Control for Irritable Bowel Syndrome.

INTRODUCTION: Gut-directed hypnotherapy (GDH) treats irritable bowel syndrome (IBS), but its accessibility is limited. This problem may be overcome by digital delivery. The aim of this study was to perform a randomized control trial comparing the efficacy of a digitally delivered program with and without GDH in IBS. METHODS: Adults with IBS were randomized to a 42-session daily digital program with the GDH Program (Nerva) or without (Active Control). Questionnaires were completed to assess gastrointestinal symptoms through IBS Symptom Severity Scale (IBS-SSS), quality of life, and psychological symptoms (Depression Anxiety and Stress Scale-21) at regular intervals during the program and 6 months following the conclusion on the intervention. The primary end point was the proportion of participants with ≥50-point decrease in IBS-SSS between the interventions at the end of the program. RESULTS: Of 240/244 randomized participants, 121 received GDH Program-the median age 38 (range 20-65) years, 90% female, IBS-SSS 321 (interquartile range 273-367)-and 119 Active Control-36 (21-65), 91% female, IBS-SSS 303 (255-360). At program completion, 81% met the primary end point with GDH Program vs 63% Active Control ( P = 0.002). IBS-SSS was median 208 (interquartile range 154-265) with GDH and 244 (190-308) with control ( P = 0.004), 30% reduction in pain was reported by 71% compared with 35% ( P < 0.001), and IBS quality of life improved by 14 (6-25) compared with 7 (1-15), respectively ( P < 0.001). Psychological status improved similarly in both groups. DISCUSSION: A digitally delivered GDH Program provided to patients with IBS was superior to the active control, with greater improvement in both gastrointestinal symptoms and quality of life and provides an equitable alternative to face-to-face behavioral strategies.

Challenges in reliable preoperative blood ordering: A qualitative interview study.

BACKGROUND: Presurgical blood orders are important for patient safety during surgery, but excess orders can be costly to patients and the healthcare system. We aimed to assess clinician perceptions on the presurgical blood ordering process and perceived barriers to reliable decision-making. METHODS: This descriptive qualitative study was conducted at a single large academic medical center. Semi-structured interviews were conducted with surgeons, anesthesiologists, nurse anesthetists, nurse practitioners working in preoperative assessment clinics, and transfusion medicine physicians to assess perceptions of current blood ordering processes. Interview responses were analyzed using an inductive open coding approach followed by thematic analysis. RESULTS: Twenty-three clinicians were interviewed. Clinicians felt that the current blood ordering process was frequently inconsistent. One contributor was a lack of information on surgical transfusion risk, related to lack of experience in ordering clinicians, insufficient communication between stakeholders, high turnover in academic settings, and lack of awareness of the maximum surgical blood ordering schedule. Other contributors included differing opinions about the benefits and harms of over- and under-preparing blood products, leading to variation in transfusion risk thresholds between clinicians, and disagreement about the safety of emergency-release blood. CONCLUSION: Several barriers to reliable decision-making for presurgical blood orders exist. Future efforts to improve ordering consistency may benefit from improved information sharing between stakeholders and education on safe transfusion practices.

Global prevalence of anemia among women of reproductive age, 2000-2019.

A common disease with significant impacts on health and quality of life, anemia is particularly prevalent in women of reproductive age due to blood losses during menstruation and pregnancy. Data from the World Health Organization (WHO) was analyzed to compare trends in prevalence of anemia in women aged 15-49 among countries and over time with the goal of identifying regions both successful and in need of assistance in combatting anemia. Worldwide from 2000 to 2013 the prevalence of anemia among women aged 15-49 decreased, and then increased from 2013 to 2019; severe anemia decreased throughout the world from 2000 to 2019. Throughout all years, African countries had the highest prevalence of anemia and severe anemia while American and European countries had the lowest. With each decrease in human development index (HDI) category (very high to high, etc.) there was a significant increase in prevalence of total anemia (P < 0.001 for all). This data suggests that although the prevalence of anemia among reproductive age women has decreased over time there is still much work remaining, particularly in low HDI countries. More effort is needed in preventing, recognizing and treating anemia.

Gratitude, optimism, and satisfaction with life and patient-reported outcomes in patients undergoing hematopoietic stem cell transplantation.

OBJECTIVE: Associations between positive psychological well-being (PPWB) and patient-reported outcomes (PROs, e.g., quality of life [QOL]) have yet to be studied extensively in patients with hematologic malignancies who are allogeneic hematopoietic stem cell transplant (HSCT) survivors, despite substantial evidence that PPWB impacts PROs of other medical populations. METHODS: We conducted a secondary analysis of cross-sectional data examining the association of PPWB and PROs at day 100 post-transplant among 158 allogeneic HSCT recipients. Optimism, gratitude, life satisfaction, and PROs (i.e., QOL, anxiety, depression, and PTSD symptoms) were assessed using the Life Orientation Test-Revised, Gratitude Questionnaire, Satisfaction with Life Scale, Functional Assessment of Cancer Therapy-Bone Marrow Transplant, Hospital Anxiety and Depression Scale, and Post-Traumatic Stress Disorder (PTSD) Checklist-Civilian Version, respectively. We used linear and multivariate regressions for all analyses and controlled for patient factors. RESULTS: Optimism was associated with better QOL (ß = 1.46; p < 0.001) and lower levels of anxiety (ß = -0.28; p < 0.001), depression (ß = -0.31; p < 0.001), and PTSD (ß = -0.58; p < 0.001). Gratitude was associated with better QOL (ß = 1.11; p < 0.001) and lower levels of anxiety (ß = -0.21; p = 0.001), depression (ß = -0.14; p = 0.021), and PTSD (ß = -0.32; p = 0.032). Finally, satisfaction with life was associated with better QOL (ß = 1.26; p < 0.001) and lower levels of anxiety (ß = -0.18; p < 0.001), depression (ß = -0.21; p < 0.001), and PTSD (ß = -0.49; p < 0.001). CONCLUSION: Optimism, gratitude, and satisfaction with life were all associated with better QOL and lower levels of psychological distress in allogeneic HSCT survivors. These data support studies to harness PPWB as a therapeutic intervention for this population throughout HSCT recovery.

"Dr. AI Will See You Now": How Do ChatGPT-4 Treatment Recommendations Align With Orthopaedic Clinical Practice Guidelines?

BACKGROUND: Artificial intelligence (AI) is engineered to emulate tasks that have historically required human interaction and intellect, including learning, pattern recognition, decision-making, and problem-solving. Although AI models like ChatGPT-4 have demonstrated satisfactory performance on medical licensing exams, suggesting a potential for supporting medical diagnostics and decision-making, no study of which we are aware has evaluated the ability of these tools to make treatment recommendations when given clinical vignettes and representative medical imaging of common orthopaedic conditions. As AI continues to advance, a thorough understanding of its strengths and limitations is necessary to inform safe and helpful integration into medical practice. QUESTIONS/PURPOSES: (1) What is the concordance between ChatGPT-4-generated treatment recommendations for common orthopaedic conditions with both the American Academy of Orthopaedic Surgeons (AAOS) clinical practice guidelines (CPGs) and an orthopaedic attending physician's treatment plan? (2) In what specific areas do the ChatGPT-4-generated treatment recommendations diverge from the AAOS CPGs? METHODS: Ten common orthopaedic conditions with associated AAOS CPGs were identified: carpal tunnel syndrome, distal radius fracture, glenohumeral joint osteoarthritis, rotator cuff injury, clavicle fracture, hip fracture, hip osteoarthritis, knee osteoarthritis, ACL injury, and acute Achilles rupture. For each condition, the medical records of 10 deidentified patients managed at our facility were used to construct clinical vignettes that each had an isolated, single diagnosis with adequate clarity. The vignettes also encompassed a range of diagnostic severity to evaluate more thoroughly adherence to the treatment guidelines outlined by the AAOS. These clinical vignettes were presented alongside representative radiographic imaging. The model was prompted to provide a single treatment plan recommendation. Each treatment plan was compared with established AAOS CPGs and to the treatment plan documented by the attending orthopaedic surgeon treating the specific patient. Vignettes where ChatGPT-4 recommendations diverged from CPGs were reviewed to identify patterns of error and summarized. RESULTS: ChatGPT-4 provided treatment recommendations in accordance with the AAOS CPGs in 90% (90 of 100) of clinical vignettes. Concordance between ChatGPT-generated plans and the plan recommended by the treating orthopaedic attending physician was 78% (78 of 100). One hundred percent (30 of 30) of ChatGPT-4 recommendations for fracture vignettes and hip and knee arthritis vignettes matched with CPG recommendations, whereas the model struggled most with recommendations for carpal tunnel syndrome (3 of 10 instances demonstrated discordance). ChatGPT-4 recommendations diverged from AAOS CPGs for three carpal tunnel syndrome vignettes; two ACL injury, rotator cuff injury, and glenohumeral joint osteoarthritis vignettes; as well as one acute Achilles rupture vignette. In these situations, ChatGPT-4 most often struggled to correctly interpret injury severity and progression, incorporate patient factors (such as lifestyle or comorbidities) into decision-making, and recognize a contraindication to surgery. CONCLUSION: ChatGPT-4 can generate accurate treatment plans aligned with CPGs but can also make mistakes when it is required to integrate multiple patient factors into decision-making and understand disease severity and progression. Physicians must critically assess the full clinical picture when using AI tools to support their decision-making. CLINICAL RELEVANCE: ChatGPT-4 may be used as an on-demand diagnostic companion, but patient-centered decision-making should continue to remain in the hands of the physician.

Pre-Columbian fire management and control of climate-driven floodwaters over 3,500 years in southwestern Amazonia.

In landscapes that support economic and cultural activities, human communities actively manage environments and environmental change at a variety of spatial scales that complicate the effects of continental-scale climate. Here, we demonstrate how hydrological conditions were modified by humans against the backdrop of Holocene climate change in southwestern Amazonia. Paleoecological investigations (phytoliths, charcoal, pollen, diatoms) of two sediment cores extracted from within the same permanent wetland, ∼22 km apart, show a 1,500-y difference in when the intensification of land use and management occurred, including raised field agriculture, fire regime, and agroforestry. Although rising precipitation is well known during the mid to late Holocene, human actions manipulated climate-driven hydrological changes on the landscape, revealing differing histories of human landscape domestication. Environmental factors are unable to account for local differences without the mediation of human communities that transformed the region to its current savanna/forest/wetland mosaic beginning at least 3,500 y ago. Regional environmental variables did not drive the choices made by farmers and fishers, who shaped these local contexts to better manage resource extraction. The savannas we observe today were created in the post-European period, where their fire regime and structural diversity were shaped by cattle ranching.

MRLocus: Identifying causal genes mediating a trait through Bayesian estimation of allelic heterogeneity.

Expression quantitative trait loci (eQTL) studies are used to understand the regulatory function of non-coding genome-wide association study (GWAS) risk loci, but colocalization alone does not demonstrate a causal relationship of gene expression affecting a trait. Evidence for mediation, that perturbation of gene expression in a given tissue or developmental context will induce a change in the downstream GWAS trait, can be provided by two-sample Mendelian Randomization (MR). Here, we introduce a new statistical method, MRLocus, for Bayesian estimation of the gene-to-trait effect from eQTL and GWAS summary data for loci with evidence of allelic heterogeneity, that is, containing multiple causal variants. MRLocus makes use of a colocalization step applied to each nearly-LD-independent eQTL, followed by an MR analysis step across eQTLs. Additionally, our method involves estimation of the extent of allelic heterogeneity through a dispersion parameter, indicating variable mediation effects from each individual eQTL on the downstream trait. Our method is evaluated against other state-of-the-art methods for estimation of the gene-to-trait mediation effect, using an existing simulation framework. In simulation, MRLocus often has the highest accuracy among competing methods, and in each case provides more accurate estimation of uncertainty as assessed through interval coverage. MRLocus is then applied to five candidate causal genes for mediation of particular GWAS traits, where gene-to-trait effects are concordant with those previously reported. We find that MRLocus's estimation of the causal effect across eQTLs within a locus provides useful information for determining how perturbation of gene expression or individual regulatory elements will affect downstream traits. The MRLocus method is implemented as an R package available at https://mikelove.github.io/mrlocus.

Association between positive affect, flourishing, quality of life, and psychological distress in allogeneic hematopoietic stem cell transplantation.

PURPOSE: To examine the associations between state positive psychological well-being (PPWB) constructs, mood, and quality of life (QOL) in hematopoietic stem cell transplantation (HSCT) survivors. DESIGN: The study was a secondary analysis of cross-sectional data. SAMPLE/METHODS: We analyzed self-report data assessing positive affect, flourishing, QOL, depression and anxiety, and PTSD symptoms from 158 allogeneic HSCT recipients at day-100 post-transplant enrolled in supportive care studies. FINDINGS: Univariate analysis showed that factors associated with greater levels of various state PPWB constructs include older age, disability status, greater social support, and presence of graft-versus-host disease. Multivariate analysis showed that state PPWB constructs-greater levels of positive affect and flourishing-were significantly associated with better QOL and lower PTSD, anxiety, and depression symptomatology. IMPLICATIONS: Our findings suggest that longitudinal studies are needed to examine the links between state PPWB constructs and HSCT outcomes, which may inform population specific interventions and opportunities to improve outcomes.

DNA Damage in Bat Blood Leukocytes Using a Chromatin Dispersion Test (CDT): Biomarker of Environmental Genotoxicity.

Environmental pollutants produce adverse effects on organisms and ecosystems. Biomonitoring and biomarkers offer a reasonable approach to make these assessments. Induced genetic changes can be using as a biomarker in organisms that react to a given compound in the ecosystem. Monitoring environmental genotoxicity necessitates the choice of model animals known as "sentinels or biological monitors" and the suitability of validated tests for DNA damage evaluation. We aimed to estimate the DNA damage produced by thermal stress in the leukocytes of the Mexican free-tailed bat (Tadarida brasiliensis). The DNA damage in bat leukocytes exposed to different temperatures (35 °C, 45 °C, and 55 °C) was evaluated by the adapted chromatin dispersion test (CDT) and the results were confirmed by the alkaline comet test. The CDT permitted a clear representation of leukocytes with fragmented DNA and of nonfragmented DNA. In addition, we detected nuclear anomalies in relation to cell death cellular swelling, nuclear fragmentation, and chromatin lysis. The alkaline comet assay revealed that the halos of diffuse chromatin include fragmented DNA. The assay of the method employing the CDT is well established, precise, and cost-effective for the routine quantitative analysis of DNA damage on the effect of the leukocytes of bats exposed to thermal stress. This could also apply as a sensitive screening tool for the evaluation of genotoxicity in environmental protection programs.

Paradoxical improvement of cognitive control in older adults under dual-task walking conditions is associated with more flexible reallocation of neural resources: A Mobile Brain-Body Imaging (MoBI) study.

Combining walking with a demanding cognitive task is traditionally expected to elicit decrements in gait and/or cognitive task performance. However, it was recently shown that, in a cohort of young adults, most participants improved performance when walking was added to performance of a Go/NoGo response inhibition task. The present study aims to extend these previous findings to an older adult cohort, to investigate whether this improvement when dual-tasking is observed in healthy older adults. Mobile Brain/Body Imaging (MoBI) was used to record electroencephalographic (EEG) activity, three-dimensional (3D) gait kinematics and behavioral responses in the Go/NoGo task, during sitting or walking on a treadmill, in 34 young adults and 37 older adults. Increased response accuracy during walking, independent of age, was found to correlate with slower responses to stimuli (r = 0.44) and with walking-related EEG amplitude modulations over frontocentral regions (r = 0.47) during the sensory gating (N1) and conflict monitoring (N2) stages of inhibition, and over left-lateralized prefrontal regions (r = 0.47) during the stage of inhibitory control implementation (P3). These neural activity changes are related to the cognitive component of inhibition, and they were interpreted as signatures of behavioral improvement during walking. On the other hand, aging, independent of response accuracy during walking, was found to correlate with slower treadmill walking speeds (r = -0.68) and attenuation in walking-related EEG amplitude modulations over left-dominant frontal (r = -0.44) and parietooccipital regions (r = 0.48) during the N2 stage, and over centroparietal regions (r = 0.48) during the P3 stage. These neural activity changes are related to the motor component of inhibition, and they were interpreted as signatures of aging. Older adults whose response accuracy 'paradoxically' improved during walking manifested neural signatures of both behavioral improvement and aging, suggesting that their flexibility in reallocating neural resources while walking might be maintained for the cognitive but not for the motor inhibitory component. These distinct neural signatures of aging and behavior can potentially be used to identify 'super-agers', or individuals at risk for cognitive decline due to aging or neurodegenerative disease.

Stem cell collection after lenalidomide, bortezomib and dexamethasone plus elotuzumab or isatuximab in newly diagnosed multiple myeloma patients: a single centre experience from the GMMG-HD6 and -HD7 trials.

BACKGROUND: While quadruplet induction therapies deepen responses in newly diagnosed multiple myeloma patients, their impact on peripheral blood stem cell (PBSC) collection remains incompletely understood. This analysis aims to evaluate the effects of prolonged lenalidomide induction and isatuximab- or elotuzumab-containing quadruplet induction therapies on PBSC mobilization and collection. METHODS: A total of 179 transplant-eligible patients with newly diagnosed MM treated at a single academic center were included. The patients were evaluated based on PBSC mobilization and collection parameters, including overall collection results, CD34+ cell levels in peripheral blood, leukapheresis (LP) delays, overall number of LP sessions, and the rate of rescue mobilization with plerixafor. The patients underwent four different induction regimens: Lenalidomide, bortezomib, and dexamethasone (RVd, six 21-day cycles, n = 44), isatuximab-RVd (six 21-day cycles, n = 35), RVd (four 21-day cycles, n = 51), or elotuzumab-RVd (four 21-day cycles, n = 49). RESULTS: The patients' characteristics were well balanced across the different groups. Collection failures, defined as the inability to collect three sufficient PBSC transplants, were rare (n = 3, 2%), with no occurrences in the isatuximab-RVd and elotuzumab-RVd groups. Intensified induction with six 21-day cycles of RVd did not negatively impact the overall number of collected PBSCs (9.7 × 106/kg bw versus 10.5 × 106/kg bw, p = 0.331) compared to four 21-day cycles of RVd. Plerixafor usage was more common after six cycles of RVd compared to four cycles (16% versus 8%). Addition of elotuzumab to RVd did not adversely affect overall PBSC collection (10.9 × 106/kg bw versus 10.5 × 106/kg bw, p = 0.915). Patients treated with isatuximab-RVd (six cycles) had lower numbers of collected stem cells compared to those receiving RVd (six cycles) induction (8.8 × 106/kg bw versus 9.7 × 106/kg bw, p = 0.801), without experiencing significant delays in LP or increased numbers of LP sessions in a multivariable logistic regression analysis. Plerixafor usage was more common after isatuximab plus RVd compared to RVd alone (34% versus 16%). CONCLUSIONS: This study demonstrates that stem cell collection is feasible after prolonged induction with isatuximab-RVd without collection failures and might be further explored as induction therapy. TRIAL REGISTRATION: Patients were treated within the randomized phase III clinical trials GMMG-HD6 (NCT02495922, 24/06/2015) and GMMG-HD7 (NCT03617731, 24/07/2018). However, during stem cell mobilization and -collection, no study-specific therapeutic intervention was performed.

The benefit of diagnostic whole genome sequencing in schizophrenia and other psychotic disorders.

Schizophrenia has a multifactorial etiology, involving a polygenic architecture. The potential benefit of whole genome sequencing (WGS) in schizophrenia and other psychotic disorders is not well studied. We investigated the yield of clinical WGS analysis in 251 families with a proband diagnosed with schizophrenia (N = 190), schizoaffective disorder (N = 49), or other conditions involving psychosis (N = 48). Participants were recruited in Israel and USA, mainly of Jewish, Arab, and other European ancestries. Trio (parents and proband) WGS was performed for 228 families (90.8%); in the other families, WGS included parents and at least two affected siblings. In the secondary analyses, we evaluated the contribution of rare variant enrichment in particular gene sets, and calculated polygenic risk score (PRS) for schizophrenia. For the primary outcome, diagnostic rate was 6.4%; we found clinically significant, single nucleotide variants (SNVs) or small insertions or deletions (indels) in 14 probands (5.6%), and copy number variants (CNVs) in 2 (0.8%). Significant enrichment of rare loss-of-function variants was observed in a gene set of top schizophrenia candidate genes in affected individuals, compared with population controls (N = 6,840). The PRS for schizophrenia was significantly increased in the affected individuals group, compared to their unaffected relatives. Last, we were also able to provide pharmacogenomics information based on CYP2D6 genotype data for most participants, and determine their antipsychotic metabolizer status. In conclusion, our findings suggest that WGS may have a role in the setting of both research and genetic counseling for individuals with schizophrenia and other psychotic disorders and their families.

Can We Quickly Learn to "Translate" Bioactive Molecules with Transformer Models?

Meaningful exploration of the chemical space of druglike molecules in drug design is a highly challenging task due to a combinatorial explosion of possible modifications of molecules. In this work, we address this problem with transformer models, a type of machine learning (ML) model originally developed for machine translation. By training transformer models on pairs of similar bioactive molecules from the public ChEMBL data set, we enable them to learn medicinal-chemistry-meaningful, context-dependent transformations of molecules, including those absent from the training set. By retrospective analysis on the performance of transformer models on ChEMBL subsets of ligands binding to COX2, DRD2, or HERG protein targets, we demonstrate that the models can generate structures identical or highly similar to most active ligands, despite the models having not seen any ligands active against the corresponding protein target during training. Our work demonstrates that human experts working on hit expansion in drug design can easily and quickly employ transformer models, originally developed to translate texts from one natural language to another, to "translate" from known molecules active against a given protein target to novel molecules active against the same target.

A mental workload and biomechanical assessment during split-belt locomotor adaptation with and without optic flow.

Adaptive human performance relies on the central nervous system to regulate the engagement of cognitive-motor resources as task demands vary. Despite numerous studies which employed a split-belt induced perturbation to examine biomechanical outcomes during locomotor adaptation, none concurrently examined the cerebral cortical dynamics to assess changes in mental workload. Additionally, while prior work suggests that optic flow provides critical information for walking regulation, a few studies have manipulated visual inputs during adaption to split-belt walking. This study aimed to examine the concurrent modulation of gait and Electroencephalography (EEG) cortical dynamics underlying mental workload during split-belt locomotor adaptation, with and without optic flow. Thirteen uninjured participants with minimal inherent walking asymmetries at baseline underwent adaptation, while temporal-spatial gait and EEG spectral metrics were recorded. The results revealed a reduction in step length and time asymmetry from early to late adaptation, accompanied by an elevated frontal and temporal theta power; the former being well corelated to biomechanical changes. While the absence of optic flow during adaptation did not affect temporal-spatial gait metrics, it led to an increase of theta and low-alpha power. Thus, as individuals adapt their locomotor patterns, the cognitive-motor resources underlying the encoding and consolidation processes of the procedural memory were recruited to acquire a new internal model of the perturbation. Also, when adaption occurs without optic flow, a further reduction of arousal is accompanied with an elevation of attentional engagement due to enhanced neurocognitive resources likely to maintain adaptive walking patterns.

Carotenoids from Starfish Patiria pectinifera: Therapeutic Activity in Models of Inflammatory Diseases.

The carotenoids mixture (MC) isolated from the starfish Patiria. pectinifera contains more than 50% astaxanthin, 4-6% each zeaxanthine and lutein, and less pharmacologically active components such as free fatty acids and their glycerides. Astaxanthin, the major component of MC, belongs to the xanthophyll class of carotenoids, and is well known for its antioxidant properties. In this work, in vitro and in vivo studies on the biological activity of MC were carried out. The complex was shown to exhibit anti-inflammatory, anti-allergic and cancer-preventive activity, without any toxicity at a dose of 500 mg/kg. MC effectively improves the clinical picture of the disease progressing, as well as normalizing the cytokine profile and the antioxidant defense system in the in vivo animal models of inflammatory diseases, namely: skin carcinogenesis, allergic contact dermatitis (ACD) and systemic inflammation (SI). In the skin carcinogenesis induced by 7,12-dimethylbenzanthracene, the incidence of papillomas was decreased 1.5 times; 1% MC ointment form in allergic contact dermatitis showed an 80% reduced severity of pathomorphological skin manifestations. Obtained results show that MC from starfish P. pectinifera is an effective remedy for the treatment and prevention of inflammatory processes.

Diet as a therapeutic tool in chronic gastrointestinal disorders: Lessons from the FODMAP journey.

BACKGROUND AND AIM: Diet is a powerful tool in the management of gastrointestinal disorders, but developing diet therapies is fraught with challenge. This review discusses key lessons from the FODMAP diet journey. METHODS: Published literature and clinical experience were reviewed. RESULTS: Key to designing a varied, nutritionally adequate low-FODMAP diet was our accurate and comprehensive database of FODMAP composition, made universally accessible via our user-friendly, digital application. Our discovery that FODMAPs coexist with gluten in cereal products and subsequent gluten/fructan challenge studies in nonceliac gluten-sensitive populations highlighted issues of collinearity in the nutrient composition of food and confirmation bias in the interpretation of dietary studies. Despite numerous challenges in designing, funding, and executing dietary randomized controlled trials, efficacy of the low-FODMAP diet has been repeatedly demonstrated, and confirmed by real-world experience, giving this therapy credibility in the eyes of clinicians and researchers. Furthermore, real-world application of this diet saw the evolution of a safe and effective three-phased approach. Specialist dietitians must deliver this diet to optimize outcomes as they can target and tailor the therapy and to mitigate the key risks of compromising nutritional adequacy and precipitating disordered eating behaviors, skills outside the gastroenterologist's standard tool kit. While concurrent probiotics are ineffective, specific fiber supplements may improve short-term and long-term outcomes. CONCLUSIONS: The FODMAP diet is highly effective, but optimal outcomes are contingent on the involvement of a gastroenterological dietitian who can assess, educate, and monitor patients and manage risks associated with implementation of this restrictive diet.

Comparative Study of the Pharmacological Properties of Luteolin and Its 7,3'-Disulfate.

The global spread of the metabolic syndrome, oncological and viral diseases forces researchers to pay increased attention to the secondary metabolites of marine hydrobionts, which often have a high therapeutic potential in the treatment of these pathologies and are effective components of functional food. The flavone luteolin (LT), as one of the most widely distributed and studied plant metabolites, is distinguished by a diverse spectrum of biological activity and a pleiotropic nature of the mechanism of action at the molecular, cellular and organismal levels. However, there is still practically no information on the spectrum of biological activity of its sulfated derivatives, which are widely represented in seagrasses of the genus Zostera. In the present work, a comparative study of the pharmacological properties of LT and its 7,3'-disulfate was carried out with a brief analysis of the special role of sulfation in the pharmacological activity of flavonoids.