Miracle-dz/UniFAR-FTUs huggingface dataset:
The role of state feelings of loneliness in the situational regulation of social affiliative behavior: Exploring the regulatory relations within a multilevel framework

Previous empirical evidence suggests that the engagement in social interactions across different everyday contexts occurs in a manner highly responsive to a person’s social affiliation needs. As has been shown repeatedly, social engagement (as well as disengagement) can be predicted from earlier situational need states, implying that homeostatic principles underlie a person’s social affiliative behaviors. However, little is known about the role of emotion in these regulative processes. For this reason, the present exploratory study investigated the predictive role of state feelings of loneliness in subsequent engagement in social interaction. Since loneliness is conceptually associated with both the need to reaffiliate as well as self-protecting tendencies potentially hindering engagement in social contact, the study investigated the possibility of both increases and decreases in social contacts resulting from state feelings of loneliness. Adopting an experience sampling methodology (ESM), a sample of 65 participants was recruited from a local university and was followed for 14 days. Subjects were prompted several times a day to rate their feeling states and the quantity of social interactions, using a fixed interval assessment schedule. Statistical analyses using multilevel analysis indicated that state feelings of loneliness had complex quadratic effects upon subsequent social interaction, leading to both increases and decreases in subsequent social interaction. Moreover, these effects were contingent upon previous engagement in social interaction, implying spillover effects across social contexts that are conditionally mediated by feelings of loneliness. These findings clearly imply an important, albeit complex role of state feelings of loneliness in the regulation of social affiliation, both as a predictor and a consequence of social interaction. These exploratory findings are discussed against the background of methodological and conceptual limitations, and several recommendations for future studies are made.
Changes in family medicine visits across sociodemographic groups after the onset of the COVID-19 pandemic in Ontario: a retrospective cohort study

Background: It has been suggested that the COVID-19 pandemic has worsened socioeconomic disparities in access to primary care. Given these concerns, we investigated whether the pandemic affected visits to family physicians differently across sociodemographic groups. Methods: We conducted a retrospective cohort study using electronic medical records from family physician practices within the University of Toronto Practice-Based Research Network. We evaluated primary care visits for a fixed cohort of patients who were active within the database as of Jan. 1, 2019, to estimate the number of patients who visited their family physician (visitor rate) and the number of distinct visits (visit volume) between Jan. 1, 2019, to June 30, 2020. We compared trends in visitor rate and visit volume during the pandemic (Mar. 14 to June 30, 2020) with the same period in the previous year (Mar. 14 to June 30, 2019) across sociodemographic factors, including age, sex, neighbourhood income, material deprivation and ethnic concentration. Results: We included 365 family physicians and 372 272 patients. Compared with the previous year, visitor rates during the pandemic period dropped by 34.5%, from 357 visitors per 1000 people to 292 visitors per 1000 people. Declines in visit volume during the pandemic were less pronounced (21.8% fewer visits), as the mean number of visits per patient increased during the pandemic (from 1.64 to 1.96). The declines in visitor rate and visit volume varied based on patient age and sex, but not socioeconomic status. Interpretation: Although the number of visits to family physicians dropped substantially during the first few weeks of the COVID-19 pandemic in Ontario, patients from communities with low socioeconomic status did not appear to be disproportionately affected. In this primary care setting, the pandemic appears not to have worsened socioeconomic disparities in access to care.
Impaired antibody response to COVID‐19 vaccination in patients with chronic myeloid neoplasms

The COVID-19 pandemic has had a severe impact on people with blood cancers. Patients with blood cancer are at an increased risk of poor outcomes after COVID-19 infection, with more severe infections and a higher case fatality rate (1-3), which may reflect immunocompromise due to their underlying disease and/or immunosuppressive treatments. As a result, regulatory approval and the subsequent rapid roll out of COVID-19 vaccines has been extremely well received by the blood cancer community.
Determination of apparent solubility,apparent partition coefficient and dissociation constant of tetrandrine

OBJECTIVE To determine the solubility,oil /water partition coefficient and dissociation constant of tetrandrine.METHODS An equilibrium solubility method and shake flask method were established to determine the apparent solubility and oil/water partition coefficients(P) of tetrandrine in phosphoric buffer solutions with different pH,respectively.The dissociation constant(pK a) of tetrandrine in ethanol solution with different concentrations was measured according to spectrophotometric indicator method.RESULTS With pH increased,apparent solubility of tetrandrine was decreased while its apparent P showed the increasing trend.The pK a of tetrandrine in water was 8.08. CONCLUSION Tetrandrine is a strong base with high lipophilia,it's absorption position may be at small intestine.
Early Maladaptive Schemas and Depression in Adulthood: A Systematic Review and Meta-Analysis.

BACKGROUND Improved understanding of the specific cognitive risk factors associated with depression is needed to inform prevention and treatment approaches. Recent research has examined the relationship between Early Maladaptive Schemas (EMS) and depression, but the findings were yet to be integrated using meta-analytic methods. The aim of this review was to synthesize the evidence on the relationship between depression and EMS. METHOD A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, by searching the PsycINFO, PubMed, and CINAHL databases. Included studies were peer-reviewed journal articles that examined the relationship between one or more EMS and depression in adulthood in participants aged 18 years or older. RESULTS A total of 51 studies were included (k = 743; Pooled N = 17,830). All 18 EMS were positively correlated with depression, with effect sizes ranging from small (r = .23 [.17, .29]; Entitlement) to large (r =.53 [.46, .60]; Social Isolation; r = .50, 95% CI [.45, .54]; Defectiveness/Shame). CONCLUSION The evidence suggests that individuals who feel like they do not belong, or that they are flawed, bad, or unlovable, report higher levels of depression. However, most studies used cross-sectional designs and further longitudinal research is needed to establish the direction of the relationship between EMS and depression. These findings can guide preventative and treatment approaches. Focusing treatment on the Social Isolation and Defectiveness/Shame EMS may aid in relieving depressive symptoms.
Amniotic fluid and urine metabolomic alterations associated with pregnant women with Down syndrome fetuses

Abstract Background Down syndrome (DS) is a chromosomal disorder caused by a third copy of all or part of chromosome 21. Clinical observations and preclinical studies both suggest that DS may be associated with significant metabolic and bioenergetic alterations. But the metabolic alterations in pregnant women carrying DS fetuses still remains unclear. In this study, we investigated the characteristic metabolomics and lipidomics changes during fetal development of DS. Methods The AF and random urine specimens were selected from 20 pregnant women carrying DS fetuses and 20 pregnant women carrying healthy fetuses. The diagnosis of DS was screened according to chromosome karyotype analysis, and untargeted metabolomic and lipidomic analyses were performed. Results Through the analyses of AF, 308 differential metabolites were selected between DS and controls. The metabolites with significant changes mainly involved lipid molecules, organic acids, nucleotides and carbon. Further analysis of lipidomics showed 64 differential metabolites, mainly involving glycerides, sphingolipids and glycerolipids. As for urine metabolomic and lipidomic analyses, there existed consistent metabolites with AF, but the number was much less. Conclusions Compared with the controls, carbon metabolism, amino acid metabolism, glyceride metabolism, sphingolipid metabolism and glycerophospholipid metabolism were significantly changed in DS cases. In addition, characterized biomarkers in AF and urine were screened for DS diagnosis, and these metabolites were mainly involved in energy metabolism and liver dysfunction. This finding may help improve the efficiency of prenatal screening for DS.
Biogeographic regionalization by spatial and environmental components: Numerical proposal

Regionalization through the analysis of species groups offers important advantages in conservation biology, compared to the single taxon approach in areas of high species richness. We use a systematic framework for biogeographic regionalization at a regional scale based on species turnover and environmental drivers (climate variables and soil properties) mainly of herbaceous plant species richness. To identify phytogeographic regions in the Balsas Depression (BD), we use Asteraceae species, a family widely distributed in Seasonally Dry Tropical Forest (SDTF) and the most diverse of the vascular plants in Mexico. Occurrence records of 571 species were used to apply a quantitative analysis based on the species turnover, the rate of changes in their composition between sites (β-Simpson index) and the analysis of the identified environmental drivers. Also, the environmental predictors that influence species richness in the SDTF were determined with a redundancy analysis. We identified and named two phytogeographic districts within the SDTF of the BD (Upper Balsas and Lower Balsas). According to the multi-response permutation procedure, floristic composition of the two districts differs significantly, and the richness of exclusive species in Upper Balsas was higher (292 species) than in the Lower Balsas (32 species). The proportion of Mg and Ca in the soil and the precipitation of the driest three-month period were the environmental factors with greatest positive influence on species richness. The division of geographic districts subordinated to the province level, based on diverse families such as Asteraceae, proved to be appropriate to set up strategies for the conservation of the regional flora, since at this scale, variation in species richness is more evident. Our findings are consistent with a growing body of biogeographic literature that indicates that the identification of smaller biotic districts is more efficient for the conservation of biodiversity, particularly of endemic or rare plants, whose distribution responds more to microhabitats variation.
Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (US, UK and Sweden)

Use and dosing of guideline‐directed medical therapy (GDMT) in patients with heart failure (HF) have been shown to be suboptimal. Among new users of GDMT in HF, we followed the real‐life patterns of dose titration and discontinuation of angiotensin‐converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), beta‐blockers, mineralocorticoid receptor antagonists (MRA) and angiotensin receptor–neprilysin inhibitors (ARNI).
Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study

OBJECTIVE To identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study. RESEARCH DESIGN AND METHODS A total of 91 youth (10–19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA1c increase ≥0.5% from baseline). RESULTS Glycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 (P = 0.008) and in 36% of youth versus 20% of adults at month 21 (P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05–0.96, P = 0.044). In both age-groups, lower baseline clamp-derived β-cell responses predicted month 12 and month 21 glycemic worsening (P < 0.01). Lower baseline OGTT-derived β-cell responses predicted month 21 worsening (P < 0.05). In youth, higher baseline HbA1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening (P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening (P < 0.05). CONCLUSIONS Glycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline β-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults.
The molecular mechanisms underlying acrosome biogenesis elucidated by gene-manipulated mice

Abstract Sexual reproduction requires the fusion of two gametes in a multistep and multifactorial process termed fertilization. One of the main steps that ensures successful fertilization is acrosome reaction. The acrosome, a special kind of organelle with a cap-like structure that covers the anterior portion of sperm head, plays a key role in the process. Acrosome biogenesis begins with the initial stage of spermatid development, and it is typically divided into four successive phases: the Golgi phase, cap phase, acrosome phase, and maturation phase. The run smoothly of above processes needs an active and specific coordination between the all kinds of organelles (endoplasmic reticulum, trans-Golgi network, and nucleus) and cytoplasmic structures (acroplaxome and manchette). During the past two decades, an increasing number of genes have been discovered to be involved in modulating acrosome formation. Most of these proteins interact with each other and show a complicated molecular regulatory mechanism to facilitate the occurrence of this event. This review focuses on the progresses of studying acrosome biogenesis using gene-manipulated mice and highlights an emerging molecular basis of mammalian acrosome formation. Summary sentence The acrosome is generated from a combination of many membrane trafficking systems and the morphology and integrity are maintained by the coordination of the cytoskeletal structures during spermiogenesis.
A Phase I, First‐in‐Human Study of GSK2849330, an Anti‐HER3 Monoclonal Antibody, in HER3‐Expressing Solid Tumors

Abstract Background GSK2849330, an anti‐HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody‐dependent cellular cytotoxicity and complement‐dependent cytotoxicity. This phase I, first‐in‐human, open‐label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3‐expressing advanced solid tumors. Patients and Methods Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose‐escalation phase, patients received GSK2849330 1.4–30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose‐expansion phase, patients received 30 mg/kg GSK2849330 IV weekly. Results Twenty‐nine patients with HER3‐expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose‐limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment‐emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose‐proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74‐NRG1‐rearranged non‐small cell lung cancer (NSCLC). Conclusion GSK2849330 demonstrated a favorable safety profile, dose‐proportional PK, and evidence of target engagement, but limited antitumor activity in HER3‐expressing cancers. The exceptional response seen in a patient with CD74‐NRG1‐rearranged NSCLC suggests further exploration in NRG1‐fusion–positive cancers. Implications for Practice This first‐in‐human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3‐expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody‐dependent cell‐mediated cytotoxicity– and complement‐dependent cytotoxicity–enhanced anti‐HER3 antibody. The only confirmed durable response achieved was in a patient with CD74‐NRG1‐rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti‐HER3 agents in ongoing trials.
Azole resistance in Aspergillus species: promising therapeutic options

ABSTRACT Introduction Azoles are the first-line antifungal agents used for the treatment of Aspergillus infection. There is an increasing concern for azole resistance all over the world mainly from agricultural fungicide use. Choosing safe and effective antifungal regimens has become a challenge. Areas covered Here, the authors review the epidemiology, mechanisms, and detection of azole resistance along with management options for azole-resistant Aspergillus infection, including new antifungal agents under development. Expert opinion Routine global epidemiological surveillance is required to understand azole resistance prevalence. Azole-resistant Aspergillus infections are associated with high mortality. No good therapeutic options are currently available. High index of suspicion of resistance is required if a patient is not responding to 4–7 days of azole therapy, particularly in the areas of resistance. Susceptibility testing for Aspergillus is not routinely available in many parts of the world, which makes it difficult to diagnose azole resistance in Aspergillus infection. There are several new antifungal classes with novel mechanisms of action; clinical trials are ongoing.
Model-Based Planning Deficits in Compulsivity Are Linked to Faulty Neural Representations of Task Structure

Compulsive individuals have deficits in model-based planning, but the mechanisms that drive this have not been established. We examined two candidates—that compulsivity is linked to (1) an impaired model of the task environment and/or (2) an inability to engage cognitive control when making choices. To test this, 192 participants performed a two-step reinforcement learning task with concurrent EEG recordings, and we related the neural and behavioral data to their scores on a self-reported transdiagnostic dimension of compulsivity. To examine subjects' internal model of the task, we used established behavioral and neural responses to unexpected events [reaction time (RT) slowing, P300 wave, and parietal-occipital alpha band power] measured when an unexpected transition occurred. To assess cognitive control, we probed theta power at the time of initial choice. As expected, model-based planning was linked to greater behavioral (RT) and neural (alpha power, but not P300) sensitivity to rare transitions. Critically, the sensitivities of both RT and alpha to task structure were weaker in those high in compulsivity. This RT-compulsivity effect was tested and replicated in an independent pre-existing dataset (N = 1413). We also found that mid-frontal theta power at the time of choice was reduced in highly compulsive individuals though its relation to model-based planning was less pronounced. These data suggest that model-based planning deficits in compulsive individuals may arise, at least in part, from having an impaired representation of the environment, specifically how actions lead to future states. SIGNIFICANCE STATEMENT Compulsivity is linked to poorer performance on tasks that require model-based planning, but it is unclear what precise mechanisms underlie this deficit. Do compulsive individuals fail to engage cognitive control at the time of choice? Or do they have difficulty in building and maintaining an accurate representation of their environment, the foundation needed to behave in a goal-directed manner? With reaction time and EEG measures in 192 individuals who performed a two-step decision-making task, we found that compulsive individuals are less sensitive to surprising action–state transitions, where they slow down less and show less alpha band suppression following a rare transition. These findings implicate failures in maintaining an accurate model of the world in model-based planning deficits in compulsivity.
Energy Restriction Suppresses Muscle Protein Synthesis, and High Protein Diets Extend Protein Half-Lives Across the Muscle Proteome in Obese Female Zucker Rats.

BACKGROUND Effects of high protein (HP) diets and prolonged energy restriction (ER) on integrated muscle protein kinetics have not been determined. OBJECTIVE The objective of this study was to measure protein kinetics in response to prolonged ER and HP on muscle protein synthesis (MPS; absolute rates of synthesis) and muscle protein breakdown (MPB; half-lives) for proteins across the muscle proteome. METHODS Female 6-wk-old obese Zucker rats (Leprfa+/fa+, n = 48) were randomly assigned to one of four diets for 10 wk: ad libitum-standard protein (AL-SP; 15% kcal from protein), AL-HP (35% kcal from protein), ER-SP, and ER-HP (both fed 60% feed consumed by AL-SP). During week 10, heavy/deuterated water (2H2O) was administered by intraperitoneal injection, and isotopic steady-state was maintained via 2H2O in drinking water. Rats were euthanized after 1 wk, and mixed-MPS as well as fractional replacement rate (FRR), relative concentrations, and half-lives of individual muscle proteins were quantified in the gastrocnemius. Data were analyzed using 2-factor (energy × protein) ANOVAs and 2-tailed t-tests or binomial tests as appropriate. RESULTS Absolute MPS was lower in ER than AL for mixed-MPS (-29.6%; P < 0.001) and MPS of most proteins measured [23/26 myofibrillar, 48/60 cytoplasmic, and 46/60 mitochondrial (P < 0.05)], corresponding with lower gastrocnemius mass in ER compared with AL (-29.4%; P < 0.001). Although mixed-muscle protein half-life was not different between groups, prolonged half-lives were observed for most individual proteins in HP compared with SP in ER and AL (P < 0.001), corresponding with greater gastrocnemius mass in HP than SP (+5.3%; P = 0.043). CONCLUSIONS ER decreased absolute bulk MPS and most individual MPS rates compared with AL, and HP prolonged half-lives of most proteins across the proteome. These data suggest that HP, independent of energy intake, may reduce MPB, and reductions in MPS may contribute to lower gastrocnemius mass during ER by reducing protein deposition in obese female Zucker rats.