Miracle-dz/UniFAR-FTUs huggingface dataset:
Drosophila Gene Expression Pattern Annotation through Multi-Instance Multi-Label Learning

In the studies of Drosophila embryogenesis, a large number of two-dimensional digital images of gene expression patterns have been produced to build an atlas of spatio-temporal gene expression dynamics across developmental time. Gene expressions captured in these images have been manually annotated with anatomical and developmental ontology terms using a controlled vocabulary (CV), which are useful in research aimed at understanding gene functions, interactions, and networks. With the rapid accumulation of images, the process of manual annotation has become increasingly cumbersome, and computational methods to automate this task are urgently needed. However, the automated annotation of embryo images is challenging. This is because the annotation terms spatially correspond to local expression patterns of images, yet they are assigned collectively to groups of images and it is unknown which term corresponds to which region of which image in the group. In this paper, we address this problem using a new machine learning framework, Multi-Instance Multi-Label (MIML) learning. We first show that the underlying nature of the annotation task is a typical MIML learning problem. Then, we propose two support vector machine algorithms under the MIML framework for the task. Experimental results on the FlyExpress database (a digital library of standardized Drosophila gene expression pattern images) reveal that the exploitation of MIML framework leads to significant performance improvement over state-of-the-art approaches.
Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer

SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260–570 mg/m2) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort (N = 19; unselected population, including three patients with MET-amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m2. Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade ≥ 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m2 in the dose-expansion cohort, comprising patients with MET-amplified tumors (N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m2 has acceptable tolerability and modest antitumor activity in patients with MET-amplified gastric cancer.
Van der Waals Heteroepitaxial Growth of Monolayer Sb in a Puckered Honeycomb Structure

Atomically thin 2D crystals have gained tremendous attention owing to their potential impact on future electronics technologies, as well as the exotic phenomena emerging in these materials. Monolayers of α‐phase Sb (α‐antimonene), which shares the same puckered structure as black phosphorous, are predicted to be stable with precious properties. However, the experimental realization still remains challenging. Here, high‐quality monolayerα‐antimonene is successfully grown, with the thickness finely controlled. The α‐antimonene exhibits great stability upon exposure to air. Combining scanning tunneling microscopy, density functional theory calculations, and transport measurements, it is found that the electron band crossing the Fermi level exhibits a linear dispersion with a fairly small effective mass, and thus a good electrical conductivity. All of these properties make the α‐antimonene promising for future electronic applications.
TAN lines

Nuclear position is actively controlled and can be adjusted according to the needs of a cell by nuclear movement. Microtubules mediate the majority of nuclear movements studied to date, although examples of nuclear movements mediated by the actin cytoskeleton have been described. One such actin-dependent nuclear movement occurs during centrosome orientation in fibroblasts polarizing for migration. Here, the centrosome is maintained at the cell center while the nucleus is moved to the cell rear by actin retrograde flow thus positioning the centrosome between the nucleus and the leading edge of the cell. We have explored the molecular mechanism for actin dependent movement of the nucleus during centrosome centration. We found that a novel linear array of nuclear envelope membrane proteins composed of nesprin-2G and SUN2, called transmembrane actin-associated nuclear (TAN) lines, couple the nucleus to moving actin cables resulting in the nucleus being positioned toward the cell rear. TAN lines are anchored by A-type lamins and this allows the forces generated by the actin cytoskeleton to be transmitted across the nuclear envelope to move the nucleus. Here we review the data supporting this mechanism for nuclear movement, discuss questions remaining to be addressed and consider how this new mechanism of nuclear movement may shed light on human disease.
Population Pharmacokinetics and Dosing Optimization of Amoxicillin in Neonates and Young Infants

Amoxicillin is widely used to treat bacterial infections in neonates. However, considerable intercenter variability in dosage regimens of antibiotics exists in clinical practice. ABSTRACT Amoxicillin is widely used to treat bacterial infections in neonates. However, considerable intercenter variability in dosage regimens of antibiotics exists in clinical practice. The pharmacokinetics of amoxicillin has been described in only a few preterm neonates. Thus, we aimed to evaluate the population pharmacokinetics of amoxicillin through a large sample size covering the entire age range of neonates and young infants and to establish evidence-based dosage regimens based on developmental pharmacokinetics-pharmacodynamics. This is a prospective, multicenter, pharmacokinetic study using an opportunistic sampling design. Amoxicillin plasma concentrations were determined using high-performance liquid chromatography. Population pharmacokinetic analysis was performed using NONMEM. A total of 224 pharmacokinetic samples from 187 newborns (postmenstrual age range, 28.4 to 46.3 weeks) were available for analysis. A two-compartment model with first-order elimination was used to describe population pharmacokinetics. Covariate analysis showed that current weight, postnatal age, and gestational age were significant covariates. The final model was further validated for predictive performance in an independent cohort of patients. Monte Carlo simulation demonstrated that for early-onset sepsis, the currently used dosage regimen (25 mg/kg twice daily [BID]) resulted in 99.0% of premature neonates and 87.3% of term neonates achieving the pharmacodynamic target (percent time above MIC), using a MIC breakpoint of 1 mg/liter. For late-onset sepsis, 86.1% of premature neonates treated with 25 mg/kg three times a day (TID) and 79.0% of term neonates receiving 25 mg/kg four times a day (QID) reached the pharmacodynamic target, using a MIC breakpoint of 2 mg/liter. The population pharmacokinetics of amoxicillin was assessed in neonates and young infants. A dosage regimen was established based on developmental pharmacokinetics-pharmacodynamics.
Peripheral blood biomarkers of early immune reconstitution in newly diagnosed multiple myeloma

Peripheral blood biomarkers of tumor microenvironment and immune surveillance are independent prognostic factors in multiple myeloma. The timing and prognostic impact of immune reconstitution has been studied after autologous hematopoietic stem cell transplantation, less is known about its significance in newly diagnosed multiple myeloma. We studied absolute lymphocyte (ALC) and absolute monocyte (AMC) counts at the time of treatment initiation and 1 month thereafter in 771 newly diagnosed patients. Two hundred and thirty‐four patients (31%) had evidence of immune dysregulation at baseline (abnormal biomarkers). Eighty‐seven of these patients (37%) recovered normal biomarkers at 1 month (early immune reconstitution). The absence of immune dysregulation at baseline (compared to the presence thereof) was associated with better overall survival (HR 0.77, 95% CI 0.61‐0.97, P = 0.025, n = 771). The absence of immune dysregulation at 1 month (compared to the persistence or development thereof) was associated with better overall survival (HR 0.63, 95% CI 0.50‐0.80, P < 0.001, n = 771). Early immune reconstitution (compared to the persistence or development of immune dysregulation) was associated with better overall survival (HR 0.62, 95% CI 0.43‐0.92, P = 0.016, n = 771). Cytogenetic high‐risk disease was negatively, and treatment with immunomodulators positively, associated with early immune reconstitution. The presence or development of immune dysregulation in newly diagnosed multiple myeloma is an independent risk factor. The favorable impact of early immune reconstitution suggests immune dysregulation to be a potentially modifiable risk factor that may be exploited for therapeutic benefit.
Does incident circumcision lead to risk compensation? Evidence from a population cohort in KwaZulu-Natal, South Africa

Background: Voluntary medical male circumcision reduces men's risk of HIV acquisition and may thus increase HIV risk-related sexual behaviors through risk compensation. We analyze longitudinal data from one of Africa's largest population cohorts using fixed-effects panel estimation to measure the effect of incident circumcision on sexual behaviors. Setting: KwaZulu-Natal, South Africa. Methods: An open population cohort of men was followed from 2009 to 2015. Men self-reported their circumcision status and sexual behavior annually. We used linear regression models with individual-level fixed effects to measure the effect of incident circumcision on recent sex (past 12 months) and sexual behaviors that increase HIV risk (not using a condom at last sex, never using condoms with the most recent sexual partner, concurrent sexual partners at present, and multiple sexual partners in the past 12 months). We controlled for potential time-varying confounders: calendar year, age, education, and sexual debut. Results: The 5127 men in the cohort had a median age of 18 years (interquartile range 16–24) at cohort entry. Over the study period, almost 1 in 5 of these men (19.4%) became newly circumcised. Incident circumcision affected neither recent sex [percentage point (PP) change 0.0, 95% confidence interval: −1.2 to 1.3] nor sexual behaviors that increase HIV risk (PP −1.6, 95% confidence interval: −4.5 to 1.4). Conclusions: The data from this study strongly reject the hypothesis that circumcision affects sexual risk-taking. Risk compensation should not serve as an argument against increased and accelerated scale-up of circumcision in this and similar communities in South Africa.
Evaluation of the Measuring and Improving Quality in Palliative Care Survey.

PURPOSE To evaluate the reliability, content validity, and variation among sites of a survey to assess facilitators and barriers to quality measurement and improvement in palliative care programs. METHODS We surveyed a sample of diverse US and Canadian palliative care programs and conducted postcompletion discussion groups. The survey included constructs addressing educational support and training, communication, teamwork, leadership, and prioritization for quality measurement and improvement. We tested internal consistency reliability, described variation among sites, and reported descriptive feedback on content validity. RESULTS Of 103 respondents in 11 sites, the most common roles were attending physician (38.9%) and nurse practitioner, clinical nurse specialist, or physician assistant (16.5%). Internal consistency reliability was acceptable (Cronbach's α = .70 to .99) for all but one construct. Results varied across sites by more than 1 point on the 1 to 5 scales between the 10th and 90th percentiles of sites for two constructs in recognition and focus on quality measurement (score range by site, 1.7 to 4.8), one construct in teamwork (score range, 3.1 to 4.6), and five constructs in quality improvement (score range, 1.8 to 4.6). In descriptive content validity evaluation, respondents described the survey as an opportunity for assessing quality initiatives and discussing potential improvements, particularly improvements in communication, training, and engagement of team members regarding program quality efforts. CONCLUSION This survey to assess palliative care team perspectives on barriers and facilitators for quality measurement and improvement demonstrated reliability, content validity, and initial evidence of variation among sites. Our findings highlight how palliative care team members' perspectives may be valuable to plan, evaluate, and monitor quality-of-care initiatives.
Differential Innovativeness Outcomes of User and Employee Participation in an Online User Innovation Community

Abstract Firm-hosted online user innovation communities (OUICs) have emerged as a vital source of knowledge and expertise for innovation and new product development. Prior research on OUICs has primarily focused on participation of external product users and benefits obtained from their contributions. However, the role of internal employees of the host firm, albeit essential for the community’s long-term success, has not yet received much attention. This study attempts to bridge this gap by investigating the innovation outcomes of employees participating in OUICs. By analyzing a longitudinal data set collected from Salesforce.com’s IdeaExchange community, we find that accessing product user ideas with diverse and well-codified content drives idea promotion and generation of participating employees. Moreover, ideas contributed and promoted by employees are more likely to be implemented than those contributed and only promoted by product users. We discuss important implications of our study for the online innovation community literature and for the development of overall employee engagement in OUICs.
Implementation of the Street Outreach Office in the perspective of health care.

OBJECTIVE To report the experience of implementation of a clinical equipment of health care production to homeless people, denominated Street Outreach Office. METHOD Experience report in the city of Rio de Janeiro, Brazil. RESULTS The Street Outreach Office implementation resulted from a demand for health care practices for homeless people. This implementation had intersectoral articulations, causing health professionals to carry out street care practices, which led them to strive for public policies, to rethink their actions in order to increase the resolution of care to this population. CONCLUSION We should emphasize the importance of health professionals to reinvent their practices, daily, seeking partnerships and acquisition of new knowledge in order to achieve results that can reduce the demands of these individuals throughout their life routes.
Measuring quantity and function of pneumococcal antibodies in immunoglobulin products

Immunoglobulin replacement therapy is a cornerstone of the treatment of primary immunodeficiencies. Preparations used for replacement therapy are processed by purifying immunoglobulins from large pools of plasma, which were obtained from healthy donors. The constituent antibodies in these products depend on the immune history of the donor pool as well as manufacturing processes that differ among manufacturers. For these reasons various methods have been proposed to examine the levels and function of antibodies to organisms such as Streptococcus pneumoniae, which frequently causes infections in patients with immunodeficiencies. Pneumococcal antibody levels or antibody function can be measured with enzyme‐linked immunosorbent assay (ELISA) or multiplexed opsonophagocytosis assay (MOPA). Although these assays were developed initially to assess the immunogenicity of pneumococcal vaccines, the techniques have been adapted to evaluate immunoglobulin products as well.
Efficacy and acceptability of antidepressants in patients with ischemic heart disease: systematic review and meta-analysis

To assess the efficacy and acceptability of antidepressants in adults with ischemic heart disease (IHD). We gathered all available randomized-controlled trials comparing antidepressants versus placebo or other antidepressants in adults with IHD. The primary outcome was depressive symptoms at the study endpoint, as measured by validated rating scales. We pooled data in a meta-analysis using a random-effects model. The confidence in the estimates (or certainty of the evidence) was assessed using the GRADE approach. Antidepressants appeared to be more effective than placebo in reducing depressive symptoms (11 comparisons; 1685 participants; standardized mean difference −0.71, 95% confidence interval: −1.11 to −0.30; GRADE quality: moderate). This result was confirmed in the subgroup of serotonin selective reuptake inhibitors, and for the single drugs sertraline and citalopram, with a greater magnitude of effect and a higher quality of evidence for the former. No differences between antidepressants and placebo emerged in terms of acceptability and tolerability, quality of life, mortality, and cardiovascular events. Only two small head-to-head studies were identified. Sertraline is a reasonable first-line choice in patients with IHD and depression, whereas the role of citalopram as the first-line agent should be reconsidered.
The renin–angiotensin system in the arcuate nucleus controls resting metabolic rate

Purpose of review Obesity represents the primary challenge to improving cardiovascular health, and suppression of resting metabolic rate (RMR) is implicated in the maintenance of obesity. Increasing evidence supports a major role for the renin–angiotensin system (RAS) within the brain in the control of RMR. Recent findings The angiotensin II (ANG) Agtr1a receptor colocalizes with the leptin receptor (Lepr) primarily within cells of the arcuate nucleus (ARC) of the hypothalamus that also express Agouti-related peptide (Agrp). This sub-population of Agtr1a receptors is required for stimulation of thermogenic sympathetic nervous activity and RMR, but not the suppression of food intake or increasing blood pressure, in response to various stimuli including high-fat diet, deoxycorticosterone acetate and salt, and leptin. Agtr1a is localized to a specific subset (SST3) of Agrp neurons within the ARC. Summary The RAS within the ARC is implicated specifically in RMR control, primarily through Agtr1a localized to the SST3 subset of Agrp neurons. Ongoing research is focused on understanding the unique anatomical projections, neurotransmitter utilization, and signal transduction pathways of Agtr1a within this subset of neurons. Understanding these projections and molecular mechanisms may identify therapeutic targets for RMR and thus obesity, independent of blood pressure and appetite.
HIV controllers suppress viral replication and evolution and prevent disease progression following intersubtype HIV-1 superinfection

Objective: The aim of this study was to investigate the impact of intersubtype HIV-1 superinfection on viremia, reservoir reseeding, viral evolution and disease progression in HIV controllers (HIC). Design: A longitudinal analysis of two Brazilian HIC individuals (EEC09 and VC32) previously identified as dually infected with subtypes B and F1 viruses. Methods: Changes in plasma viremia, total HIV-1 DNA levels, CD4+ T-cell counts and HIV-1 quasispecies composition were measured over time. HIV-1 env diversity in peripheral blood mononuclear cell (PBMC) and plasma samples was accessed by single genome amplification and next-generation sequencing approaches, respectively. Viral evolution was evaluated by estimating nucleotide diversity and divergence. Results: Individual EEC09 was probably initially infected with a CCR5-tropic subtype B strain and sequentially superinfected with a CXCR4-tropic subtype B strain and with a subtype F1 variant. Individual VC32 was infected with a subtype B strain and superinfected with a subtype F1 variant. The intersubtype superinfection events lead to a moderate increase in viremia and extensive turnover of viral population in plasma but exhibited divergent impact on the size and composition of cell-associated HIV DNA population. Both individuals maintained virologic control (<2000 copies/ml) and presented no evidence of viral evolution or immunologic progression for at least 2 years after the intersubtype superinfection event. Conclusion: These data revealed that some HIC are able to repeatedly limit replication and evolution of superinfecting viral strains of a different subtype with no signs of disease progression.
Diuretic, Natriuretic, and Vasodepressor Activity of a Lipid Fraction Enhanced in Medium of Cultured Mouse Medullary Interstitial Cells by a Selective Fatty Acid Amide Hydrolase Inhibitor

The relationship between the endocannabinoid system in the renal medulla and the long-term regulation of blood pressure is not yet understood. To investigate the possible role of the endocannabinoid system in renomedullary interstitial cells, mouse medullary interstitial cells (MMICs) were obtained, cultured, and characterized for their responses to treatment with a selective inhibitor of fatty acid amide hydrolase, PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide). Treatment of MMICs with PF-3845 increased cytoplasmic lipid granules detected by Sudan Black B staining and multilamellar bodies identified by transmission electron microscopy. High-performance liquid chromatography (HPLC) analyses of lipid extracts of MMIC culture medium revealed a 205-nm absorbing peak that showed responsiveness to PF-3845 treatment. The biologic activities of the PF-3845–induced product (PIP) isolated by HPLC were investigated in anesthetized, normotensive surgically instrumented mice. Intramedullary and intravenous infusion of PIP at low dose rates (0.5–1 area units under the peak/10 min) stimulated diuresis and natriuresis, whereas these parameters returned toward baseline at higher doses but mean arterial pressure (MAP) was lowered. Whereas intravenous bolus doses of PIP stimulated diuresis, the glomerular filtration rate, and medullary blood flow (MBF) and reduced or had no effect on MAP, an intraperitoneal bolus injection of PIP reduced MAP, increased MBF, and had no effect on urine parameters. These data support a model whereby PF-3845 treatment of MMICs results in increased secretion of a neutral lipid that acts directly to promote diuresis and natriuresis and indirectly through metabolites to produce vasodepression. Efforts to identify the structure of the PF-3845–induced lipid and its relationship to the previously proposed renomedullary antihypertensive lipids are ongoing.