Miracle-dz/UniFAR-FTUs huggingface dataset:
Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Origin: Retrospective Molecular Classification Considering the CUPISCO Study Design

Abstract Background Carcinoma of unknown primary origin (CUP) accounts for 2%–5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm. Materials and Methods Centrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture‐based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death‐ligand 1 (PD‐L1) positivity were determined. Results A total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB ≥16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD‐L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%. Conclusions Thirty‐two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD‐L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP‐informed treatment. Clinical trial identification number. NCT03498521 Implications for Practice The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death‐ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling‐informed treatment.
Polygenic Risk Score of Longevity Predicts Longer Survival Across an Age Continuum

Abstract Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N = 343), a population-matched cohort of older adults from 5 cohorts (N = 2905), and summary statistics data from genome-wide association studies on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older adults. This PRS was also associated with longer survival in an independent sample of younger individuals (p = .02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human life span is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.
Propylene Glycol and Maize Grain Supplementation Improve Fertility Parameters in Dairy Cows

Simple Summary The excessive mobilization of fatty acids from dairy cows’ adipose tissue increases blood non-esterified fatty acid concentrations and could have a negative effect on the fertility parameters and milk yield, as well as increase the risk of metabolic disorders and also result in early-lactation culling risk. Propylene glycol and rumen-protected starch from maize grain are commonly used as glucose precursors reducing nonesterified fatty acid levels; however, no such comparisons are available, thus it was decided to assume it as the aim of this study. Propylene glycol had a positive effect on shortening the period to first ovulation. Propylene glycol and maize grain improved the first service conception rate and decreased the number of services per conception in cows. In conclusion, both treatments with propylene glycol and maize grain had a slight effect on the metabolic profile and no effect on milking performance, yet they improved fertility parameters, which could indirectly enhance milk production economics. Abstract The aim of the study was to determine the effect of propylene glycol and maize grain content by-pass starch supplementation during the transition period and the first 56 days of lactation on blood metabolic indices, milk production and fertility parameters in dairy cows. Seventy-five Polish Holstein-Friesian dairy cows were assigned to treatment 21 days before calving. The treatments included: TG—2.5 kg triticale grain/cow per day supplemented from 14 days prepartum to day 56 postpartum, PG—2.5 kg triticale grain/cow per day supplemented from day 14 before parturition to day 56 postpartum, and 400 g propylene glycol/cow per day from 14 days prepartum to 14 days of lactation and MG—2.5 kg maize grain/cow per day supplemented from day 14 before parturition to day 56 postpartum. PG and MG had an effect resulting in the highest glucose concentration at 28 d of lactation. Cows assigned to the PG and MG groups had significantly higher cholesterol levels confronted with TG group at day 14 of lactation, while at days 28 and 56 the same difference was observed only between the MG and TG groups. PG had an effect on shortening the period to first ovulation. PG and MG improved the first service conception rate and decreased the number of services per conception in cows. In conclusion, both treatments of dairy cows with PG and MG improved their fertility parameters, while they had a slight effect on their metabolic profile and no effect on their milking performance.
CRISPR-Cas Diversity in Clinical Salmonella enterica Serovar Typhi Isolates from South Asian Countries

Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), is a global health concern and its treatment is problematic due to the rise in antimicrobial resistance (AMR). Rapid detection of patients infected with AMR positive S. Typhi is, therefore, crucial to prevent further spreading. Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated genes (CRISPR-Cas), is an adaptive immune system that initially was used for typing purposes. Later, it was discovered to play a role in defense against phages and plasmids, including ones that carry AMR genes, and, at present, it is being explored for its usage in diagnostics. Despite the availability of whole-genome sequences (WGS), very few studied the CRISPR-Cas system of S. Typhi, let alone in typing purposes or relation to AMR. In the present study, we analyzed the CRISPR-Cas system of S. Typhi using WGS data of 1059 isolates obtained from Bangladesh, India, Nepal, and Pakistan in combination with demographic data and AMR status. Our results reveal that the S. Typhi CRISPR loci can be classified into two groups: A (evidence level >2) and B (evidence level ≤2), in which we identified a total of 47 unique spacers and 15 unique direct repeats. Further analysis of the identified spacers and repeats demonstrated specific patterns that harbored significant associations with genotype, demographic characteristics, and AMR status, thus raising the possibility of their usage as biomarkers. Potential spacer targets were identified and, interestingly, the phage-targeting spacers belonged to the group-A and plasmid-targeting spacers to the group-B CRISPR loci. Further analyses of the spacer targets led to the identification of an S. Typhi protospacer adjacent motif (PAM) sequence, TTTCA/T. New cas-genes known as DinG, DEDDh, and WYL were also discovered in the S. Typhi genome. However, a specific variant of the WYL gene was only identified in the extensively drug-resistant (XDR) lineage from Pakistan and ciprofloxacin-resistant lineage from Bangladesh. From this work, we conclude that there are strong correlations between variations identified in the S. Typhi CRISPR-Cas system and endemic AMR positive S. Typhi isolates.
Phenotypic Adaptation of Pseudomonas aeruginosa in the Presence of Siderophore-Antibiotic Conjugates during Epithelial Cell Infection

Iron acquisition pathways have often been considered to be gateways for the uptake of antibiotics into bacteria. Bacteria excrete chelators, called siderophores, to access iron. Antibiotic molecules can be covalently attached to siderophores for their transport into pathogens during the iron-uptake process. P. aeruginosa produces two siderophores and is also able to use many siderophores produced by other bacteria. We investigated the phenotypic plasticity of iron-uptake pathway expression in an epithelial cell infection assay in the presence of two different siderophore–antibiotic conjugates, one with a hydroxamate siderophore and the second with a tris-catechol. Proteomic and RT-qPCR approaches showed that P. aeruginosa was able to sense the presence of both compounds in its environment and adapt the expression of its iron uptake pathways to access iron via them. Moreover, the catechol-type siderophore–antibiotic was clearly more efficient in inducing the expression of its corresponding transporter than the hydroxamate compound when both were simultaneously present. In parallel, the expression of the proteins of the two iron uptake pathways using siderophores produced by P. aeruginosa was significantly repressed in the presence of both conjugates. Altogether, the data indicate that catechol-type siderophores are more promising vectors for antibiotic vectorization using a Trojan-horse strategy.
Transcranial magnetic stimulation and neuroimaging for cocaine use disorder: Review and future directions

ABSTRACT Background: Cocaine use disorder (CUD) is a public health problem with limited treatment options and a significant relapse rate. Neuroimaging studies have identified abnormal functional connectivity in individuals with substance use disorders. Neuromodulation has been proposed to target this altered neurocircuitry. Combining TMS with neuroimaging has the potential to inform identification of biomarkers, diagnosis, and treatment. Objectives: We review the literature of transcranial magnetic stimulation (TMS) with neuroimaging for CUD and outline a research path forward whereby TMS can be used to identify brain network features as diagnostic or prognostic biomarkers for treatment. Methods: We reviewed the literature for primary research studies of TMS with neuroimaging for CUD. We searched PubMed using search terms of “cocaine,” “transcranial magnetic stimulation,” and “neuroimaging. ” Identified studies were screened by title and abstract. Full-text studies were reviewed for inclusion. Results: In our initial search, we identified 73 studies. Six studies met our inclusion criteria. These studies used rTMS (n = 3) and single or paired pulse TMS (n = 3) and included a total of 289 participants. All studies used fMRI as the neuroimaging modality. The most common outcome measure was craving and cue-reactivity (n = 3). Conclusion: The literature combining TMS with neuroimaging is small and heterogeneous. We propose that combining TMS with neuroimaging will accelerate our understanding of substance use disorder neurobiology and treatment. Once network biomarkers of substance use have been identified, TMS can be used to manipulate the dysfunctional circuits in order to identify a causal relationship between connectivity and psychopathology.
Insomnia, fatigue and psychosocial well‐being during COVID‐19 pandemic: A cross‐sectional survey of hospital nursing staff in the United States

Abstract Aims and objectives To describe the levels of insomnia, fatigue and intershift recovery, and psychological well‐being (burnout, post‐traumatic stress and psychological distress), and to examine differences in these measures based on work‐related characteristics among nursing staff during COVID‐19 pandemic in the United States. Background The COVID‐19 pandemic has created a major physical and psychological burden on nursing staff in the United States and worldwide. A better understanding of these conditions will lead to tailored support and resources for nursing staff during and after the pandemic. Design Cross‐sectional study. Methods Hospital nurses and nursing assistants (N = 587) were recruited online between May–June 2020. The survey included measures on insomnia (Insomnia Severity Index) fatigue and intershift recovery (Occupational Fatigue and Exhaustion Recovery‐15), burnout (Maslach Burnout Inventory‐Human Services Survey), post‐traumatic stress (Short Post‐Traumatic Stress Disorder Rating Interview) and psychological distress (Patient Health Questionnaire‐4), and questions on work and demographics. The STROBE checklist was followed for reporting. Results The sample had subthreshold insomnia, moderate‐to‐high chronic fatigue, high acute fatigue and low‐to‐moderate intershift recovery. The sample experienced increased emotional exhaustion and depersonalisation, increased personal accomplishment, moderate psychological distress and high post‐traumatic stress. Nurses who cared for COVID‐19 patients had significantly scored worse on almost all measures than their co‐workers. Certain factors such as working hours per week and the frequency of 30‐min breaks were significant. Conclusion Nursing staff experienced poor sleep, fatigue and multiple psychological problems during the COVID‐19 pandemic. Moreover, staff who were involved in the care of COVID‐19 patients, worked more than 40 h per week and skipped 30‐min breaks showed generally worse self‐reported outcomes. Relevance to clinical practice Nursing administration is recommended to monitor for fatigue and distress on nursing units, re‐visit current scheduling practices, reinforce rest breaks and provide access to mental health and sleep wellness resources with additional support for their front‐line nursing groups.
Comparative study between ground-based observations and NAVGEM-HA analysis data in the mesosphere and lower thermosphere region

Abstract. Recent studies have shown that day-to-day variability of the migrating semidiurnal solar (SW2) tide within the mesosphere and lower thermosphere (MLT) is a key driver of anomalies in the thermosphere–ionosphere system. Here, we study the variability in both the amplitude and phase of SW2 using meteor radar wind and lidar temperature observations at altitudes of 75–110 km as well as wind and temperature output from the Navy Global Environmental Model – High Altitude (NAVGEM-HA), a high-altitude meteorological analysis system. Application of a new adaptive spectral filter technique to both local radar wind observations and global NAVGEM-HA analyses offers an important cross-validation of both data sets and makes it possible to distinguish between migrating and non-migrating tidal components, which is difficult using local measurements alone. Comparisons of NAVGEM-HA, meteor radar and lidar observations over a 12-month period show that the meteorological analyses consistently reproduce the seasonal as well as day-to-day variability in mean winds, mean temperatures and SW2 features from the ground-based observations. This study also examines in detail the day-to-day variability in SW2 during two sudden stratospheric warming, events that have been implicated in producing ionospheric anomalies. During this period, both meteor radar and NAVGEM-HA winds show a significant phase shift and amplitude modulation, but no signs of coupling to the lunar tide as previous studies have suggested. Overall, these findings demonstrate the benefit of combining global high-altitude meteorological analyses with ground-based observations of the MLT region to better understand the tidal variability in the atmosphere.
MARKETS, HIERARCHIES, AND FAMILIES: TOWARD A TRANSACTION COST THEORY OF THE FAMILY FIRM.

What factors explain the versatility, limitations and successes of Family Firms' (FFs) within and across different industrial and geographic contexts? We develop a transaction cost framework addressing this question. In doing so, we identify a class of asset we term 'generic non-tradables' (GNTs), that are firm-specific, but generic in application. We argue the governance structures of FFs provide them relative advantages in developing and appropriating rents from GNTs.
Mechanisms of arsenite binding to natural organic matter

Terrestrial ecosystems rich in natural organic matter (NOM) can act as a sink for As. Recently, the complexation of trivalent As by sulfhydryl groups of NOM was proposed as the main mechanism for As-NOM interactions in anoxic Sand NOM-rich environments. Here, we tested the molecular-scale interaction of bisulfide (S(-II)) with NOM and its consequences for arsenite (As(III)) binding. We reacted 0.2 mol C/L peat and humic acid (HA) with up to 5.8 mM S(-II) at pH 7 and 5, respectively, and subsequently equilibrated the reaction products with 55 μM As(III) under anoxic conditions. The speciation of S and the local coordination environment of As in the solid phase were studied by X-ray absorption spectroscopy. Our results document a rapid reaction of S(-II) with peat and HA and the concomitant formation of reduced organic S species. These species were highly reactive toward As(III). Shell fits of As K-edge extended X-ray absorption fine structure spectra revealed that the coordination environment of trivalent As was progressively occupied by S atoms. Fitted As-S distances of 2.24-2.34 Å were consistent with sulfhydryl-bound As(III). Besides As(III) complexation by organic monosulfides, our data suggests the formation of nanocrystalline As sulfide phases in HA samples and an As sorption process for both organic sorbents in which As(III) retained its first-shell oxygens. In conclusion, this study documents that S(-II) reaction with NOM can greatly enhance the ability of NOM to bind As in anoxic environments. Chapter 2. Bisulfide reaction with NOM enhances As(III) sorption: Insights from XAS
Reconstructing and analyzing China's fifty-nine year (1951–2009) drought history using hydrological model simulation

Abstract. The 1951–2009 drought history of China is reconstructed using daily soil moisture values generated by the Variable Infiltration Capacity (VIC) land surface macroscale hydrology model. VIC is applied over a grid of 10 458 points with a spatial resolution of 30 km × 30 km, and is driven by observed daily maximum and minimum air temperature and precipitation from 624 long-term meteorological stations. The VIC soil moisture is used to calculate the Soil Moisture Anomaly Percentage Index (SMAPI), which can be used as a measure of the severity of agricultural drought on a global basis. We have developed a SMAPI-based drought identification procedure for practical uses in the identification of both grid point and regional drought events. As a result, a total of 325 regional drought events varying in time and strength are identified from China's nine drought study regions. These drought events can thus be assessed quantitatively at different spatial and temporal scales. The result shows that the severe drought events of 1978, 2000 and 2006 are well reconstructed, which indicates that the SMAPI is capable of identifying the onset of a drought event, its progression, as well as its termination. Spatial and temporal variations of droughts in China's nine drought study regions are studied. Our result shows that on average, up to 30% of the total area of China is prone to drought. Regionally, an upward trend in drought-affected areas has been detected in three regions (Inner Mongolia, Northeast and North) from 1951–2009. However, the decadal variability of droughts has been weak in the rest of the five regions (South, Southwest, East, Northwest, and Tibet). Xinjiang has even been showing steadily wetter since the 1950s. Two regional dry centres are discovered in China as the result of a combined analysis on the occurrence of drought events from both grid points and drought study regions. The first centre is located in the area partially covered by the North and the Northwest, which extends to the southeastern portion of Inner Mongolia and the southwest part of Northeast. The second one is found on the central to southern portion of the South. Our study demonstrates the applicability and the value of using modeled soil moisture for reconstructing drought histories, and the SMAPI is useful for analyzing drought at different spatial and temporal scales.
Sugar transport and metabolism in gram-positive bacteria

reader can obtain more detail without being faced by a multitude of alternative references. I read chapter 6, ‘From Egg to Embryo’, in detail for accuracy, since I have been interested and taught in this area for several years. There were some confusions arising from typographical errors (e.g. p. 109: micromeres have a stronger vegetalizing (not animalizing) influence than macromeres). More serious confusion may be generated by the statement that polar lobes are sensitive to inhibition by actinomycin D, where they are insensitive (p. 104). Having read most of the book with interest I was authors were content with one-line summaries of the intrinsic and extrinsic factors which can be involved. The diagram (fig. 11.8) of a possible sequence for gene activation might have been balanced by a scheme of cytoskeletal movements in the egg generating asymmetries of cytoplasmic components, particularly since the book starts with the welcome emphasis that mechanisms of gene regulation do not explain commitment. Despite this I found the book easy to read and interesting. The topic, the length and the approach make it a valuable overview for advanced undergraduates.
Innovative technique of keyhole ovariohysterectomy in bitches for post-operative pain management

Present study was undertaken to determine the intraperitoneal analgesic effect of bupivacaine in bitches undergoing keyhole ovariohystercetomy. The pain assessment was done before surgery and at different time intervals up to 18th hour after surgery using two pain scales {Glasgow composite pain scale (GCPS) and University of Melbourne pain scale (UMPS)}. To undertake the study animals were divided into two groups, group A and group B (each containing 12 animals). The animals of group B were given bupivacaine intraperitoneally and in group A animals normal saline was used intraperitonealy. Significant number of animals in Group B showed earlier recovery after 8 hours post-operatively of the study and group A showed recovery at the end of the study that is at the 18th post-operative hour.