Miracle-dz/UniFAR-FTUs huggingface dataset:
The Psychometric Properties of the Hypersexual Behavior Inventory Using a Large-Scale Nonclinical Sample

The conceptualization of hypersexuality has begun to converge as a result of proposed diagnostic criteria. However, its measurement is still diverse. The Hypersexual Behavior Inventory (HBI) is one of the most appropriate scales used to assess hypersexuality, but further examination is needed to test its psychometric properties among different clinical and nonclinical groups, including samples outside of the United States. The aim of the present study was to investigate the reliability and the generalizability of HBI and to determine a cutoff score on a large, diverse, online, nonclinical sample (N = 18,034 participants; females = 6132; 34.0%; Mage = 33.6 years, SDage = 11.1). Confirmatory factor analysis (CFA) and reliability indices provided support for the structure of the HBI and demonstrated excellent reliability. Employing latent profile analysis (LPA), seven classes emerged, but they could not be reliably distinguished by objective sexuality-related characteristics. Moreover, it was not possible to determine an adequate cutoff score, most likely due to the low prevalence rate of hypersexuality in the population. HBI can be reliably used to measure the extent of hypersexual urges, fantasies, and behavior; however, objective indicators and a clinical interview are essential to claim that a given individual may exhibit features of problematic sexual behavior.
Gluconeogenic precursor availability regulates flux through the glyoxylate shunt in Pseudomonas aeruginosa

The glyoxylate shunt bypasses the oxidative decarboxylation steps of the tricarboxylic acid (TCA) cycle, thereby conserving carbon skeletons for gluconeogenesis and biomass production. In Escherichia coli, carbon flux is redirected through the first enzyme of the glyoxylate shunt, isocitrate lyase (ICL), following phosphorylation and inactivation of the TCA cycle enzyme, isocitrate dehydrogenase (ICD), by the kinase/phosphatase, AceK. In contrast, mycobacterial species lack AceK and employ a phosphorylation-insensitive isocitrate dehydrogenase (IDH), which is allosterically activated by the product of ICL activity, glyoxylate. However, Pseudomonas aeruginosa expresses IDH, ICD, ICL, and AceK, raising the question of how these enzymes are regulated to ensure proper flux distribution between the competing pathways. Here, we present the structure, kinetics, and regulation of ICL, IDH, and ICD from P. aeruginosa. We found that flux partitioning is coordinated through reciprocal regulation of these enzymes, linking distribution of carbon flux to the availability of the key gluconeogenic precursors, oxaloacetate and pyruvate. Specifically, a greater abundance of these metabolites activated IDH and inhibited ICL, leading to increased TCA cycle flux. Regulation was also exerted through AceK-dependent phosphorylation of ICD; high levels of acetyl-CoA (which would be expected to accumulate when oxaloacetate is limiting) stimulated the kinase activity of AceK, whereas high levels of oxaloacetate stimulated its phosphatase activity. In summary, the TCA cycle–glyoxylate shunt branch point in P. aeruginosa has a complex enzymology that is profoundly different from those in other species characterized to date. Presumably, this reflects its predilection for consuming fatty acids, especially during infection scenarios.
Neuropathic Pain Creates an Enduring Prefrontal Cortex Dysfunction Corrected by the Type II Diabetic Drug Metformin But Not by Gabapentin

Chronic pain patients suffer from pain-related cognitive deficits, even when taking commonly prescribed analgesics. These deficits are likely related to pain-related maladaptive plasticity in the frontal cortex. We sought to model cognitive deficits in mice with neuropathic pain to examine maladaptive morphological plasticity in the mPFC and to assess the effects of several therapeutics. We used an attentional set-shifting task in mice with spared nerve injury (SNI) who received either a single intrathecal injection of an analgesic dose of clonidine, 7 d of 100 mg/kg gabapentin, or 7 d of 200 mg/kg metformin. Male SNI mice were significantly more impaired in the set-shifting task than females. This deficit correlated with a loss of parvalbumin (PV) and reductions in axon initial segment (AIS) length in layers 5/6 of the infralimbic (IL) cortex. Acute pain relief with clonidine had no effect on set-shifting performance, whereas pain relief via 7 day treatment with gabapentin worsened the impairment in both SNI and sham mice. Gabapentin reversed the PV loss in the IL but had no effect on AIS length. Treatment with the AMPK-activator metformin completely reversed the pain-related cognitive impairment and restored AIS length in the IL but had little effect on PV expression. Our findings reveal that neuropathic pain-related cognitive impairments in male mice are correlated to bilateral morphological changes in PV interneurons and layer 5/6 IL pyramidal neuron AIS. Pain relief with metformin can reverse some of the functional and anatomical changes. SIGNIFICANCE STATEMENT Cognitive impairments are a comorbidity of neuropathic pain but are inadequately addressed by existing therapeutics. We used a neuropathic pain model in mice to demonstrate that male (but not female) mice show a robust pain-related deficit in attentional set-shifting, which is associated with structural plasticity in axon initial segments in the infralimbic cortex. These deficits were completely reversed by 7 day treatment with the antidiabetic drug metformin, suggesting that this drug can be repurposed for the treatment of neuropathic pain and its cognitive comorbidities. Our findings have implications for our understanding of how neuropathic pain causes structural plasticity in the brain, and they point to a marked sexual dimorphism in neuropathic pain mechanisms in mice.
Exploration and stabilization of Ras1 mating zone: A mechanism with positive and negative feedbacks

In mating fission yeast cells, sensing and response to extracellular pheromone concentrations occurs through an exploratory Cdc42 patch that stochastically samples the cell cortex before stabilizing towards a mating partner. Active Ras1 (Ras1-GTP), an upstream regulator of Cdc42, and Gap1, the GTPase-activating protein for Ras1, localize at the patch. We developed a reaction-diffusion model of Ras1 patch appearance and disappearance with a positive feedback by a Guanine nucleotide Exchange Factor (GEF) and Gap1 inhibition. The model is based on new estimates of Ras1-GDP, Ras1-GTP and Gap1 diffusion coefficients and rates of cytoplasmic exchange studied by FRAP. The model reproduces exploratory patch behavior and lack of Ras1 patch in cells lacking Gap1. Transition to a stable patch can occur by change of Gap1 rates constants or local increase of the positive feedback rate constants. The model predicts that the patch size and number of patches depend on the strength of positive and negative feedbacks. Measurements of Ras1 patch size and number in cells overexpressing the Ras1 GEF or Gap1 are consistent with the model.
Organizing the World

Zwei Jahrzehnte nach dieser Bestandsaufnahme stellt sich die Situation kaum anders dar. So finden sich damals wie heute lediglich vereinzelte Studien, die internationale Organisationen »als Organisationen« begreifen und die Integration von IBund Organisationstheorien versuchen. Dass der Austausch zwischen beiden Disziplinen gering ist, liegt sicherlich auch an der Mehrdeutigkeit des Organisationsbegriffs, der in beiden Disziplinen zum Teil unterschiedlich verstanden wird. Nach einer frühen Phase, in der formale Organisationen im Zentrum des Interesses standen, wurde »Organisation« in den IB zumeist sehr weit im Sinne von Ordnung interpretiert (vgl. Kratochwil/Ruggie 1986; Rochester 1986). Erst in den vergangenen Jahren sind die von konkreten interund transnationalen Organisationen erbrachten Ordnungsleistungen wieder verstärkt in den Blick gerückt; in diesem Zusammenhang ist auch ein gesteigertes Interesse an internationalen Bürokratien zu beobachten (siehe Biermann/Bauer 2005; Liese/ Weinlich 2006). Umgekehrt war das Interesse der Organisationstheorie an internationalen Organisationen lange Zeit bestenfalls gering. Indem sie zunehmend transnationale Verregelungsprozesse in den Blick nimmt, bewegt sich die Organisationstheorie jedoch auf die Internationalen Beziehungen zu. Vor diesem Hintergrund bietet die vom Stockholm Centre for Organizational Research (SCORE) im Oktober vergangenen Jahres veranstaltete Konferenz »Organizing the World: Rules and Rule-Setting among Organizations« Gelegenheit, im Rahmen eines gemeinsamen Forschungsgegenstands – dem globalen Organisieren durch Regeln – den potenziellen Mehrwert der Organisationsforschung für die Internationalen Beziehungen zu erkunden.
On selection of an appropriate logistic model to determine the risk factors of childhood stunting in Bangladesh

Stunting is the core measure of child health inequalities as it reveals multiple dimensions of child health and development status. The main focus of this study is to show the procedure of selecting the most appropriate logistic regression model for stunting by developing and comparing several plausible models, which ultimately helps to identify the predictors of childhood stunting in Bangladesh. This study utilizes child anthropometric data collected in the 2014 Bangladesh Demographic and Health Survey. Valid height-for-age anthropometric indices were available for a total of 6,931 children aged 0-59 months, of which about 36% were stunted. Ordinary logistic, survey logistic, marginal logistic, and random intercept logistic regression models were developed assuming independence, sampling design, cluster effect, and hierarchy of the data. Based on a number of model selection criteria, random intercept logistic model is found the most appropriate for the studied children. A number of child, mother, household, regional, and community-level variables were included in the model specification. The factors that increased the odds of stunting are children older than 11 months, short birth interval, recent morbidity of children, lower maternal education, young maternity, lower maternal body mass index, poor household wealth, urban residential place, and living in Sylhet division. Findings of this study recommend to utilize an appropriate logistic model considering the issues relevant to the data, particularly sampling design and clustering for determining the risk factors of childhood stunting in Bangladesh.
p53 upregulated by HIF-1α promotes hypoxia-induced G2/M arrest and renal fibrosis in vitro and in vivo

Abstract Hypoxia plays an important role in the genesis and progression of renal fibrosis. The underlying mechanisms, however, have not been sufficiently elucidated. We examined the role of p53 in hypoxia-induced renal fibrosis in cell culture (human and rat renal tubular epithelial cells) and a mouse unilateral ureteral obstruction (UUO) model. Cell cycle of tubular cells was determined by flow cytometry, and the expression of profibrogenic factors was determined by RT-PCR, immunohistochemistry, and western blotting. Chromatin immunoprecipitation and luciferase reporter experiments were performed to explore the effect of HIF-1α on p53 expression. We showed that, in hypoxic tubular cells, p53 upregulation suppressed the expression of CDK1 and cyclins B1 and D1, leading to cell cycle (G2/M) arrest (or delay) and higher expression of TGF-β, CTGF, collagens, and fibronectin. p53 suppression by siRNA or by a specific p53 inhibitor (PIF-α) triggered opposite effects preventing the G2/M arrest and profibrotic changes. In vivo experiments in the UUO model revealed similar antifibrotic results following intraperitoneal administration of PIF-α (2.2 mg/kg). Using gain-of-function, loss-of-function, and luciferase assays, we further identified an HRE3 region on the p53 promoter as the HIF-1α-binding site. The HIF-1α–HRE3 binding resulted in a sharp transcriptional activation of p53. Collectively, we show the presence of a hypoxia-activated, p53-responsive profibrogenic pathway in the kidney. During hypoxia, p53 upregulation induced by HIF-1α suppresses cell cycle progression, leading to the accumulation of G2/M cells, and activates profibrotic TGF-β and CTGF-mediated signaling pathways, causing extracellular matrix production and renal fibrosis.
18F-FDG PET/CT for response assessment in Hodgkin lymphoma undergoing immunotherapy with checkpoint inhibitors

Abstract Our aim was to evaluate Hodgkin Lymphoma (HL) response to checkpoint inhibitors with 18F-FDG PET/CT. Forty three refractory or relapsed HL patients were investigated before immunotherapy, 8 weeks and 17 weeks after administration of either nivolumab or pembrolizumab. The median follow-up was 19 months. Best clinical response was complete response (CR) in 26 patients, partial response (PR) in 5 patients, stable disease (SD) in 8 patients, and progression disease (PD) in 4 patients. At the early assessment, Deauville Score (DS) resulted significantly different in responder group compared to nonresponders. SUVmax was significantly lower in responders, while there was no relevant modification in the tumor burden. At interim evaluation, DS well differentiated responder group. A significant decrease in glucose metabolism and tumor burden parameters was observed in responder patients, who presented with a longer progression-free survival then nonresponders. 18F-FDG PET/CT provides a reliable indication of treatment response under checkpoints inhibitors, even at an early assessment.
Mechanistic insights into the regulation of transcription and transcription-coupled DNA repair by Cockayne syndrome protein B

Abstract Cockayne syndrome protein B (CSB) is a member of the SNF2/SWI2 ATPase family and is essential for transcription-coupled nucleotide excision DNA repair (TC-NER). CSB also plays critical roles in transcription regulation. CSB can hydrolyze ATP in a DNA-dependent manner, alter protein-DNA contacts and anneal DNA strands. How the different biochemical activities of CSB are utilized in these cellular processes have only begun to become clear in recent years. Mutations in the gene encoding CSB account for majority of the Cockayne syndrome cases, which result in extreme sun sensitivity, premature aging features and/or abnormalities in neurology and development. Here, we summarize and integrate recent biochemical, structural, single-molecule and somatic cell genetic studies that have advanced our understanding of CSB. First, we review studies on the mechanisms that regulate the different biochemical activities of CSB. Next, we summarize how CSB is targeted to regulate transcription under different growth conditions. We then discuss recent advances in our understanding of how CSB regulates transcription mechanistically. Lastly, we summarize the various roles that CSB plays in the different steps of TC-NER, integrating the results of different studies and proposing a model as to how CSB facilitates TC-NER.
Size Distribution of Small Interfering RNAs in Various Organs at Different Developmental Stages is Primarily Determined by the Dicing Activity of Dicer-Like Proteins in Plants

RNA silencing is a fundamental mechanism to maintain plant growth and development, and regulation of the size distribution of small interfering RNAs (siRNAs) is critical in the control of normal gene expression throughout a plant's life cycle. However, the cause of organ- and developmental stage-specific accumulation of siRNAs has never been reported. Whereas 24 nt siRNAs accumulated about 5.3-fold more than 21 nt siRNAs in Arabidopsis rosette leaves, 21 and 24 nt siRNAs accumulated to similar levels in Arabidopsis pollen grains, rice spikelets and maize anthers. We successfully detected two distinct double-stranded RNA (dsRNA)-cleaving activities that produced 21 and 24 nt RNAs in cell-free extracts prepared from various organs at different developmental stages of A. thaliana, Brassica rapa, rice and maize. Although DCL4 transcript was expressed more than DCL3 transcript in most organs, the 21 nt RNA-producing activity of DCL4 or its orthologs was very low and was 5- to 10-fold lower than the 24 nt RNA-producing activity of DCL3 or its orthologs particularly in leaves, indicating that DCL4 activity is negatively regulated translationally or post-translationally in leaves. High dicing activity of DCL3 and DCL4 was detected in immature inflorescences, developing seeds, germinating embryos and callus, all of which contain actively dividing cells. In various organs at different developmental stages, the size distribution of siRNAs was positively correlated with the dicing activity of two Dicers, DCL3 and DCL4, or their orthologs. Taken together, the size distribution of siRNAs in most organs is primarily determined by the dicing activity of DCL3 and DCL4.
Longitudinal Associations Between Parent-Child Relationships in Middle Childhood and Child-Perceived Loneliness

Loneliness may affect children’s psychological well-being and academic achievement. Parent-child relationships have been consistently associated with child adjustment. However, parental antecedents of child loneliness have been relatively understudied. Guided by attachment theory, we examined the trajectories of father-child and mother-child relationship closeness and conflict, and their associations with trajectories of child loneliness with National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development (SECCYD) data to understand parents’ roles in child loneliness in middle childhood. In Grades 1 (Mage = 6.57, SD = .29), 3, 4, and 5, both resident fathers and mothers reported on parent-child relationships. At Grades 1, 3, and 5, children reported on their loneliness. Loneliness declined from Grade 1 to Grade 5. After controlling for socioeconomic status (SES), the slope of father-child relationship closeness was negatively associated with the slope of loneliness for girls (n = 341), but not for boys (n = 354). The more slowly father-child closeness declined, the more quickly girls’ loneliness declined. These findings highlight the role of father-child relationships in child loneliness for girls. Future research on child loneliness should take both maternal and paternal roles into consideration.
Anatomical variations in the circle of Willis in canines

The circle of Willis (CW) supplies blood to the brain. In humans, anatomical variations in the CW are an important risk factor for transient ischaemic attack and stroke. In canines, anatomical variations in the CW have not been reported. The aim of this study was to determine anatomical variations in the CW in dogs by magnetic resonance angiography. Normal configuration of the CW was observed in 82%, aplasia of the precommunicating segment of the rostral cerebral artery was observed in 14%, and aplasia of the rostral communicating artery was observed in 4% of dogs included in the study.
Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression

A homozygous truncating frameshift mutation in CEP57 (CEP57T/T) has been identified in a subset of mosaic-variegated aneuploidy (MVA) patients; however, the physiological roles of the centrosome-associated protein CEP57 that contribute to disease are unknown. To investigate these, we have generated a mouse model mimicking this disease mutation. Cep57T/T mice died within 24 hours after birth with short, curly tails and severely impaired vertebral ossification. Osteoblasts in lumbosacral vertebrae of Cep57T/T mice were deficient for Fgf2, a Cep57 binding partner implicated in diverse biological processes, including bone formation. Furthermore, a broad spectrum of tissues of Cep57T/T mice had severe aneuploidy at birth, consistent with the MVA patient phenotype. Cep57T/T mouse embryonic fibroblasts and patient-derived skin fibroblasts failed to undergo centrosome maturation in G2 phase, causing premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high rates of chromosome missegregation. Mice heterozygous for the truncating frameshift mutation or a Cep57-null allele were overtly indistinguishable from WT mice despite reduced Cep57 protein levels, yet prone to aneuploidization and cancer, with tumors lacking evidence for loss of heterozygosity. This study identifies Cep57 as a haploinsufficient tumor suppressor with biologically diverse roles in centrosome maturation and Fgf2-mediated bone formation.
On Statistical Modeling of Sequencing Noise in High Depth Data to Assess Tumor Evolution

One cause of cancer mortality is tumor evolution to therapy-resistant disease. First line therapy often targets the dominant clone, and drug resistance can emerge from preexisting clones that gain fitness through therapy-induced natural selection. Such mutations may be identified using targeted sequencing assays by analysis of noise in high-depth data. Here, we develop a comprehensive, unbiased model for sequencing error background. We find that noise in sufficiently deep DNA sequencing data can be approximated by aggregating negative binomial distributions. Mutations with frequencies above noise may have prognostic value. We evaluate our model with simulated exponentially expanded populations as well as data from cell line and patient sample dilution experiments, demonstrating its utility in prognosticating tumor progression. Our results may have the potential to identify significant mutations that can cause recurrence. These results are relevant in the pretreatment clinical setting to determine appropriate therapy and prepare for potential recurrence pretreatment.