Miracle-dz/UniFAR-FTUs huggingface dataset:
Germline-activating mutations in PIK3CD compromise B cell development and function

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110&dgr; subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd. In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110&dgr; inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110&dgr; inhibitors.
Spin-fluctuation and spin-relaxation effects of single adatoms from first principles

Single adatoms offer an exceptional playground for studying magnetism and its associated dynamics at the atomic scale. Here we review recent results on single adatoms deposited on metallic substrates, based on time-dependent density functional theory. First we analyze quantum zero-point spin-fluctuations (ZPSF) as calculated from the fluctuation-dissipation theorem, and show how they affect the magnetic stability by modifying the magnetic anisotropy energy. We also assess the impact of ZPSF in the limit of small hybridization to the substrate characteristic of semi-insulating substrates, connecting to recent experimental investigations where magnetic stability of a single adatom was achieved for the first time. Secondly, we inspect further the dynamics of single adatoms by considering the longitudinal and transverse spin-relaxation processes, whose time-scales are analyzed and related to the underlying electronic structure of both the adatom and the substrate. Thirdly, we analyze spin-fluctuation modes of paramagnetic adatoms, i.e. adatoms where the Stoner criterion for magnetism is almost fulfilled. Interestingly, such modes can develop well-defined peaks in the meV range, their main characteristics being determined by two fundamental electronic properties, namely the Stoner parameter and the density of states at the Fermi level. Furthermore, simulated inelastic scanning tunneling spectroscopy curves reveal that these spin-fluctuation modes can be triggered by tunneling electrons, opening up potential applications also for paramagnetic adatoms. Lastly, an overview of the outstanding issues and future directions is given.
A novel homozygous frame‐shift variant in the LHCGR gene is associated with primary ovarian insufficiency in a Pakistani family

To the Editor: Primary ovarian insufficiency (POI) affects 1% to 2% of women and is a genetically heterogeneous condition characterized by hypergonadotropic hypogonadism, amenorrhea, and infertility. POI patients are evaluated for chromosomal, iatrogenic, endocrine, autoimmune, and infectious causes. Women with POI onset prior to age 20 are more likely to have a strong genetic component. In this study, we investigated a consanguineous Pakistani family belonging to the district Hazara of Khyber Pakhtunkhwa. Parents were first cousins and had three daughters and one son. Two daughters presented with primary amenorrhea, hypergonadotropic hypogonadism, and normal 46, XX karyotypes. The Ethical Review Board of Khyber Medical University, approved this study and all participants provided informed consent. The first proband presented at 20 years of age with primary amenorrhea and hormonal evaluation was consistent with hypergonadotropic hypogonadism. Luteinizing hormone (37.50 IU/L; normal follicular range is 1.8-11.78 IU/L) and follicle stimulating hormone (26.30 IU/L; normal range is 3.03-8.08 IU/L) levels were elevated, while estradiol (25 pg/mL; normal range is 21-251), anti-mullerian hormone (1.51 ng/mL; normal range is 1-4), and testosterone (17.52 ng/dL; normal range is 11-57) levels were normal. Ultrasonography showed an anteverted uterus measuring 5.5 × 2 × 3.3 cm with a thin endometrium of 0.2 cm and normal sized ovaries with an anechoic cyst (8 cm) in the left ovary. The second proband presented at 24 years of age with primary amenorrhea, hypergonadotropic hypogonadism, and had a history of
Evaluation of Insect Pests on Edamame Varieties in Minnesota

Abstract Edamame, Glycine max (L.) Merrill, consumption continues to rise in the United States. Improved understanding of production threats, including insect pests, could facilitate increasing production of edamame in the north-central United States. Two years of complimentary field and laboratory experiments were performed to assess insect pest populations on commercially available edamame varieties. Fourteen varieties of edamame and four grain-type soybean varieties were tested in the laboratory with soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), and subsets of these varieties were tested in the field with naturally occurring insect populations. In the laboratory, mean aphid densities on the edamame varieties Agate and Chiba Green did not differ from the aphid-resistant grain-type soybean. Among edamame, aphid densities on Agate, Chiba Green, and Kuroshinju were significantly lower than on Hokkaido Black. In both years of the field experiment, aphid densities were significantly lower on the aphid-resistant grain-type compared to all others varieties. In 2016, aphid populations on edamame varieties did not differ from the aphid-susceptible grain-types. However, in 2017 with greater aphid exposure, differences were seen among edamame varieties, and between edamame and aphid-susceptible grain-types. In both years, potato leafhopper, Empoasca fabae (Harris) (Hemiptera: Cicadellidae), densities tended to be higher on edamame varieties compared to grain-types, and varied significantly among edamame varieties. In a laboratory study, differences were seen among varieties in mean density of trichomes, with grain-types generally having more trichomes than edamame. Results of this research will provide a foundation for development of production recommendations for edamame in the north-central United States.
Missing the point: re-evaluating the earliest lithic technology in the Middle Orinoco

The Culebra site, located in close proximity to the Atures Rapids, is one of the very few open-air occupations in the entire Orinoco valley that is thought to date to the early Holocene. Following renewed excavations in this location, we characterize the stone technology in unprecedented detail and perform both quantitative and qualitative analyses of the assemblage deposited in the first cultural layers. Additionally, we directly date the sediment forming the depositional context of the assemblage using stratigraphically stable components of soil organic matter. Coupled with our stratigraphic and paedological data, the deposit is, contrary to established estimates, shown to date to the late Holocene, well after the appearance of ceramics in the region. The toolkit identified through the lithic analysis, therefore, does not reflect an Archaic hunter–gatherer adaptation as previously assumed. Our findings are placed in the context of previous research in the Orinoco and lowland South America more broadly. More work is needed to understand the changing role of different stone tool reduction sequences with reference to adaptational strategies and bioclimatic variability.
Improving the value of ultrasound in children with suspected appendicitis: a prospective study integrating secondary sonographic signs

Purpose The purpose of this study was to determine whether the awareness and inclusion of secondary sonographic signs of appendicitis, in combination with a structured evaluation as part of engagement and training for sonographers, improved appendix visualization rates and reduced equivocal findings in children with suspected acute appendicitis. Methods This was a prospective study of 230 children at a tertiary children’s hospital in Australia referred for an ultrasound examination of suspected appendicitis. The ultrasound findings, radiology reports, histology, clinical results, and follow-up were collated. Secondary signs were used as an additional assessment of the likelihood of disease where possible, even in the absence of an identified appendix. Results The implementation of a structured evaluation as part of sonographer engagement and training resulted in a 28% improvement in appendix visualization (68.7%) compared with a prior retrospective study in a similar population (40.7%). The diagnostic accuracy was 91.7%, with likelihood ratios suggesting a meaningful influence of the pre-test probability of appendicitis in children studied (positive likelihood ratio, 11.22; negative likelihood ratio, 0.09.). Only 7.8% of the findings were equivocal. A binary 6-mm diameter cut-off did not account for equivocal cases, particularly lymphoid hyperplasia. Conclusion Engagement of sonographers performing pediatric appendiceal ultrasound through training in the scanning technique and awareness of secondary signs significantly improved the visualization rate and provided more meaningful findings to referrers.
ape 5.0: an environment for modern phylogenetics and evolutionary analyses in R

Summary After more than fifteen years of existence, the R package ape has continuously grown its contents, and has been used by a growing community of users. The release of version 5.0 has marked a leap towards a modern software for evolutionary analyses. Efforts have been put to improve efficiency, flexibility, support for 'big data' (R's long vectors), ease of use and quality check before a new release. These changes will hopefully make ape a useful software for the study of biodiversity and evolution in a context of increasing data quantity. Availability and implementation ape is distributed through the Comprehensive R Archive Network: http://cran.r-project.org/package=ape. Further information may be found at http://ape-package.ird. fr/.
Immunogenicity and Induction of Functional Antibodies in Rabbits Immunized with a Trivalent Typhoid-Invasive Nontyphoidal Salmonella Glycoconjugate Formulation

Typhoid fever due to Salmonella Typhi and invasive nontyphoidal Salmonella (iNTS) infections caused by serovars Enteritidis (SE) and Typhimurium (STm) are major pediatric health problems in sub-Saharan Africa. Typhoid has high complication rates, and iNTS infections have high case fatality rates; moreover, emerging antimicrobial resistance is diminishing treatment options. Vi capsule-based typhoid conjugate vaccine (Typbar-TCV™), licensed in India and pre-qualified by the World Health Organization, elicits durable immunity when administered to infants, but no iNTS vaccines are licensed or imminent. We have developed monovalent SE and STm glycoconjugate vaccines based on coupling lipopolysaccharide-derived core-O polysaccharide (COPS) to phase 1 flagellin protein (FliC) from the homologous serovar. Herein, we report the immunogenicity of multivalent formulations of iNTS COPS:FliC conjugates with Typbar-TCV™. Rabbits immunized with the trivalent typhoid-iNTS glycoconjugate vaccine generated high titers of serum IgG antibody to all three polysaccharide antigens for which anti-COPS IgG antibodies were directed primarily against serogroup-specific OPS epitopes. Responses to SE and STm FliC were lower relative to anti-COPS titers. Post-vaccination rabbit sera mediated bactericidal activity in-vitro, and protected mice after passive transfer against challenge with virulent SE or STm Malian blood isolates. These results support accelerated progression to clinical trials.
Corticospinal changes induced by fatiguing eccentric versus concentric exercise

Abstract The present study assessed neuromuscular and corticospinal changes during and after a fatiguing submaximal exercise of the knee extensors in different modes of muscle contraction. Twelve subjects performed two knee extensors exercises in a concentric or eccentric mode, at the same torque and with a similar total impulse. Exercises consisted of 10 sets of 10 repetitions at an intensity of 80% of the maximal voluntary isometric contraction torque (MVIC). MVIC, maximal voluntary activation level (VAL) and responses of electrically evoked contractions of the knee extensors were assessed before and after exercise. Motor evoked potential amplitude (MEP) and cortical silent period (CSP) of the vastus medialis (VM) and rectus femoris (RF) muscles were assessed before, during and after exercise. Similar reductions of the MVIC (−13%), VAL (−12%) and a decrease in the peak twitch (−12%) were observed after both exercises. For both VM and RF muscles, MEP amplitude remained unchanged during either concentric or eccentric exercises. No change of the MEP amplitude input–output curves was observed post-exercise. For the RF muscle, CSP increased during the concentric exercise and remained lengthened after this exercise. For the VM muscle, CSP was reduced after the eccentric exercise only. For a similar amount of total impulse, concentric and eccentric knee extensor contractions led to similar exercise-induced neuromuscular response changes. For the two muscles investigated, no modulation of corticospinal excitability was observed during or after either concentric or eccentric exercises. However, intracortical inhibition showed significant modulations during and after exercise.
Catalpol alleviates renal damage by improving lipid metabolism in diabetic db/db mice.

OBJECTIVE To evaluate the protective effect of catalpol against diabetic nephropathy in db/db mouse. METHODS 8 week old C57BLKS/J db/db mice (type 2 diabetic mouse model) were divided into three groups to feed for 16 weeks on chow diet with or without catalpol supplementation. Their food intake, water consumption, body weight, and fasting glucose levels were recorded every 4 weeks. At the end of study, urine and blood samples were examined for several metabolic variables, and kidneys were harvested for structural characterization and microarray analysis. RESULTS Catalpol efficiently lowers the fasting glucose and the 24 h urinary albumin excretion rate. Catalpol significantly lowers serum triglycerides, increases high-density lipoproteins, and improves serum creatinine and urea nitrogen. Catalpol-fed mice preserve their kidney structure and renal function better than chow fed db/db mice. Microarray data indicates that lipid metabolism is a potential target of catalpol in exerting protective effect. CONCLUSION Catalpol has a renal protective effect in diabetic db/db mice.
An Anopheles by Any Other Name …?

Abstract The physical characteristics of a nematoceran fly that evokes the image of a mosquito of the genus Anopheles Meigen (Diptera: Culicidae) has existed since the genus was defined in the early part of the twentieth century. Is that image likely to change with the recent proposal to elevate four Neotropical subgenera to generic status based on relationships generated by phylogenetic analyses of mitochondrial protein-coding genes? Reasons for retaining the traditional concept of Anopheles, with its traditionally recognized subgenera, are presented. However, as the ranking of taxa as genera or subgenera is subjective, the choice of rank of a genus-group name may be considered a subjective decision and a matter of user preference.
Impact of Routine Cryptococcal Antigen Screening and Targeted Preemptive Fluconazole Therapy in Antiretroviral-naive Human Immunodeficiency Virus–infected Adults With CD4 Cell Counts <100/&mgr;L: A Systematic Review and Meta-analysis

Cryptococcal antigen (CrAg) screening and targeted preemptive fluconazole in antiretroviral-naive human immunodeficiency virus-infected adults with CD4 cell counts <100/μL seems promising as a strategy to reduce the burden of cryptococcal meningitis (CM). We searched MEDLINE, EMBASE, and Web of Science and used random-effect meta-analysis to assess the prevalence of blood CrAg positivity (31 studies; 35644 participants) and asymptomatic CM in CrAg-positive participants and the incidence of CM and the all-cause mortality rate in screened participants. The pooled prevalence of blood CrAg-positivity was 6% (95% confidence interval [CI], 5%-7%), and the prevalence of asymptomatic CM in CrAg-positive participants was 33% (95% CI, 21%-45%). The incidence of CM was 21.4% (95% CI, 11.6%-34.4%) without preemptive fluconazole and 5.7% (95% CI, 3.0%-9.7%) with preemptive fluconazole therapy initiated at 800 mg/d. In CrAg-positive participants, postscreening lumbar puncture before initiating preemptive fluconazole at 800 mg/d further reduced the incidence of CM to null and showed some survival benefits. However, the all-cause mortality rate remained significantly higher in CrAg-positive than in CrAg-negative participants (risk ratio, 2.2; 95% CI, 1.7-2.9; P < .001).
Toward Understanding the Repeated Occurrence of Associations between Melanin-Based Coloration and Multiple Phenotypes

Melanin is the most widespread pigment in organisms. Melanin-based coloration has been repeatedly observed to be associated with the same traits and in the same direction in different vertebrate and insect species. However, whether any factors that are common to different taxa account for the repeated evolution of melanin-phenotype associations remains unclear. We propose to approach this question from the perspective of convergent and parallel evolution to clarify to what extent different species have evolved the same associations owing to a shared genetic basis and being subjected to similar selective pressures. Our current understanding of the genetic basis of melanin-phenotype associations allows for both convergent and parallel evolution, but this understanding is still limited. Further research is needed to clarify the generality and interdependencies of the different proposed mechanisms (supergenes, pleiotropy based on hormones, or neural crest cells). The general ecological scenarios whereby melanin-based coloration is under selection—protection from ultraviolet radiation, thermoregulation in cold environments, or as a signal of social status—offer a good opportunity to study how melanin-phenotype associations evolve. Reviewing these scenarios shows that some traits associated with melanin-based coloration might be selected together with coloration by also favoring adaptation but that other associated traits might impede adaptation, which may be indicative of genetic constraints. We therefore encourage further research on the relative roles that selection and genetic constraints play in shaping multiple melanin-phenotype associations. Placed into a phylogenetic context, this will help clarify to what extent these associations result from convergent or parallel evolutionary processes and why melanin-phenotype associations are so common across the tree of life.
Cardioprotective effect of lipstatin derivative orlistat on normotensive rats submitted to cardiac ischemia and reperfusion.

PURPOSE To evaluate in vivo animal model of cardiac ischemia/reperfusion the cardioprotective activity of pancreatic lipase inhibitor of the orlistat. METHODS Adult male Wistar rats were anesthetized, placed on mechanical ventilation and underwent surgery to induce cardiac I/R by obstructing left descending coronary artery followed by reperfusion to evaluation of ventricular arrhythmias (VA), atrioventricular block (AVB) and lethality (LET) with pancreatic lipase inhibitor orlistat (ORL). At the end of reperfusion, blood samples were collected for determination of triglycerides (TG), very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), lactate dehydrogenase (LDH), creatine kinase (CK), and creatine kinase-MB (CK-MB). RESULTS Treatment with ORL has been able to decrease the incidence of VA, AVB and LET. Besides that, treatment with ORL reduced serum concentrations of CK and LDL, but did not alter the levels of serum concentration of TG, VLDL and HDL. CONCLUSION The reduction of ventricular arrhythmias, atrioventricular block, and lethality and serum levels of creatine kinase produced by treatment with orlistat in animal model of cardiac isquemia/reperfusion injury suggest that ORL could be used as an efficient cardioprotective therapeutic strategy to attenuate myocardial damage related to acute myocardial infarction.
Amphibian (Xenopus laevis) Tadpoles and Adult Frogs Differ in Their Use of Expanded Repertoires of Type I and Type III Interferon Cytokines

While amphibians around the globe are facing catastrophic declines, in part because of infections with pathogens such as the Frog Virus 3 (FV3) ranavirus; the mechanisms governing amphibian susceptibility and resistance to such pathogens remain poorly understood. The type I and type III interferon (IFN) cytokines represent a cornerstone of vertebrate antiviral immunity, while our recent work indicates that tadpoles and adult frogs of the amphibian Xenopus laevis may differ in their IFN responses to FV3. In this respect, it is notable that anuran (frogs and toads) tadpoles are significantly more susceptible to FV3 than adult frogs, and thus, gaining greater insight into the differences in the tadpole and adult frog antiviral immunity would be invaluable. Accordingly, we examined the FV3-elicited expression of a panel of type I and type III IFN genes in the skin (site of FV3 infection) and kidney (principal FV3 target) tissues and isolated cells of X. laevis tadpoles and adult frogs. We also examined the consequence of tadpole and adult frog skin and kidney cell stimulation with hallmark pathogen-associated molecular patterns (PAMPs) on the IFN responses of these cells. Together, our findings indicate that tadpoles and adult frogs mount drastically distinct IFN responses to FV3 as well as to viral and non-viral PAMPs, while these expression differences do not appear to be the result of a distinct pattern recognition receptor expression by tadpoles and adults.
M ay 2 01 8 Quantum Bose-Fermi droplets

We study stability of a zero temperature mixture of attractively interacting degenerate bosons and spin-polarized fermions in the absence of confinement. We demonstrate that higher order corrections to the standard mean field energy of the system can lead to a formation of liquid droplets – self-bound incompressible systems in a three-dimensional space. The stability analysis of the homogeneous system is supported by numerical simulations of finite systems by explicit inclusion of surface effects. Our results indicate that Bose-Fermi droplets can be realized experimentally.
Estimating Value Creation from Revealed Preferences: Application to Value-Based Strategies

We develop and apply a new set of empirical tools consistent with the tenets of value-based business strategies, leveraging the principle that “no good deal comes undone” and the methods of revealed preferences to empirically estimate drivers of value creation. We demonstrate how to use these tools in an analysis of value creation in buyer-supplier relationships in the UK corporate legal market. We show how the method can uncover evidence of subtle mechanisms that traditional methods cannot easily distinguish from each other. Furthermore, we show how these estimates can be used as parameters of biform games for out-of-sample analyses of strategic decisions. With readily available data on relationships between firms, this approach can be applied to many other contexts of interest to strategy researchers.