Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic determinants of VWF clearance and FVIII-binding modify FVIII pharmacokinetics in pediatric hemophilia A patients.

Factor VIII (FVIII) pharmacokinetic properties show high inter-patient variability in hemophilia A patients. While previous studies have determined that age, body mass index, von Willebrand factor (VWF) antigen levels, and ABO blood group status can influence FVIII pharmacokinetics, they do not account for all observed variability. In this study, we aim to describe the genetic determinants that modify the FVIII pharmacokinetic profile in a population of 43 pediatric hemophilia A patients. We observed that VWF:Ag and VWFpp/VWF:Ag, but not VWFpp, associated with FVIII half-life. VWFpp/VWF:Ag negatively correlated with FVIII half-life in patients with non-O blood type, but no correlation was observed for type O patients, suggesting that VWF half-life as modified by ABO blood group is a strong regulator of FVIII pharmacokinetics. The FVIII-binding activity of VWF positively correlated with FVIII half-life and the rare or low frequency, non-synonymous VWF variants p.(Arg826Lys) and p.(Arg852Glu) were identified in patients with reduced VWF:FVIIIB but not VWF:Ag. Common variants at the VWF, CLEC4M, and STAB2 loci, which have been previously associated with plasma levels of VWF and FVIII, associated with the FVIII pharmacokinetic profile. Together, these studies characterize the mechanistic basis by which VWF clearance and ABO glycosylation modify FVIII pharmacokinetics in a pediatric population. Moreover, this study is the first to identify non--VWF and ABO variants that modify FVIII pharmacokinetics in pediatric hemophilia A patients.
Effect of combined testing of ceramides with high-sensitive troponin T on the detection of acute coronary syndrome in patients with chest pain in China: a prospective observational study

Objective Ceramides are associated with coronary plaque vulnerability. We aim to investigate the potential diagnostic value of ceramides for acute coronary syndrome (ACS) in Chinese patients with chest pain. Design Prospective observational survey. Setting Shanghai, China, 2016–2017. Participants A total of 2773 patients with chest pain from four hospitals in Shanghai, China, between August 2016 and October 2017. Main outcome measures Performance of metabolites model in detection of ACS cases including ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and unstable angina. Results Plasma levels of 12 ceramide molecules and corresponding ratios were compared between patients diagnosed with ACS and those without. Cer(d18:1/24:1(15Z))/Cer(d18:1/24:0) ratio, Cer(d18:1/14:0) and Cer(d18:1/22:0) were independent predictors of ACS after adjustment of traditional risk factors and high-sensitivecardiac troponin T. Receiver operating characteristic curve analysis showed a significant improvement in detecting ACS in the multivariable model with ceramides compared with that without (0.865 (0.840 to 0.889) vs 0.808 (0.776 to 0.841), p<0.001). Conclusion Distinct plasma ceramides are independent diagnostic predictors of ACS among patients with chest pain. Ceramides together with high-sensitive troponin and traditional factors showed great potential in identifying ACS among patients with chest pain.
An expanded landscape of human long noncoding RNA

Abstract Long noncoding RNAs (lncRNAs) are emerging as key regulators of multiple essential biological processes involved in physiology and pathology. By analyzing the largest compendium of 14,166 samples from normal and tumor tissues, we significantly expand the landscape of human long noncoding RNA with a high-quality atlas: RefLnc (Reference catalog of LncRNA). Powered by comprehensive annotation across multiple sources, RefLnc helps to pinpoint 275 novel intergenic lncRNAs correlated with sex, age or race as well as 369 novel ones associated with patient survival, clinical stage, tumor metastasis or recurrence. Integrated in a user-friendly online portal, the expanded catalog of human lncRNAs provides a valuable resource for investigating lncRNA function in both human biology and cancer development.
Ferredoxin5 Deletion Affects Metabolism of Algae during the Different Phases of Sulfur Deprivation1

Omics approaches reveal that knocking out FERREDOXIN5 in Chlamydomonas reinhardtii results in pathway-specific physiological changes in response to sulfur deprivation. Ferredoxin5 (FDX5), a minor ferredoxin protein in the alga Chlamydomonas (Chlamydomonas reinhardtii), helps maintain thylakoid membrane integrity in the dark. Sulfur (S) deprivation has been used to achieve prolonged hydrogen production in green algae. Here, we propose that FDX5 is involved in algal responses to S-deprivation as well as to the dark. Specifically, we tested the role of FDX5 in both the initial aerobic and subsequent anaerobic phases of S-deprivation. Under S-deprived conditions, absence of FDX5 causes a distinct delay in achieving anoxia by affecting photosynthetic O2 evolution, accompanied by reduced acetate uptake, lower starch accumulation, and delayed/lower fermentative metabolite production, including photohydrogen. We attribute these differences to transcriptional and/or posttranslational regulation of acetyl-CoA synthetase and ADP-Glc pyrophosphorylase, and increased stability of the PSII D1 protein. Interestingly, increased levels of FDX2 and FDX1 were observed in the mutant under oxic, S-replete conditions, strengthening our previously proposed hypothesis that other ferredoxins compensate in response to a lack of FDX5. Taken together, the results of our omics and pull-down experiments confirmed biochemical and physiological results, suggesting that FDX5 may have other effects on Chlamydomonas metabolism through its interaction with multiple redox partners.
Protective Effects of Nanoparticle-Loaded Aliskiren on Cardiovascular System in Spontaneously Hypertensive Rats

Aliskiren, a renin inhibitor, has been shown to have cardioprotective and blood pressure (BP) lowering effects. We aimed to determine the effects of nanoparticle-loaded aliskiren on BP, nitric oxide synthase activity (NOS) and structural alterations of the heart and aorta developed due to spontaneous hypertension in rats. Twelve week-old male spontaneously hypertensive rats (SHR) were divided into the untreated group, group treated with powdered or nanoparticle-loaded aliskiren (25 mg/kg/day) and group treated with nanoparticles only for 3 weeks by gavage. BP was measured by tail-cuff plethysmography. NOS activity, eNOS and nNOS protein expressions, and collagen content were determined in both the heart and aorta. Vasoactivity of the mesenteric artery and wall thickness, inner diameter, and cross-sectional area (CSA) of the aorta were analyzed. After 3 weeks, BP was lower in both powdered and nanoparticle-loaded aliskiren groups with a more pronounced effect in the latter case. Only nanoparticle-loaded aliskiren increased the expression of nNOS along with increased NOS activity in the heart (by 30%). Moreover, nanoparticle-loaded aliskiren decreased vasoconstriction of the mesenteric artery and collagen content (by 11%), and CSA (by 25%) in the aorta compared to the powdered aliskiren group. In conclusion, nanoparticle-loaded aliskiren represents a promising drug with antihypertensive and cardioprotective effects.
Metal ligands in micronutrient acquisition and homeostasis.

Acquisition and homeostasis of micronutrients such as iron (Fe) and zinc (Zn) pose specific challenges. Poor solubility and high reactivity require controlled synthesis and supply of ligands to complex these metals extra- and intracellularly. Cytosolic labile pools represent only a minute fraction of the total cellular content. Several low molecular weight ligands are known in plants, including sulphur ligands (cysteine, peptides), nitrogen/oxygen ligands (S-adenosylmethionine-derived molecules, histidine) and oxygen ligands (phenolics, organic acids). Some ligands are secreted into the extracellular space and influence the phytoavailability of metal ions. A second principal function is the intracellular buffering of micronutrients as well as the facilitation of long-distance transport in xylem and phloem. Furthermore, low molecular weight ligands are involved in the storage of metals, predominantly in vacuoles. A detailed molecular understanding is hampered by technical limitations, in particular the difficulty to detect and quantify cellular metal-ligand complexes. More, but still too little, is known about ligand synthesis and the transport across membranes, either with or without a complexed metal. Metal ligands have an immediate impact on human well-being. Engineering metal ligand synthesis and distribution in crops has tremendous potential to improve the nutritional quality of food and to tackle major human health risks.
Language processing skills linked to FMR1 variation: A study of gaze-language coordination during rapid automatized naming among women with the FMR1 premutation

The FMR1 premutation (PM) is relatively common in the general population. Evidence suggests that PM carriers may exhibit subtle differences in specific cognitive and language abilities. This study examined potential mechanisms underlying such differences through the study of gaze and language coordination during a language processing task (rapid automatized naming; RAN) among female carriers of the FMR1 PM. RAN taps a complex set of underlying neuropsychological mechanisms, with breakdowns implicating processing disruptions in fundamental skills that support higher order language and executive functions, making RAN (and analysis of gaze/language coordination during RAN) a potentially powerful paradigm for revealing the phenotypic expression of the FMR1 PM. Forty-eight PM carriers and 56 controls completed RAN on an eye tracker, where they serially named arrays of numbers, letters, colors, and objects. Findings revealed a pattern of inefficient language processing in the PM group, including a greater number of eye fixations (namely, visual regressions) and reduced eye-voice span (i.e., the eyes’ lead over the voice) relative to controls. Differences were driven by performance in the latter half of the RAN arrays, when working memory and processing load are the greatest, implicating executive skills. RAN deficits were associated with broader social-communicative difficulties among PM carriers, and with FMR1-related molecular genetic variation (higher CGG repeat length, lower activation ratio, and increased levels of the fragile X mental retardation protein; FMRP). Findings contribute to an understanding of the neurocognitive profile of PM carriers and indicate specific gene-behavior associations that implicate the role of the FMR1 gene in language-related processes.
Professionals’ views and experiences in supporting decision-making involvement for people living with dementia

Background The provision of supported decision-making for people living with disabilities is an emerging area of practice and rights-based law reform, and is required under international law. Objectives This qualitative study aimed to understand how Australian health and legal professionals conceptualised their professional roles in the practice of providing decision-making support for people living with dementia. Methods The methods were informed by grounded theory principles. In-depth, semi-structured interviews were conducted with 28 health and legal professionals involved in providing care or services for people with dementia. Interviews explored how professionals described their practice of providing support for decision-making and how they conceptualised their roles. The analysis was underpinned by the theoretical perspective of symbolic interactionism. Results Participants described providing support across a range of decision domains, some of which were specific to their professional role. Four key themes were identified: ‘establishing a basis for decision-making’, ‘the supportive toolbox’, ‘managing professional boundaries’ and ‘individualist advocacy versus relational practice’. Participants identified a range of generic and specialised techniques they used to provide support for people with dementia. These techniques were applied subject to resource limitations and perceived professional obligations and boundaries. A continuum of professional practice, ranging from ‘individualist advocacy’ to ‘relational practice’ describes the approaches adopted by different professionals. Discussion Professionals conceptualised their role in providing support for decision-making through the lens of their own profession. Differences in positioning on the continuum of ‘individualist advocacy’ through to ‘relational practice’ had practical implications for capacity assessment, engaging with persons with impaired decision-making capacity, and the inclusion of supporters and family members in decision-making processes. Further progress in implementing supported decision-making (including through law and policy reform) will require an understanding of these inter-professional differences in perceived roles relating to the practice of providing decision-making support.
Leptin signaling impairs macrophage defenses against Salmonella Typhimurium

Significance In the present study, we identify and describe an important cross-talk between leptin signaling and macrophage functions in the context of Salmonella Typhimurium infection. Genetic ablation of leptin receptor or pharmacological antagonization of leptin augmented lysosomal functions in macrophages, reduced S. Typhimurium burden, and diminished inflammation both in vitro and in vivo. Leptin signaling activates mTORC2/Akt pathway through the down-regulation of Phlpp1 phosphatase, thus impairs lysosome-mediated pathogen clearance. The dynamic interplay between metabolism and immune responses in health and disease, by which different immune cells impact on metabolic processes, are being increasingly appreciated. However, the potential of master regulators of metabolism to control innate immunity are less understood. Here, we studied the cross-talk between leptin signaling and macrophage function in the context of bacterial infections. We found that upon infection with Gram-negative pathogens, such as Salmonella Typhimurium, leptin receptor (Lepr) expression increased in both mouse and human macrophages. Unexpectedly, both genetic Lepr ablation in macrophages and global pharmacologic leptin antagonization augmented lysosomal functions, reduced S. Typhimurium burden, and diminished inflammation in vitro and in vivo. Mechanistically, we show that leptin induction activates the mTORC2/Akt pathway and subsequently down-regulates Phlpp1 phosphatase, allowing for phosphorylated Akt to impair lysosomal-mediated pathogen clearance. These data highlight a link between leptin signaling, the mTORC2/Phlpp1/Akt axis, and lysosomal activity in macrophages and have important therapeutic implications for modulating innate immunity to combat Gram-negative bacterial infections.
Current Findings on Gut Microbiota Mediated Immune Modulation against Viral Diseases in Chicken

Chicken gastrointestinal tract is an important site of immune cell development that not only regulates gut microbiota but also maintains extra-intestinal immunity. Recent studies have emphasized the important roles of gut microbiota in shaping immunity against viral diseases in chicken. Microbial diversity and its integrity are the key elements for deriving immunity against invading viral pathogens. Commensal bacteria provide protection against pathogens through direct competition and by the production of antibodies and activation of different cytokines to modulate innate and adaptive immune responses. There are few economically important viral diseases of chicken that perturb the intestinal microbiota diversity. Disruption of microbial homeostasis (dysbiosis) associates with a variety of pathological states, which facilitate the establishment of acute viral infections in chickens. In this review, we summarize the calibrated interactions among the microbiota mediated immune modulation through the production of different interferons (IFNs) ILs, and virus-specific IgA and IgG, and their impact on the severity of viral infections in chickens. Here, it also shows that acute viral infection diminishes commensal bacteria such as Lactobacillus, Bifidobacterium, Firmicutes, and Blautia spp. populations and enhances the colonization of pathobionts, including E. coli, Shigella, and Clostridial spp. , in infected chickens.
Terrestrial mammal surveillance using hybridization capture of environmental DNA from African waterholes

Determining species distributions can be extremely challenging but is crucial to ecological and conservation research. Environmental DNA (eDNA) approaches have shown particular promise in aquatic systems for several vertebrate and invertebrate species. For terrestrial animals, however, eDNA‐based surveys are considerably more difficult due to the lack of or difficulty in obtaining appropriate sampling substrate. In water‐limited ecosystem where terrestrial mammals are often forced to congregate at waterholes, water and sediment from shared water sources may be a suitable substrate for noninvasive eDNA approaches. We characterized mitochondrial DNA sequences from a broad range of terrestrial mammal species in two different African ecosystems (in Namibia and Tanzania) using eDNA isolated from native water, sediment and water filtered through glass fibre filters. A hybridization capture enrichment with RNA probes targeting the mitochondrial genomes of 38 mammal species representing the genera/families expected at the respective ecosystems was employed, and 16 species were identified, with a maximum mitogenome coverage of 99.8%. Conventional genus‐specific PCRs were tested on environmental samples for two genera producing fewer positive results than hybridization capture enrichment. An experiment with mock samples using DNA from non‐African mammals showed that baits covering 30% of nontarget mitogenomes produced 91% mitogenome coverage after capture. In the mock samples, over‐representation of DNA of one species still allowed for the detection of DNA of other species that was at a 100‐fold lower concentration. Hybridization capture enrichment of eDNA is therefore an effective method for monitoring terrestrial mammal species from shared water sources.
Evaluating the Implications of Varying Bluetooth Low Energy (BLE) Transmission Power Levels on Wireless Indoor Localization Accuracy and Precision

Bluetooth Low Energy (BLE) based Wireless Indoor Localization System (WILS) with high localization accuracy and high localization precision is a key requirement in enabling the Internet of Things (IoT) in today’s applications. In this paper, we investigated the effect of BLE signal variations on indoor localization caused by the change in BLE transmission power levels. This issue is not often discussed as most of the works on localization algorithms use the highest power levels but has important practical implications for energy efficiency, e.g., if a designer would like to trade-off localization performance and node lifetime. To analyze the impact, we used the established trilateration based localization model with two methods i.e., Centroid Approximation (CA) and Minimum Mean Square Error (MMSE). We observed that trilateration based localization with MMSE method outperforms the CA method. We further investigated the use of two filters i.e., Low Pass Filter (LPF) and Kalman Filter (KF) and evaluated their effects in terms of mitigating the random variations from BLE signal. In comparison to non-filter based approach, we observed a great improvement in localization accuracy and localization precision with a filter-based approach. Furthermore, in comparison to LPF based trilateration localization with CA, the performance of a KF based trilateration localization with MMSE is far better. An average of 1 m improvement in localization accuracy and approximately 50% improvement in localization precision is observed by using KF in trilateration based localization model with the MMSE method. In conclusion, with KF in trilateration based localization model with MMSE method effectively eliminates random variations in BLE RSS with multiple transmission power levels and thus results in a BLE based WILS with high accuracy and high precision.
Challenges in Caring for Linguistic Minorities in the Pediatric Population

Physicians in the United States (U.S.) face unique obstacles in providing care for persons with limited English proficiency (LEP), especially speakers of rare languages. Lack of professional resources is not a problem exclusive to health care delivery, with speakers of Mayan dialects receiving increasingly narrow representation in detention centers and immigration courts at the U.S.–Mexico border. Parent-child dynamics and other crucial information related to pediatric care may be lost in translation in the event of inadequate interpreter services. Several strategies could address disparities in medical care faced by persons with LEP, speaking rare as well as more common languages. These include increasing the availability of professional interpreters via expanded and/or incentivized training programs, providing focused education in interpreter services for medical students, and unifying interpretation services provided by local consulates and nonprofit agencies for both medical and legal purposes.