Miracle-dz/UniFAR-FTUs huggingface dataset:
Crystal Structures of the Tetratricopeptide Repeat Domains of Kinesin Light Chains: Insight into Cargo Recognition Mechanisms

Kinesin-1 transports various cargos along the axon by interacting with the cargos through its light chain subunit. Kinesin light chains (KLC) utilize its tetratricopeptide repeat (TPR) domain to interact with over 10 different cargos. Despite a high sequence identity between their TPR domains (87%), KLC1 and KLC2 isoforms exhibit differential binding properties towards some cargos. We determined the structures of human KLC1 and KLC2 tetratricopeptide repeat (TPR) domains using X-ray crystallography and investigated the different mechanisms by which KLCs interact with their cargos. Using isothermal titration calorimetry, we attributed the specific interaction between KLC1 and JNK-interacting protein 1 (JIP1) cargo to residue N343 in the fourth TRP repeat. Structurally, the N343 residue is adjacent to other asparagines and lysines, creating a positively charged polar patch within the groove of the TPR domain. Whereas, KLC2 with the corresponding residue S328 did not interact with JIP1. Based on these finding, we propose that N343 of KLC1 can form “a carboxylate clamp” with its neighboring asparagine to interact with JIP1, similar to that of HSP70/HSP90 organizing protein-1's (HOP1) interaction with heat shock proteins. For the binding of cargos shared by KLC1 and KLC2, we propose a different site located within the groove but not involving N343. We further propose a third binding site on KLC1 which involves a stretch of polar residues along the inter-TPR loops that may form a network of hydrogen bonds to JIP3 and JIP4. Together, these results provide structural insights into possible mechanisms of interaction between KLC TPR domains and various cargo proteins.
Antigenically Diverse Swine Origin H1N1 Variant Influenza Viruses Exhibit Differential Ferret Pathogenesis and Transmission Phenotypes

ABSTRACT Influenza A(H1) viruses circulating in swine represent an emerging virus threat, as zoonotic infections occur sporadically following exposure to swine. A fatal infection caused by an H1N1 variant (H1N1v) virus was detected in a patient with reported exposure to swine and who presented with pneumonia, respiratory failure, and cardiac arrest. To understand the genetic and phenotypic characteristics of the virus, genome sequence analysis, antigenic characterization, and ferret pathogenesis and transmissibility experiments were performed. Antigenic analysis of the virus isolated from the fatal case, A/Ohio/09/2015, demonstrated significant antigenic drift away from the classical swine H1N1 variant viruses and H1N1 pandemic 2009 viruses. A substitution in the H1 hemagglutinin (G155E) was identified that likely impacted antigenicity, and reverse genetics was employed to understand the molecular mechanism of antibody escape. Reversion of the substitution to 155G, in a reverse genetics A/Ohio/09/2015 virus, showed that this residue was central to the loss of hemagglutination inhibition by ferret antisera raised against a prototypical H1N1 pandemic 2009 virus (A/California/07/2009), as well as gamma lineage classical swine H1N1 viruses, demonstrating the importance of this residue for antibody recognition of this H1 lineage. When analyzed in the ferret model, A/Ohio/09/2015 and another H1N1v virus, A/Iowa/39/2015, as well as A/California/07/2009, replicated efficiently in the respiratory tract of ferrets. The two H1N1v viruses transmitted efficiently among cohoused ferrets, but respiratory droplet transmission studies showed that A/California/07/2009 transmitted through the air more efficiently. Preexisting immunity to A/California/07/2009 did not fully protect ferrets from challenge with A/Ohio/09/2015. IMPORTANCE Human infections with classical swine influenza A(H1N1) viruses that circulate in pigs continue to occur in the United States following exposure to swine. To understand the genetic and virologic characteristics of a virus (A/Ohio/09/2015) associated with a fatal infection and a virus associated with a nonfatal infection (A/Iowa/39/2015), we performed genome sequence analysis, antigenic testing, and pathogenicity and transmission studies in a ferret model. Reverse genetics was employed to identify a single antigenic site substitution (HA G155E) responsible for antigenic variation of A/Ohio/09/2015 compared to related classical swine influenza A(H1N1) viruses. Ferrets with preexisting immunity to the pandemic A(H1N1) virus were challenged with A/Ohio/09/2015, demonstrating decreased protection. These data illustrate the potential for currently circulating swine influenza viruses to infect and cause illness in humans with preexisting immunity to H1N1 pandemic 2009 viruses and a need for ongoing risk assessment and development of candidate vaccine viruses for improved pandemic preparedness.
Tobacco Use or Body Mass – Do They Predict Tuberculosis Mortality in Mumbai, India? Results from a Population-Based Cohort Study

Tobacco use and under-nutrition are major public health concerns and tuberculosis is a major cause of morbidity and mortality in India. Using a cohort of 148,173 persons (recruited 1991–1997 and followed-up 1997–2003) the joint effects of tobacco use and BMI on tuberculosis mortality was studied. Tobacco use in any form and low-BMI had joint effect on tuberculosis mortality and the interaction effect was synergistic in men and antagonistic in women. Self-reported tuberculosis was associated with increased risk of tuberculosis mortality. In contrast, no such association was observed for self-reported diabetes persons. The risk pattern remained unchanged even after excluding tuberculosis deaths occurred within 1st two years of follow-up. This study highlights importance of age consideration of individual while excluding early deaths. Around 27% male tuberculosis deaths were attributable to their being underweight and smoker, while 22% male and 37% female deaths were attributable to their being underweight and smokeless tobacco user.
Lrp5 Is Not Required for the Proliferative Response of Osteoblasts to Strain but Regulates Proliferation and Apoptosis in a Cell Autonomous Manner

Although Lrp5 is known to be an important contributor to the mechanisms regulating bone mass, its precise role remains unclear. The aim of this study was to establish whether mutations in Lrp5 are associated with differences in the growth and/or apoptosis of osteoblast-like cells and their proliferative response to mechanical strain in vitro. Primary osteoblast-like cells were derived from cortical bone of adult mice lacking functional Lrp5 (Lrp5−/−), those heterozygous for the human G171V High Bone Mass (HBM) mutation (LRP5 G171V) and their WT littermates (WTLrp5, WTHBM). Osteoblast proliferation over time was significantly higher in cultures of cells from LRP5 G171V mice compared to their WTHBM littermates, and lower in Lrp5−/− cells. Cells from female LRP5 G171V mice grew more rapidly than those from males, whereas cells from female Lrp5−/− mice grew more slowly than those from males. Apoptosis induced by serum withdrawal was significantly higher in cultures from Lrp5−/− mice than in those from WTHBM or LRP5 G171V mice. Exposure to a single short period of dynamic mechanical strain was associated with a significant increase in cell number but this response was unaffected by genotype which also did not change the ‘threshold’ at which cells responded to strain. In conclusion, the data presented here suggest that Lrp5 loss and gain of function mutations result in cell-autonomous alterations in osteoblast proliferation and apoptosis but do not alter the proliferative response of osteoblasts to mechanical strain in vitro.
Immune tolerance induction: What have we learned over time?

Development of inhibitory antibodies to infused factor VIII (FVIII) concentrates continues to be the most serious complication of haemophilia A management. Induction of immune tolerance by administering high doses of FVIII concentrate (antigen) and prothrombin complex concentrates to control bleeding was originated in the 1970s in Bonn, Germany, by Dr Hans‐Hermann Brackmann, and became known as the Bonn protocol. ITI transformed the life of the index patient, who was 19 years of age when he began treatment, and dramatically improved the medical landscape for all patients with haemophilia and inhibitors. Over the past 40 years, variations to the Bonn protocol have been proposed. All protocols are effective although some are better suited than others for use in certain situations. The specific molecular defect in FVIII and the human leucocyte antigen (HLA) type of an individual with haemophilia are major codependent determinants to inhibitor development. Given the range of potential molecular defects and the staggering number of potential HLA types, it is likely that treatment arms of randomized studies in haemophilia represent highly diverse populations, which reduces the power of a study to demonstrate differences between treatments. Although available clinical guidelines and consensus recommendations for ITI therapy are not always in complete agreement, collectively the guidelines provide a reasonable level of guidance for administering ITI therapy under different clinical scenarios. Several studies of ITI therapy are ongoing with the aim of clarifying unresolved issues in haemophilia management including the role of von Willebrand factor in inhibitor eradication.
Prenatal sonography of placental abscess and prolonged antibiotic treatment for Serratia marcescens bacteremia

Termination of pregnancy is indicated for Serratia marcescens bacteremia, a major cause of mortality. Our present case was highly challenging because the patient wished to continue with her pregnancy, and the ultrasonography showed features of a placental abscess. Although the outcomes were good after prolonged antibiotic treatment, this was an exceptional case.
Human Parasitic Diseases in Bulgaria in Between 2013-2014

Background: In Bulgaria, more than 20 autochthonous human parasitic infections have been described and some of them are widespread. Over 50 imported protozoan and helminthic infections represent diagnostic and therapeutic challenges and pose epidemiological risks due to the possibility of local transmission. Aims: To establish the distribution of autochthonous and imported parasitic diseases among the population of the country over a 2-year period (2013-2014) and to evaluate their significance in the public health system. Study Design: Cross sectional study. Methods: We used the annual reports by regional health inspectorates and data from the National Reference Laboratory at the National Centre of Infectious and Parasitic Diseases on all individuals infected with parasitic diseases in the country. Prevalence was calculated for parasitic diseases with few or absent clinical manifestations (oligosymptomatic or asymptomatic infections). Incidence per 100.000 was calculated for diseases with an overt clinical picture or those that required hospitalisation and specialised medical interventions (e.g. surgery). Results: During the research period, parasitological studies were conducted on 1441.244 persons, and parasitic infections were diagnosed in 22.039 individuals. Distribution of various parasitic pathogens among the population displayed statistically significant differences in prevalence for some intestinal parasites (enterobiasis 0.81%, giardiasis 0.34% and blastocystosis 0.22%). For certain zoonotic diseases such as cystic echinococcosis (average incidence of 3.99 per 100.000) and trichinellosis (average incidence of 0.8 per 100.000), the incidence exceeds several times the annual incidence recorded in the European Union. Conclusion: Parasitic diseases still pose a substantial problem with social and medical impacts on the residents of our country. Improved efficiency regarding autochthonous and imported parasitic diseases is essential in providing the public health system the tools it needs to combat these diseases. Attention should be focused on the various imported vector-borne parasitic diseases (e.g. malaria and cutaneous leishmaniasis) for which the country is potentially endemic.
Effects of Pre-Meal Drinks with Protein and Amino Acids on Glycemic and Metabolic Responses at a Subsequent Composite Meal

Background Whey proteins have insulinogenic properties and the effect appears to originate from a specific postprandial plasma amino acid pattern. The insulinogenic effect can be mimicked by a specific mixture of the five amino acids iso, leu, lys, thr and val. Objective The objective was to evaluate the efficacy of pre-meal boluses of whey or soy protein with or without added amino acids on glycaemia, insulinemia as well as on plasma responses of incretins and amino acids at a subsequent composite meal. Additionally, plasma ghrelin and subjective appetite responses were studied. Design In randomized order, fourteen healthy volunteers were served a standardized composite ham sandwich meal with either water provided (250 ml) during the time course of the meal, or different pre-meal protein drinks (PMPD) (100 ml provided as a bolus) with additional water (150 ml) served to the meal. The PMPDs contained 9 g protein and were based on either whey or soy protein isolates, with or without addition of the five amino acids (iso, leu, lys, thr and val) or the five amino acids + arg. Results All PMPD meals significantly reduced incremental area for plasma glucose response (iAUC) during the first 60 min. All whey based PMPD meals displayed lower glycemic indices compared to the reference meal. There were no significant differences for the insulinemic indices. The early insulin response (iAUC 0–15 min) correlated positively to plasma amino acids, GIP and GLP-1 as well as to the glycemic profile. Additionally, inverse correlations were found between insulin iAUC 0–15 min and the glucose peak. Conclusion The data suggests that a pre-meal drink containing specific proteins/amino acids significantly reduces postprandial glycemia following a composite meal, in absence of elevated insulinemic excursions. An early phase insulinemic response induced by plasma amino acids and incretins appears to mediate the effect. Trial Registration ClinicalTrials.gov NCT01586780
Challenges to the implementation of health sector decentralization in Tanzania: experiences from Kongwa district council

Background During the 1990s, the government of Tanzania introduced the decentralization by devolution (D by D) approach involving the transfer of functions, power and authority from the centre to the local government authorities (LGAs) to improve the delivery of public goods and services, including health services. Objective This article examines and documents the experiences facing the implementation of decentralization of health services from the perspective of national and district officials. Design The study adopted a qualitative approach, and data were collected using semi-structured interviews and were analysed for themes and patterns. Results The results showed several benefits of decentralization, including increased autonomy in local resource mobilization and utilization, an enhanced bottom-up planning approach, increased health workers’ accountability and reduction of bureaucratic procedures in decision making. The findings also revealed several challenges which hinder the effective functioning of decentralization. These include inadequate funding, untimely disbursement of funds from the central government, insufficient and unqualified personnel, lack of community participation in planning and political interference. Conclusion The article concludes that the central government needs to adhere to the principles that established the local authorities and grant more autonomy to them, offer special incentives to staff working in the rural areas and create the capacity for local key actors to participate effectively in the planning process.
Exact Robust Solution to TW-ToA-Based Target Localization Problem With Clock Imperfections

This letter addresses the problem of target localization based on two-way time of arrival (TW-ToA) measurements with clock imperfections. In addition to the target location, the turn-around times and clock skews are considered unknown. Since an optimal estimator for this problem cannot be tackled directly, we approximate it by a suboptimal, robust one, formulated as a generalized trust region subproblem. Even though nonconvex in general, exact solution of the derived estimator can be obtained by just a bisection procedure. Simulation results validate the effectiveness of the proposed technique, matching the performance of the state of the art with significantly lower computational complexity.
Practice patterns of neurologists regarding bone and mineral effects of antiepileptic drug therapy.

BACKGROUND Antiepileptic drug (AED) therapy has been linked to bone disease that can be treated and prevented with calcium and vitamin D. However, because there have been no definitive studies on this subject, many physicians might not be aware of this association. OBJECTIVE To determine the approaches of neurologists to skeletal disorders in patients taking AEDs. DESIGN A self-administered mail survey. PARTICIPANTS United States board-certified or board-eligible pediatric (n = 404) and adult (n = 624) neurologists. MAIN OUTCOME MEASURES Practice patterns of neurologists regarding methods of screening for bone disorders and recommendations for treatment and prophylaxis. RESULTS Few pediatric (41%) and adult (28%) neurologists routinely evaluate AED-treated patients for bone and mineral disease. Of physicians who detect bone disease through diagnostic testing, 40% of pediatric and 37% of adult neurologists prescribe calcium or vitamin D, and about half (54% of pediatric and 57% of adult neurologists) refer patients to specialists. Few neurologists (9% of pediatric and 7% of adult neurologists) prescribe prophylactic calcium or vitamin D for patients taking AEDs. CONCLUSIONS There is a lack of consensus among neurologists concerning the impact of AED therapy on bone. Because considerable evidence suggests that much of the bone pathology caused by AED therapy can be treated or prevented by administration of calcium and vitamin D, raising physician awareness of this problem could significantly improve the skeletal health of AED-treated individuals.
Evolution of Social Power in Social Networks With Dynamic Topology

The recently proposed DeGroot–Friedkin model describes the dynamical evolution of individual social power in a social network that holds opinion discussions on a sequence of different issues. This paper revisits that model, and uses nonlinear contraction analysis, among other tools, to establish several novel results. First, we show that for a social network with constant topology, each individual's social power converges to its equilibrium value exponentially fast, whereas previous results only concluded asymptotic convergence. Second, when the network topology is dynamic (i.e., the relative interaction matrix may change between any two successive issues), we show that the initial (perceived) social power of each individual is exponentially forgotten. Specifically, individual social power is dependent only on the dynamic network topology, and initial social power is forgotten as a result of sequential opinion discussion. Finally, we provide an explicit upper bound on an individual's social power as the number of issues discussed tends to infinity; this bound depends only on the network topology. Simulations are provided to illustrate our results.
Pediatric Critical Care in Resource-Limited Settings—Overview and Lessons Learned

Pediatric critical care is an important component of reducing morbidity and mortality globally. Currently, pediatric critical care in low middle-income countries (LMICs) remains in its infancy in most hospitals. The majority of hospitals lack designated intensive care units, healthcare staff trained to care for critically ill children, adequate numbers of staff, and rapid access to necessary medications, supplies and equipment. In addition, most LMICs lack pediatric critical care training programs for healthcare providers or certification procedures to accredit healthcare providers working in their pediatric intensive care units (PICU) and high dependency areas. PICU can improve the quality of pediatric care in general and, if properly organized, can effectively treat the severe complications of high burden diseases, such as diarrhea, severe malaria, and respiratory distress using low-cost interventions. Setting up a PICU in a LMIC setting requires planning, specific resources, and most importantly investment in the nursing and permanent medical staff. A thoughtful approach to developing pediatric critical care services in LMICs starts with fundamental building blocks: training healthcare professionals in skills and knowledge, selecting resource appropriate effective equipment, and having supportive leadership to provide an enabling environment for appropriate care. If these fundamentals can be built on in a sustainable manner, an appropriate critical care service will be established with the potential to significantly decrease pediatric morbidity and mortality in the context of public health goals as we reach toward the sustainable development goals.
Micromagnetic Analysis of Statistical Switching in Perpendicular Magnetic Tunnel Junctions With Double Reference Layers

The recent technological realization of perpendicular magnetic tunnel junctions (MTJs) with two reference layers has opened a new route for scaling the overall size of spin-transfer torque magnetic random-access memory. This is because, for an antiparallel configuration of the magnetization of the reference layers, the two spin-transfer torques add constructively, giving rise to more efficient switching processes of the free layer magnetization as compared to a single MTJ. We use full micromagnetic simulations to study the magnetization switching of a double MTJ. The probability distribution function (PDF) of the switching time is the same for both switching processes (parallel to antiparallel and vice versa), and the PDF approaches a Gaussian shape for switching time smaller than 1 ns. The dynamical performance (achieved for switching time below 1 ns) of double MTJs with circular shape and diameter ranging from 30 to 14 nm is comparable. Compared to full micromagnetic data, computations of the PDF within the macrospin approximation show an overestimation of the skewness for MTJ with circular shape and diameter of 30 and 20 nm, whereas they are very close for 14 nm diameter, as expected. The proper micromagnetic model and a PDF comparison can drive the design of hybrid magnetic-CMOS systems.
Regional Diversity and Diversification in Mammals

The effects of regional diversity on diversification remain controversial. The classic hypothesis that diversification decelerates as regional diversity increases has been recently revived. Yet, there is little geographic evidence for slower diversification across regions of high diversity, and diversity is often thought to promote diversification through its effects on ecological divergence and speciation. Here, we use the newest phylogeny for mammals (4,990 species) and two different methods to test the effects of regional diversity on diversification. We find that regions of high diversity are dominated by expanding clades that are far from their estimated carrying capacities. Regions of low diversity host clades that are small and mostly saturated. These results were supported across mammals and their six largest orders. They were corroborated by the two methods when controlling for clade relatedness, clade nestedness, and clade size. Together, these results reject the hypothesis that high geographic concentration of mammals effectively suppresses their further diversification. Instead, highly diverse regions (especially the tropics) seem to act as the engine of mammalian richness.