Miracle-dz/UniFAR-FTUs huggingface dataset:
Bone Morphogenetic Protein 2 Signals via BMPR1A to Regulate Murine Follicle-Stimulating Hormone Beta Subunit Transcription1

Abstract Follicle-stimulating hormone beta subunit (Fshb) expression is regulated by transforming growth factor beta superfamily ligands. Recently, we demonstrated that bone morphogenetic proteins (BMPs) stimulate Fshb transcription alone and in synergy with activins. Also, transfection of the BMP type II receptor (BMPR2) and constitutively active forms of the type I receptors (activin A receptor type I [ACVR1] or BMP receptor type IA [BMPR1A]) in immortalized gonadotroph cells (LbetaT2) stimulated murine Fshb promoter-reporter activity. A third type I receptor (BMP receptor type IB [BMPR1B]) is also expressed in LbetaT2 cells, but we did not previously assess its functional role. A point mutation in BMPR1B (Q249R) is associated with increased ovulation rates and elevated FSH levels in Booroola (FecB) sheep. Herein, we assessed whether BMPR1B can regulate Fshb transcription in LbetaT2 cells and whether its ability to do so is altered by the Q249R mutation. As with ACVR1 and BMPR1A, coexpression of BMPR1B with BMPR2 increased Fshb promoter-reporter activity in BMP2-dependent and BMP2-independent fashions. Unexpectedly, the BMPR1B-Q249R mutant was equivalent to the wild type in its ability to stimulate SMAD1/5 phosphorylation and Fshb transcription. Pharmacological inhibition of ACVR1, BMPR1A, and BMPR1B confirmed that one or more of these receptors are required for BMP2-stimulated SMAD1/5 phosphorylation and Fshb reporter activity. Knockdown of endogenous BMPR1A, but not ACVR1 or BMPR1B, significantly impaired the synergism of BMP2 with activin A. Collectively, these data suggest that BMPR1A is the preferred BMP2 type I receptor in LbetaT2 cells and that neither ACVR1 nor BMPR1B compensates for its loss. The specific mechanism(s) through which the Booroola FecB mutation alters BMPR1B function remains to be determined.
The knowledge and perception of second and third year medical students at The Nelson Mandela School of Medicine towards chiropractic

Background: Many previous South African studies exploring the relationship between the public, chiropractic and other health care professionals have indicated a poor level of knowledge and perception between the researched populations. The aim of this study was to determine the knowledge and perceptions of second and third year medical students at The Nelson Mandela School of Medicine towards chiropractic. Objectives: The objectives of this study were firstly, to document the demographic details of the second and third year participants, secondly, to determine the level of knowledge and exposure of the second and third year participants to chiropractic, thirdly, to determine the perceptions of second and third year participants regarding chiropractic and to compare this between second and third year participants, fourthly, to determine the utilization of chiropractic by second and third year participants, and finally, to determine any relationship between demographic factors, knowledge, perception and utilization of chiropractic. Method: A survey method was employed with the measuring tool being a questionnaire. It was decided that only second and third year medical students would be included in the study. Results: The response rate of the study was 42.5%. It was found that the majority of participants were female, of Black ethnicity and all participants were younger than 33 years old. Participants had a wide range, and a relatively satisfactory level of knowledge of chiropractic, however, the 3rd year participants had a significantly higher mean knowledge score than the second years. There was a wide range of perceptions of chiropractic, but a relatively negative level of perception. There were no significant differences in perception scores between the groups (p=0.859). III The third year participants seemed to have a better view of the scope of chiropractic than second year participants. The utilization of chiropractic by the participants, their friends and family was found to be low. A few areas of concern, with regards to the limited exposure that medical students at The Nelson Mandela School of Medicine have towards chiropractic, were raised. Conclusion and recommendations: It can be concluded that second and third year medical students from The Nelson Mandela School of Medicine had a generally poor knowledge and perception of the chiropractic profession, which may be a possible reason for the poor communication between chiropractors and qualified medical practitioners. The presence of chiropractic students, who served as human anatomy demonstrators at The Nelson Mandela School of Medicine, may have had an impact on the results of the study. It is therefore recommended that further studies be done to investigate the effect that these demonstrators have at The Nelson Mandela School of Medicine. Basic information on chiropractic should also be included at The Nelson Mandela School of Medicine to educate medical students on chiropractic.
Molecular and serological analysis of herpesvirus infections in the immunocompromised host

There are eight described human herpesviruses. All share the ability to achieve latency in their host following primary infection and may subsequently reactivate later in life. In immunocompetent individuals herpesvirus infections, especially those caused by reactivating virus, are usually mild however in patients with impaired cellular immune function they may cause significant morbidity and mortality. In this thesis molecular and serological techniques were used to define the prevalence of the human herpesviruses in a variety of immunocompromised groups as these individuals are at greatest risk of severe herpesviral disease. Human herpesvirus 8 (HHV8) is the most recently discovered of the human herpesviruses. A nested polymerase chain reaction (PCR) for detecting HHV8 genome was designed and used to examine the association between infection with HHV8 and FIIV-associated Kaposi's sarcoma (KS). The prevalence of HHV8 genome carriage in the general UK population was defined, as were potential routes of HHV8 transmission. Novel treatments for HIV-KS were investigated. The value of herpesviral genome detection in predicting associated disease was evaluated, together with the genome load response of cytomegalovirus (CMV), a significant herpesviral pathogen, to a novel chemotherapeutic protocol for immunosuppressed patients receiving allogenic bone marrow transplantation. The prevalence and epidemiology of HHV8 were found to be compatible with that predicted for a causal agent of KS, but not the haematological malignancy multiple myeloma. Apart from 1-IHV8, Epstein-Barr virus and CMV were found to be the most significant herpesvirus pathogens in the immunocompromised host. The use of molecular detection techniques, such as PCR, were shown to be of great value in the diagnostic and epidemiological determination of herpesviral infection in immunocompromised patients.
Mitochondrial Calcium Uptake Modulates Synaptic Vesicle Endocytosis in Central Nerve Terminals

Presynaptic calcium influx triggers synaptic vesicle (SV) exocytosis and modulates subsequent SV endocytosis. A number of calcium clearance mechanisms are present in central nerve terminals that regulate intracellular free calcium levels both during and after stimulation. During action potential stimulation, mitochondria rapidly accumulate presynaptic calcium via the mitochondrial calcium uniporter (MCU). The role of mitochondrial calcium uptake in modulating SV recycling has been debated extensively, but a definitive conclusion has not been achieved. To directly address this question, we manipulated the expression of the MCU channel subunit in primary cultures of neurons expressing a genetically encoded reporter of SV turnover. Knockdown of MCU resulted in ablation of activity-dependent mitochondrial calcium uptake but had no effect on the rate or extent of SV exocytosis. In contrast, the rate of SV endocytosis was increased in the absence of mitochondrial calcium uptake and slowed when MCU was overexpressed. MCU knockdown did not perturb activity-dependent increases in presynaptic free calcium, suggesting that SV endocytosis may be controlled by calcium accumulation and efflux from mitochondria in their immediate vicinity.
POLIOMYELITIS: WITH SOME OBSERVATIONS ON THIRTY CASES

As long ago as 1865, Taylor, 1 in referring to infantile paralysis, said, "There seems to be no doubt that this disease is much more frequent now and is rapidly increasing. " It was not until 1881, however, that the first epidemic was described. This was reported by Bergenholtz, and consisted of eighteen cases in northern Sweden. Since the Vermont 2 epidemic of 1894, there have been at least fourteen epidemics of poliomyelitis carefully recorded in different parts of the United States. These have varied in both size and intensity, and have been scattered across the country from Massachusetts to California. Previous to the present epidemic, the largest number of cases was observed in the Swedish epidemic (1,031 cases) of 1905, and in the Pennsylvania epidemic (1,000 cases) of 1910. It is easily seen, therefore, that the 1916 epidemic, which has already exceeded 5,000 cases in New York with no
A Combination of Structural and Empirical Analyses Delineates the Key Contacts Mediating Stability and Affinity Increases in an Optimized Biotherapeutic Single-chain Fv (scFv)*

Background: Antibody v-domains in scFv format often suffer from aggregation and stability issues that restrict formulation. Results: Structural and empirical analyses of an optimized scFv revealed that three VL-CDR3 mutations were sufficient to mediate significant stability and affinity improvements. Conclusion: scFv issues were resolved via removal of side-chain clashes at the VL/VH interface. Significance: CDR-restricted mutagenesis delivers stability-optimized molecules for high concentration dosing. Fully-human single-chain Fv (scFv) proteins are key potential building blocks of bispecific therapeutic antibodies, but they often suffer from manufacturability and clinical development limitations such as instability and aggregation. The causes of these scFv instability problems, in proteins that should be theoretically stable, remains poorly understood. To inform the future development of such molecules, we carried out a comprehensive structural analysis of the highly stabilized anti-CXCL13 scFv E10. E10 was derived from the parental 3B4 using complementarity-determining region (CDR)-restricted mutagenesis and tailored selection and screening strategies, and carries four mutations in VL-CDR3. High-resolution crystal structures of parental 3B4 and optimized E10 scFvs were solved in the presence and absence of human CXCL13. In parallel, a series of scFv mutants was generated to interrogate the individual contribution of each of the four mutations to stability and affinity improvements. In combination, these analyses demonstrated that the optimization of E10 was primarily mediated by removing clashes between both the VL and the VH, and between the VL and CXCL13. Importantly, a single, germline-encoded VL-CDR3 residue mediated the key difference between the stable and unstable forms of the scFv. This work demonstrates that, aside from being the critical mediators of specificity and affinity, CDRs may also be the primary drivers of biotherapeutic developability.
Personnel Selection: Test and Measurement Techniques

This book tells how to develop good tests, how to apply them efficiently, and how to interpret them accurately. Emphasis is placed on the logic behind testing methods rather than on statistical procedures. The purpose of this book is to investigate in detail the fluctuation problem of the theory of cosmic radiation. The book is in two parts: one purely mathematical and the other dealing with physics. March 1949 240 pages Illus. Methods for studying hybridization in the field are presented in this book so that the effects of hybridization in natural populations may be measured. The author offers methods for describing taxonomically an unseen species.
Hepatitis C virus enters human peripheral neuroblastoma cells – evidence for extra‐hepatic cells sustaining hepatitis C virus penetration

Summary. Patients with chronic hepatitis C virus (HCV) infection show an increased incidence of nervous system disorders such as chronic fatigue syndrome, depression and cognitive dysfunction. It is unclear whether this is because of HCV replication in the brain and in peripheral neuronal cells or to more indirect effects of HCV infection on the central or peripheral nervous system. The aim of this study was to investigate whether cells originating from these tissues are permissive for HCV cell entry, RNA replication and virus assembly. Among eight cell lines analysed, the human peripheral neuroblastoma cell line SKNMC expressed all HCV entry factors and was efficiently infected with HCV pseudoparticles (HCVpp) independent of the HCV genotype. All remaining cell types including human neuroblastoma and glioblastoma cell lines and microglial cells lacked expression of at least one host factor essential for HCV entry. When transfected with HCV luciferase reporter virus RNA, inoculated with HCV reporter viruses or challenged with high‐titre cell culture–derived HCV, none of these cells supported detectable HCV RNA replication. Thus, in conclusion, this comprehensive screening did not reveal evidence directly strengthening the notion that HCV enters and replicates in the central nervous system. However, productive viral entry into the peripheral neuroblastoma cell line SKNMC indicates that HCV may penetrate into certain nonhepatic cell types which may serve as viral reservoirs and could modulate viral pathogenesis.
Equatorin: Identification and Characterization of the Epitope of the MN9 Antibody in the Mouse1

Equatorin (MN9 antigenic molecule) is a widely distributed acrosomal protein in mammalian sperm. During the acrosome reaction, some amount of equatorin translocates to the plasma membrane, covering the equatorial region. From the results of studies of both in vitro and in vivo fertilization inhibition using the MN9 antibody, equatorin has been suggested to be involved in fusion with the oolemma. In the present study, we cloned equatorin and, using mass spectrometry and carbohydrate staining, found it to be a highly glycosylated protein. Equatorin is a sperm-specific type 1 transmembrane protein, and glycosidase treatment and recombinant protein assays verified that it is an N,O-sialoglycoprotein. In addition, the gamete interaction-related domain recognized by the MN9 antibody is posttranslationally modified. The modified domain was identified near threonine 138, which was most likely to be O-glycosylated when analyzed by amino acid substitution, dephosphorylation, and O-glycosylation inhibitor assays. Immunogold electron microscopy localized the equatorin N-terminus, where the MN9 epitope is present, on the acrosomal membrane facing the acrosomal lumen. These biochemical properties and the localization of equatorin are important for further analysis of the translocation mechanism leading to gamete interaction.
Notions of Child Health: : mothers accounts of health in their young babies

This paper is concerned with mothers’ understandings of child health in their young babies. To explore how child health is depicted, explained and contextualised by mothers, altogether 29 mothers in Stockholm and London were interviewed through the baby's first months about day-to-day experiences of the baby's health and well-being. The analysis of the mothers’ accounts reveals how the mothers, in the process of assessing health, try to ‘read’ the bodily signs and reactions in their babies. Some major themes emerge on how the mothers identify and characterise threats to the health of the baby; here described as threats of abnormalities, threats to the survival of the baby, threats to the thriving of the baby and threats from illnesses. Notions of child health are discussed in relation to the ‘bodily’ and the ‘social’, and how the embodied images of child health are intertwined with the mothers’ presentations of themselves as responsible for the health of their children and as ‘worthy’ parents.
Structural Correlation of the Neck Coil with the Coiled-coil (CC1)-Forkhead-associated (FHA) Tandem for Active Kinesin-3 KIF13A*

Processive kinesin motors often contain a coiled-coil neck that controls the directionality and processivity. However, the neck coil (NC) of kinesin-3 is too short to form a stable coiled-coil dimer. Here, we found that the coiled-coil (CC1)-forkhead-associated (FHA) tandem (that is connected to NC by Pro-390) of kinesin-3 KIF13A assembles as an extended dimer. With the removal of Pro-390, the NC-CC1 tandem of KIF13A unexpectedly forms a continuous coiled-coil dimer that can be well aligned into the CC1-FHA dimer. The reverse introduction of Pro-390 breaks the NC-CC1 coiled-coil dimer but provides the intrinsic flexibility to couple NC with the CC1-FHA tandem. Mutations of either NC, CC1, or the FHA domain all significantly impaired the motor activity. Thus, the three elements within the NC-CC1-FHA tandem of KIF13A are structurally interrelated to form a stable dimer for activating the motor. This work also provides the first direct structural evidence to support the formation of a coiled-coil neck by the short characteristic neck domain of kinesin-3.
The optimal cut‐off for predicting large oesophageal varices using transient elastography is disease specific

Summary. The diagnosis of cirrhosis requires screening for oesophageal varices by upper gastrointestinal endoscopy. In many countries, serological tests and elastography are replacing liver biopsy for diagnosing cirrhosis. The aims of this study were to see whether there was an optimal cut‐off of liver stiffness that could predict the presence of large (>F2) oesophageal varices and whether this was disease specific. A total of two hundred and twenty‐two patients with all cause cirrhosis (Child class A) were screened, and 211 had successful elastography and are included in the analysis. Of the patients studied, one hundred and thirty‐two patients had no or small F1 varices and 79 had large varices. Liver stiffness of 19.8 kPa had a negative predictive value of 91% and a positive predictive value of 55% with an area under the curve (AUC) on receiver operating characteristics (ROC) of 0.73 in differentiating between small and large varices. Seven patients with large varices would have been incorrectly classified. In the 157 patients with hepatitis C as the aetiology of cirrhosis, the negative predictive value was 98% and only one patient was misclassified. Liver stiffness was superior in diagnostic accuracy to platelet count in all patients. A liver stiffness of >19.8 kPa could be utilized as a cut‐off for endoscopy and beta blocker utilization, particularly in patients with hepatitis C.
Transferrin Receptor 1 Facilitates Poliovirus Permeation of Mouse Brain Capillary Endothelial Cells*

As a possible route for invasion of the CNS, circulating poliovirus (PV) in the blood is believed to traverse the blood-brain barrier (BBB), resulting in paralytic poliomyelitis. However, the underlying mechanism is poorly understood. In this study, we demonstrated that mouse transferrin receptor 1 (mTfR1) is responsible for PV attachment to the cell surface, allowing invasion into the CNS via the BBB. PV interacts with the apical domain of mTfR1 on mouse brain capillary endothelial cells (MBEC4) in a dose-dependent manner via its capsid protein (VP1). We found that F-G, G-H, and H-I loops in VP1 are important for this binding. However, C-D, D-E, and E-F loops in VP1-fused Venus proteins efficiently penetrate MBEC4 cells. These results imply that the VP1 functional domain responsible for cell attachment is different from that involved in viral permeation of the brain capillary endothelium. We observed that co-treatment of MBEC4 cells with excess PV particles but not dextran resulted in blockage of transferrin transport into cells. Using the Transwell in vitro BBB model, transferrin co-treatment inhibited permeation of PV into MBEC4 cells and delayed further viral permeation via mTfR1 knockdown. With mTfR1 as a positive mediator of PV-host cell attachment and PV permeation of MBEC4 cells, our results indicate a novel role of TfR1 as a cellular receptor for human PV receptor/CD155-independent PV invasion of the CNS.
IL28B polymorphisms determine early viral kinetics and treatment outcome in patients receiving peginterferon/ribavirin for chronic hepatitis C genotype 1

Summary. Single nucleotide polymorphisms (SNPs) upstream of IL28B predict the outcome of treatment in chronic hepatitis C virus (HCV) infection, but their impact on viral kinetics and relation to other predictors are not well known. Here, two SNPs, rs12979860 and rs8099917, were analysed and related to early viral kinetics during treatment in 110 patients with HCV genotype 1 infection. The reduction of HCV RNA after 7 days of therapy was more pronounced (P < 0.0001) in patients with CCrs12979860 or TTrs8099917 than in patients carrying TTrs12979860 or GGrs8099917, respectively. The two SNPs were in linkage disequilibrium (d’ = 1, r2 = 0.44), but CCrs12979860 was less common (43%vs 71%) than TTrs8099917. Patients carrying both CCrs12979860 and TTrs8099917 genotypes achieved lower levels of HCV RNA at week 4 than those with CT or TT at rs12979860 and TTrs8099917 (P = 0.0004). The viral elimination was significantly influenced by rs12979860 independently of baseline viral load, age or fibrosis. This translated into high rates of sustained viral response (SVR) among patients carrying CCrs12979860 despite the presence of high viral load at baseline (SVR 74%), high age (SVR 79%) or severe liver fibrosis (SVR 83%). We conclude that the IL28B variability influences the antiviral efficiency of interferon/ribavirin therapy and has a strong impact on SVR, independently of traditional response predictors. A combined assessment of these SNPs in conjunction with other response predictors may better predict outcome in difficult‐to‐treat patients.
Low pH and Anionic Lipid-dependent Fusion of Uukuniemi Phlebovirus to Liposomes*

Many phleboviruses (family Bunyaviridae) are emerging as medically important viruses. These viruses enter target cells by endocytosis and low pH-dependent membrane fusion in late endosomes. However, the necessary and sufficient factors for fusion have not been fully characterized. We have studied the minimal fusion requirements of a prototypic phlebovirus, Uukuniemi virus, in an in vitro virus-liposome assay. We show that efficient lipid mixing between viral and liposome membranes requires close to physiological temperatures and phospholipids with negatively charged headgroups, such as the late endosomal phospholipid bis(monoacylglycero)phosphate. We further demonstrate that bis(monoacylglycero)phosphate increases Uukuniemi virus fusion beyond the lipid mixing stage. By using electron cryotomography of viral particles in the presence or absence of liposomes, we observed that the conformation of phlebovirus glycoprotein capsomers changes from the native conformation toward a more elongated conformation at a fusion permissive pH. Our results suggest a rationale for phlebovirus entry in late endosomes.