Miracle-dz/UniFAR-FTUs huggingface dataset:
ER Chaperone BiP/GRP78 Is Required for Myelinating Cell Survival and Provides Protection during Experimental Autoimmune Encephalomyelitis

Myelinating cells synthesize large amounts of membrane protein through the secretory pathway, which makes these cells particularly sensitive to perturbations of the endoplasmic reticulum (ER). Ig binding protein (BiP), also known as glucose-regulated protein 78 (GRP78), is a critical ER chaperone that also plays a pivotal role in controlling the cellular response to ER stress. To examine the potential importance of BiP to myelinating cells, we used a conditional knock-out approach to BiP gene inactivation in oligodendrocytes during development, in adulthood, and in response to experimental autoimmune encephalomyelitis (EAE), an animal model of the inflammatory demyelinating disorder multiple sclerosis (MS). During development, mice lacking functional BiP gene expression in oligodendrocytes developed tremors and ataxia and died before reaching maturity. When BiP gene inactivation in oligodendrocytes was initiated in adulthood, the mice displayed severe neurological symptoms including tremors and hind-limb paralysis. The inactivation of BiP in oligodendrocytes during development or in adulthood resulted in oligodendrocyte loss and corresponding severe myelin abnormalities. Mice heterozygous for the oligodendrocyte-specific inactivation of BiP, which were phenotypically normal without evidence of neuropathology, displayed an exacerbated response to EAE that correlated with an increased loss of oligodendrocytes. Furthermore, mice in which the BiP gene was specifically inactivated in developing Schwann cells displayed tremor that progressed to hindlimb paralysis, which correlated with diminished numbers of myelinating Schwann cells and severe PNS hypomyelination. These studies demonstrate that BiP is critical for myelinating cell survival and contributes to the protective response of oligodendrocyte against inflammatory demyelination. SIGNIFICANCE STATEMENT The myelinating cells, oligodendrocytes in the CNS and Schwann cells in the PNS, are responsible for synthesizing an enormous amount of cellular membrane during the active phase of myelination. Therefore, these cells are particularly sensitive to insults that disrupt the function of the secretory pathway. Here, we show that the endoplasmic reticulum (ER) resident chaperone protein Ig binding protein (BiP) plays an essential role in the survival and function of myelinating cells both during the myelination process and in adult animals. Moreover, we demonstrate that BiP participates in the protective response of oligodendrocytes to inflammatory demyelinating insults. The work described here suggests that a compromised response to perturbations to the ER could contribute to myelin disorders of the CNS and PNS.
Metabolic, Neurochemical, and Histologic Responses to Vibrissa Motor Cortex Stimulation after Traumatic Brain Injury

During the prolonged metabolic depression after traumatic brain injury (TBI), neurons are less able to respond metabolically to peripheral stimulation. Because this decreased responsiveness has been attributed to circuit dysfunction, the present study examined the metabolic, neurochemical, and histologic responses to direct cortical stimulation after lateral fluid percussion injury (LFPI). This study addressed three specific hypotheses: that neurons, if activated after LFPI, will increase their utilization of glucose even during a period of posttraumatic metabolic depression; that this secondary activation results in an increase in the production of lactate and a depletion of extracellular glucose; and that because cells are known to be in a state of energy crisis after traumatic brain injury, additional energy demands resulting from activation can result in their death. The results indicate that stimulating to levels eliciting a vibrissa twitch resulted in an increase in the cerebral metabolic rate for glucose (CMRglc; μmol·100 g−1·min−1) of 34% to 61% in the sham-operated, 1-hour LFPI, and 7-day LFPI groups. However, in the 1-day LFPI group, stimulation induced a 161% increase in CMRglc and a 35% decrease in metabolic activation volume. Extracellular lactate concentrations during stimulation significantly increased from 23% in the sham-injured group to 55% to 63% in the 1-day and 7-day LFPI groups. Extracellular glucose concentrations during stimulation remained unchanged in the sham-injured and 7-day LFPI groups, but decreased 17% in the 1-day LFPI group. The extent of cortical degeneration around the stimulating electrode in the 1-day LFPI group nearly doubled when compared with controls. These results indicate that at 1 day after LFPI, the cortex can respond to stimulation with an increase in anaerobic glycolysis; however, this metabolic response to levels eliciting a vibrissa response via direct cortical stimulation appears to constitute a secondary injury in the TBI brain.
Factors associated with parents' decisions to tell their adult offspring about the offspring's donor conception.

BACKGROUND Tensions and anxieties surround secrecy within families in the context of gamete donation and family building. This paper presents the views of parents who had kept their use of donor insemination a secret from their offspring. A sub-set of these parents said that they wished to tell their now-adult offspring, and discussed the questions and issues this secrecy raised to them. METHODS In-depth interviews were undertaken with heterosexual parents (of 44 families) who had given birth to children conceived via donor insemination between 1983 and 1987. These interviews comprised a follow-up study, with the first interviews being undertaken when the children were aged up to seven. In this paper, qualitative data relating to a sub-set of 12 parents (from seven families) who now wished to tell their offspring are presented. RESULTS The parents describe the pressures that the secret-keeping had created for them as well as the impact of those pressures. They report on the reasons they now want to share the family building history and the associated fears and anxieties about doing so. The parents all say that they wish they had told their offspring much earlier. In five of the seven families, parents describe how the offspring had raised questions concerning a perceived genetic disconnection between them and their parents. CONCLUSIONS Keeping the use of donor insemination a secret from offspring created considerable pressure for these parents. Despite the secrecy, offspring can become aware of the genetic disconnection.
The kinetics of heat production in response to active shortening in frog skeletal muscle.

1. Tension and heat production were measured at 0 degree C in sartorius muscles from Rana temporaria in response to two extents of shortening at five velocities. Shortening was from approximately 2.4 to 2.2 microns, 2.4 to 2.3 microns and 2.3 to 2.2 micron at velocities per half‐sarcomere from 0.2 to 1.56 micron s‐1. 2. Tension became approximately constant at all velocities. Records of heat rate obtained by differentiating traces from which thermoelastic heat had been subtracted became negative early in shortening and then rose. Heat rate became constant during shortening only at the lowest velocity and was still rising at the end of shortening at higher velocities. The highest heat rate occurred at the end of shortening at the two highest velocities. At the end of shortening at all velocities heat rate gradually approached the isometric level measured at the short length, the half‐time for decline being largest following the slowest larger shortening. 3. Heat produced as a consequence of shortening but not associated with tension recovery was determined by subtracting shortening heat measured in response to two extents of shortening to the same muscle length. The differences in shortening heat continued to increase after shortening ended, and more of the extra heat produced in response to shortening appeared after the end of rapid shortening than during shortening itself. 4. Shortening heat coefficients calculated in different ways were similar to coefficients determined in previous studies. Coefficients calculated from measurements that excluded heat produced by tension recovery and allowed for continued production of heat by processes initiated by shortening were found to increase linearly with the force maintained during shortening. 5. The results show that the kinetics of heat production during and after shortening are very sensitive to the speed of shortening and that steady rates of energy liberation are not attained during shortening of less than or equal to 10% of muscle length at velocities greater than or equal to 12% of maximum velocity.
Radial shortening osteotomy for treatment of Lichtman Stage IIIA Kienböck disease

We carried out a retrospective study to analyse the long-term outcome of 36 patients after radial shortening osteotomy for treatment of Lichtman Stage IIIA Kienböck disease at a mean follow-up of 12.1 years (range 5.4–17.5). At review, seven wrists had progressed to Stage IIIB, eight wrists to Stage IV and 21 remained in Stage IIIA. Motion and grip strength were significantly improved. The mean Disabilities of the Arm, Shoulder, and Hand (DASH) score at review was 12 points (range 0–52), and patient satisfaction was high. Apart from plate removals in 14 patients and one wrist denervation, no subsequent surgical procedures were done. Radial shortening yields good long-term clinical results, but does not prevent radiographic progression of disease in some patients. Level of evidence: Therapeutic IV
Epigenetic Mechanisms of Human Papillomavirus-Associated Head and Neck Cancer.

CONTEXT Growing evidence suggests that as many as half of all oropharyngeal squamous cell carcinomas (OPSCCs) harbor human papillomavirus (HPV) infections. Despite being more advanced at diagnosis, HPV-positive OPSCCs are associated with a better response to therapy and longer patient survival than HPV-negative OPSCCs. Human papillomavirus-positive OPSCC has also been shown to have distinct host gene expression profiles compared with HPV-negative OPSCC. Recently, this distinction has been shown to include the epigenome. It is well supported that cancers are epigenetically deregulated. This review highlights epigenetic differences between HPV-positive and HPV-negative OPSCCs. The epigenetic mechanisms highlighted include methylation changes to host and viral DNA, and host chromatin modification. We also review the current evidence regarding host DNA methylation changes associated with smoking, and deregulation of microRNA expression in HPV-positive OPSCC. OBJECTIVE To provide an overview of epigenetic mechanisms reported in HPV-positive OPSCC, with analogies to cervical cancer, and discussion of the challenges involved in studying epigenetic changes in HPV-associated OPSCC in combination with changes associated with smoking. DATA SOURCES Sources were a literature review of peer-reviewed articles in PubMed on HPV and either OPSCC or head and neck squamous cell carcinoma, and related epigenetic mechanisms. CONCLUSIONS Epigenetic changes are reported to be a contributing factor to maintaining a malignant phenotype in HPV-positive OPSCC. The epigenetic mechanisms highlighted in this review can be studied for potential as biomarkers or as drug targets. Furthermore, continued research on the deregulation of epigenetic mechanisms in HPV-positive OPSCC (compared with HPV-negative OPSCC) may contribute to our understanding of the clinical and biologic differences between HPV-positive and HPV-negative OPSCC.
Maintaining time-decaying stream aggregates

We formalize the problem of maintaining time-decaying aggregates and statistics of a data stream: the relative contribution of each data item to the aggregate is scaled down by a factor that depends on, and is non-decreasing with, elapsed time. Time-decaying aggregates are used in applications where the significance of data items decreases over time. We develop storage-efficient algorithms, and establish upper and lower bounds. Surprisingly, even though maintaining decayed aggregates have become a widely-used tool, our work seems to be the first both to explore it formally and to provide storage-efficient algorithms for important families of decay functions, including polynomial decay.
Ras1-Induced Hyphal Development in Candida albicans Requires the Formin Bni1

ABSTRACT Formins are downstream effector proteins of Rho-type GTPases and are involved in the organization of the actin cytoskeleton and actin cable assembly at sites of polarized cell growth. Here we show using in vivo time-lapse microscopy that deletion of the Candida albicans formin homolog BNI1 results in polarity defects during yeast growth and hyphal stages. Deletion of the second C. albicans formin, BNR1, resulted in elongated yeast cells with cell separation defects but did not interfere with the ability of bnr1 cells to initiate and maintain polarized hyphal growth. Yeast bni1 cells were swollen, showed an increased random budding pattern, and had a severe defect in cytokinesis, with enlarged bud necks. Induction of hyphal development in bni1 cells resulted in germ tube formation but was halted at the step of polarity maintenance. Bni1-green fluorescent protein is found persistently at the hyphal tip and colocalizes with a structure resembling the Spitzenkörper of true filamentous fungi. Introduction of constitutively active ras1G13V in the bni1 strain or addition of cyclic AMP to the growth medium did not bypass bni1 hyphal growth defects. Similarly, these agents were not able to suppress hyphal growth defects in the wal1 mutant which is lacking the Wiskott-Aldrich syndrome protein (WASP) homolog. These results suggest that the maintenance of polarized hyphal growth in C. albicans requires coordinated regulation of two actin cytoskeletal pathways, including formin-mediated secretion and WASP-dependent endocytosis.
Protein, amino acids and the control of food intake

Purpose of reviewThe present review presents recent findings on peripheral and central pathways involved in protein and amino acid-induced satiety. Recent findingsA high-protein load leads to a higher decrease of energy intake at the next meal than carbohydrate and fat. A protein-enriched diet induces satiety, improves body composition and results in weight loss. At the peripheral level, proteins seem to induce the release of anorexigenic gut hormones cholecystokinin, glucagon-like peptide-1 and peptide YY, whereas the involvement of ghrelin remains uncertain. Energy expenditure and glucose are probably involved as metabolic signals in protein-induced satiety. Moreover, there is some evidence that the circulating level of leucine could impact food intake. Leucine has been shown to modulate the activity of the energy and nutrient sensor pathways controlled by AMPK and mTOR in the hypothalamus. Moreover, high-protein diets lead to activation of the noradrenergic/adrenergic neuronal pathway in the nucleus of the solitary tract and in melanocortin neurons in the arcuate nucleus. SummaryComplex and redundant pathways are involved in protein and amino acid-induced satiety. Significant advances have recently allowed a better understanding of the involved cellular and molecular mechanisms. The involvement of some specific area of the brain including the hypothalamus and the nucleus of the solitary tract has to be further analyzed.
Lifting the Curtain: Backstage Cognition, Frontstage Behavior, and the Interpersonal Transmission of Culture

From the schoolyard to the boardroom, the pressures of cultural assimilation pervade all walks of social life. Yet people vary in the capacity to fit in culturally, and their fit can wax and wane over time. We examine how individual cognition and social influence produce variation and change in cultural fit. We do so by lifting the curtain between the backstage (cognition) and frontstage (behavior) of cultural fit. We theorize that the backstage comprises two analytically distinct dimensions--perceptual accuracy and value congruence--and that the former matters for normative compliance on the frontstage, whereas the latter does not. We further propose that a person's behavior and perceptual accuracy are both influenced by observations of others' behavior, whereas value congruence is less susceptible to peer influence. Drawing on email and survey data from a mid-sized technology firm, we use the tools of computational linguistics and machine learning to develop longitudinal measures of frontstage and backstage cultural fit. We also take advantage of a reorganization that produced quasi-exogenous shifts in employees' peer groups to identify the causal impact of social influence.
Intraembryonic Origin of Lymphoid Stem Cells in the Chicken: Studies with Sex Chromosome and IgG Allotype Markers in Histocompatible Yolk Sac‐Embryo Chimaeras

Two‐day‐old chick embryonic bodies were transplanted onto the area vasculosa of age‐matched histocompatible blastoderms, resulting in the development of yolk sac‐embryo chimaeras. Eighteen of these succeeded in hatching and became adults. Differences in the sex chromosomes and in IgG allotype between the embryo and the yolk sac were used to study the contribution of these two components to the lymphoid cell development. At 5–7 weeks of age the chimaeras proved to be completely normal in the IgM and IgG antibody production against human gamma globulin and Brucella abortus and in the lymphocyte responses to phytohaemagglutinin and concanavalin A. For the sex chromosome analyses bursa cells and specifically stimulated B and T lymphocytes were used. The latter was achieved by stimulating thymus, spleen, and bone marrow cells in vitro with anti‐Ig and Con A. Only four out of 1498 mitoses analysed belonged to the sex opposite to that of the bird. Among the chimaeras eleven were marked through IgG allotypes. At the age of 3–20 weeks all eleven chimaeras showed serum IgG of the embryo allotype and none of the yolk sac type. These results, based on the use of two different markers, indicate that lymphoid stem cells in the chicken are originally derived from an intraembryonic source and not from the yolk sac.
The Role of Plasmapheresis in the Treatment of Severe Central Nervous System Neuropsychiatric Systemic Lupus Erythematosus

Abstract: Twenty‐six patients, who received plasmapheresis (PP) either alone or synchronized with cyclophosphamide (IV‐CYC/PP), are retrospectively reviewed from Medline searches and personal experience from 1976 to 2002. Patients with central nervous system neuropsychiatric systemic lupus erythematosus (CNS‐NPSLE) were evaluated according to the American College of Rheumatology (ACR) case definitions of 1999. Eleven of the patients were under the age of 21 years (range 7–21 years), highlighting the need for an aggressive treatment option for young patients who are refractory to other treatments. After treatment with PP or IV‐CYC/PP, 74% of patients improved, 13% stabilized, and 13% progressed. Major side‐effects occurred from central line placement rather than immunomodulation from PP itself. Step‐down therapies are needed to supplement IV‐CYC/PP once improvement has reached a plateau. Newer combinations of PP and intravenous immunoglobulin (IVIg), human stem cell transplant (HSCT) and rituximab (RTX) should be considered in the future. In the absence of randomized controlled trials (RCT), experienced clinicians must weigh risk, benefit, and cost profiles in considering the treatment of severe CNS‐NPSLE with PP.
Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Mutations in the PINK1 gene are linked to the autosomal recessive early onset familial form of PD. The physiological function of PINK1 and pathological abnormality of PD-associated PINK1 mutants are largely unknown. We here show that inactivation of Drosophila PINK1 (dPINK1) using RNAi results in progressive loss of dopaminergic neurons and in ommatidial degeneration of the compound eye, which is rescued by expression of human PINK1 (hPINK1). Expression of human SOD1 suppresses neurodegeneration induced by dPINK1 inactivation. Moreover, treatment of dPINK1 RNAi flies with the antioxidants SOD and vitamin E significantly inhibits ommatidial degeneration. Thus, dPINK1 plays an essential role in maintaining neuronal survival by preventing neurons from undergoing oxidative stress, thereby suggesting a potential mechanism by which a reduction in PINK1 function leads to PD-associated neurodegeneration.
Isolation and characterization of a family of porin proteins from Helicobacter pylori

Two-dimensional gel electrophoresis was used to identify heat-modifiable outer membrane proteins, which were candidates for porins, from Helicobacter pylori membrane preparations. Four such proteins with apparent molecular masses of 48, 49, 50, and 67 kDa were isolated. The four proteins copurified together after selective detergent solubilizations followed by anion-exchange chromatography, and each protein was ultimately purified to homogeneity by gel purification. These proteins were then tested for pore-forming ability with a planar lipid bilayer model membrane system. All four proteins appeared to be present as monomers, and they formed pores with low single-channel conductances in 1.0 M KCl of 0.36, 0.36, 0.30, and 0.25 nS, respectively, for the 48-, 49-, 50-, and 67-kDa proteins which we propose to designate HopA, HopB, HopC, and HopD. N-terminal amino acid sequence analyses showed a high degree of homology among all four proteins, and it appears that these proteins constitute a family of related porins in H. pylori.
Phenylephrine Infusions during Cesarean Section Under Spinal Anesthesia

Prevention of hypotension and its associated side effects during spinal anesthesia for cesarean section has been the “holy grail” of obstetric anesthesia for decades. Without intervention, the incidence of hypotension is as high as 85%. The dominant cause of hypotension with spinal anesthesia has been long believed to be an increase in venous capacitance, further exacerbated by aorto-caval compression by the gravid uterus, and blunted baroreceptor-mediated increases in heart rate with sympathectomy above T4. This notion is beginning to be challenged, with the argument being that the major contributing cause is reduced sympathetic tone in the arterial system. This could explain why the infusion of crystalloids and colloids has been shown to be insufficient to sustain maternal cardiac output and arterial pressure and why vasopressor administration has become the most important and effective component in preserving maternal blood pressure. On the basis of the available evidence, a wide consensus has been reached that the agent of choice for elective cesarean delivery during spinal anesthesia is phenylephrine.