Miracle-dz/UniFAR-FTUs huggingface dataset:
Dosage regulation, and variation in gene expression and copy number of human Y chromosome ampliconic genes

The Y chromosome harbors nine multi-copy ampliconic gene families expressed exclusively in testis. The gene copies within each family are >99% identical to each other, which poses a major challenge in evaluating their copy number. Recent studies demonstrated high variation in Y ampliconic gene copy number among humans. However, how this variation affects expression levels in human testis remains understudied. Here we developed a novel computational tool Ampliconic Copy Number Estimator (AmpliCoNE) that utilizes read sequencing depth information to estimate Y ampliconic gene copy number per family. We applied this tool to whole-genome sequencing data of 149 men with matched testis expression data whose samples are part of the Genotype-Tissue Expression (GTEx) project. We found that the Y ampliconic gene families with low copy number in humans were deleted or pseudogenized in non-human great apes, suggesting relaxation of functional constraints. Among the Y ampliconic gene families, higher copy number leads to higher expression. Within the Y ampliconic gene families, copy number does not influence gene expression, rather a high tolerance for variation in gene expression was observed in testis of presumably healthy men. No differences in gene expression levels were found among major Y haplogroups. Age positively correlated with expression levels of the HSFY and PRY gene families in the African subhaplogroup E1b, but not in the European subhaplogroups R1b and I1. We also found that expression of five Y ampliconic gene families is coordinated with that of their non-Y (i.e. X or autosomal) homologs. Indeed, five ampliconic gene families had consistently lower expression levels when compared to their non-Y homologs suggesting dosage regulation, while the HSFY family had higher expression levels than its X homolog and thus lacked dosage regulation.
Factors associated with newborn care knowledge and practices in the upper Himalayas

Background Globally, neonatal deaths remain a major public health challenge and account for the majority of deaths occurring among children under five years of age. Despite Nepal’s significant achievements in meeting the maternal and child health targets of the Millennium Development Goals, an estimated 23,000 Nepalese children under five years die every year, with three out of five babies dying within the first 28 days of life. This study therefore aimed to examine the level of knowledge and practices of newborn care among Nepalese mothers in the upper Himalayas and the factors associated with these. Materials and methods A community based cross-sectional study was conducted among 302 randomly selected mothers with children under two years of age in Tripurasundari Municipality of Dolpa district, an upper Himalayan region of Nepal. Mothers were interviewed using semi-structured questionnaires. Mean score for knowledge and Bloom’s criteria for practice were considered to categorize newborn care knowledge and practices. Multivariate logistic regression was used to identify factors associated with the newborn care knowledge and practices. Results In this study, 147 (48.7%) of the mothers were found to have inadequate knowledge of newborn care, while 102 (33.8%) mothers had reported unsatisfactory newborn care practices. Mothers with at least secondary level of formal education were more likely to possess adequate newborn care knowledge compared to mothers who never attended school (AOR 4.93 at 95% CI 1.82–13.33). Mothers whose first pregnancy occurred between the ages of 20–24 years (AOR 3.89 at 95% CI 1.81–8.37) were also more likely to possess adequate newborn care knowledge, compared to mothers with a younger age at first pregnancy. Furthermore, mothers who had completed at least four ANC visits (AOR 2.89 at 95% CI 1.04–7.96), mothers who had completed three PNC visits (AOR 2.79 at 95% CI 1.16–6.72) and mothers who reported that their nearest health facility was less than one hour (30–59 minutes) walking distance (AOR 3.66 at 95% CI 1.43–9.33) had higher odds of having adequate newborn care knowledge. Similarly, mothers whose household monthly income was more than $100 (AOR 4.17 at 95% CI 1.75–9.69), mothers who had completed three PNC visits (AOR 3.27 at 95% CI 1.16–9.20) and mothers with adequate newborn care knowledge (AOR 15.35 at 95% CI 5.82–40.47) were found to be more likely to practice a satisfactory level of newborn care practices in adjusted analysis. Conclusion The study revealed high prevalence of inadequate newborn care and knowledge amongst mothers in upper Himalayan dwellings. Approximately one third of all interviewed mothers practiced suboptimal newborn care. The results indicate an urgent need to increase awareness of neonatal services available to mothers and to prioritize investments by local governments in neonatal health services, in order to improve accessibility and quality of care for mothers and newborns.
Breast cancer screening practices among American Indians and Alaska Natives in the Midwest

American Indian and Alaska Native (AI/AN) women currently have some of the highest mortality rates from breast cancer for any racial/ethnic group in the United States and some of the lowest screening rates. However, current data are not available for regional differences in screening, which can result in dramatically different stage at diagnosis and mortality. We conducted surveys with 120 focus group participants in a needs assessment of mammography among AI/AN in the greater Kansas City metropolitan area and parts of Northeast Kansas. We found that among women under age 40, for whom recommended screenings include only annual clinical breast examination and breast self-examination, more women reported breast self-examination than clinical breast examination (85.3% versus 55.0% in the past year). Among women age 40 and older, more women reported breast self-examination (80.0% in the past year) than either clinical breast examination or mammography (50.8% and 46.9%, respectively, in the past year). These low rates of breast cancer screening are consistent with low rates reported around the country among AI/AN and have strong implications for stage at diagnosis and prognosis for AI/AN breast cancer patients.
Probing Single Molecule Binding and Free Energy Profile with Plasmonic Imaging of Nanoparticles.

Measuring binding between molecules is critical for understanding basic biochemical processes, developing molecular diagnosis, and screening drugs. Here we study molecular binding at the single molecule level by attaching nanoparticles to the molecular binding pairs. We track the thermal fluctuations of the individual nanoparticles with sub-nm precision using a plasmonic scattering imaging technique and show that the fluctuations are controlled by the molecular binding pairs rather than by the nanoparticles. Analysis of the thermal fluctuations provides unique information on molecular binding, including binding energy profile, effective spring constant, and switching between single and multiple molecular binding events. The method provides new insights into molecular binding and also allows to differentiate non-specific binding from specific binding, which has been a difficult task in biosensors.
Cardiovascular Response to Dynamic Functional Electrical Stimulation during Head-up Tilt

Orthostatic hypotension (OH) is a prevalent condition among individuals with spinal cord injury (SCI). After an injury, OH often reduces the benefit of neurorehabilitation and also prolongs periods of inactivity that lead to secondary complications. This study investigated whether the cardiovascular response to head-up tilting can be improved using functional electrical stimulation (FES) and rhythmic passive movements of the lower extremities. Participants with high thoracic and cervical SCI were recruited. While the participants were tilted head-up to 70 degrees, four conditions were applied in a random sequence: 1) no intervention, 2) rhythmic passive leg movements, 3) isometric FES, and 4) a combination of FES and passive leg movements. The measured cardiovascular parameters indicated that a combination of FES and passive leg movements induced the most desirable response to head-up tilting. The proposed intervention will enable more individuals with SCI to participate in beneficial neurorehabilitation that uses a
Tolerance induction for vascularized composite allotransplantation through induction of stable hematopoietic mixed chimerism

Vascularized composite allotransplantation has developed as a specialty at the interface of reconstructive and transplant surgery, offering restoration of function and form in scenarios where options for autologous reconstruction are limited, and for which the burden of donor-site morbidity may be high. Over the past 15 years some 28 patients have received face, and 85 patients upper extremity transplants. Results have been encouraging, with good functional outcomes, and the majority of patients reporting return to independence, employment and improved quality of life. However, the immunological management of these patients remains a significant challenge. While conventional immunosuppressive regimens have proven effective in preventing graft loss to rejection, they have failed to protect patients from acute rejection episodes, which have been reported in 85% during the first year post-transplant. When considered alongside the burden of comorbidity associated with life-long immunosuppression, the impetus for development of novel approaches to the prevention of rejection is clear. Induction of hematopoietic mixed chimerism has successfully achieved transplant tolerance, defined as specific unresponsiveness to donor antigens permitting life-long acceptance of transplanted tissues without maintenance immunosuppression, in numerous animal models and recently, of renal allografts in clinical trials. The work presented in this thesis investigates mixed chimerism for induction of tolerance of vascularized composite allografts (VCAs) across class I and II major histocompatibility (MHC) barriers in the Massachusetts General Hospital miniature swine model; a large animal model with defined MHC immunogenetics, and skin closely analogous to that of humans. The data presented demonstrate development of a reproducible model of VCA tolerance and stable hematopoietic mixed chimerism in a preclinical model. Importantly, tolerance extended to all components of VCAs including the epidermis and dermis, a previously un-reproducible finding. In vitro analysis demonstrated no evidence for either IL-2 reversible anergy or cellular regulation as mechanisms of donor-specific unresponsiveness, suggesting that at a systemic level, tolerance in this model may be primarily mediated by clonal deletion. In contrast, characterization of the cutaneous immune system demonstrated rapid infiltration of VCAs with recipient T cells and Langerhans? cells, which in chimeric recipients did not cause rejection but rather established stable chimerism in all tissue-resident populations including dermal T cells with the phenotype of Tregs (CD25+FoxP3+); findings which suggest tissue-specific, and regulatory, mechanisms may play important roles.These data support the hypothesis that mixed chimerism is sufficient for whole-skin tolerance of VCAs, but further work is required to demonstrate the necessity of stable, rather than transient, chimerism and to confirm the necessity of other systemic or tissue-specific factors for prevention of epidermal rejection.
The effect of gender-specific invitation letters on utilization of colorectal cancer screening

Abstract Background and aim Colorectal cancer (CRC) screening can effectively reduce cancer-associated mortality. In Germany, individuals over the age of 50 or 55 have access to CRC screening services. However, utilization rates are persistently low, particular in the male population. This observational study investigates the effect of standard versus gender-specific invitation letters on utilization of CRC screening services. Methods We analyzed utilization rates of individuals who were insured by a large health insurance fund in Bavaria, Germany. Persons who became eligible for CRC screening received a standard (2013–2014) or a gender-specific invitation letter (2015–2016). We compared utilization rates within 6 months after receipt of the invitation letter using billing codes of the health insurance fund. Results Invitation letters were sent to 49 535 individuals, of which 48.8 % were gender-specific. The overall utilization rate did not differ between recipients of the standard versus gender-specific invitation letter (11.6 % vs 11.1 %; RR: 0.97 [0.92–1.02], p = 0.19). However, uptake of screening colonoscopy was significantly higher among recipients of gender-specific invitations (2.9 % vs 3.5 %; RR: 1.21 [1.04–1.39], p = 0.01), whereas utilization of fecal occult blood tests declined (10.4 % vs 9.7 %; RR: 0.93 [0.88–0.99], p = 0.016). Conclusions Gender-specific design of invitation letters can modify the patients’ preference for specific CRC screening services and increase the acceptance of screening colonoscopy.
Critical individual roles of the BCR and FGFR1 kinase domains in BCR‐FGFR1‐driven stem cell leukemia/lymphoma syndrome

Constitutive activation of FGFR1, as a result of diverse chromosome translocations, is the hallmark of stem cell leukemia/lymphoma syndrome. The BCR‐FGFR1 variant is unique in that the BCR component contributes a serine–threonine kinase (STK) to the N‐terminal end of the chimeric FGFR1 kinase. We have deleted the STK domain and mutated the critical Y177 residue and demonstrate that the transforming activity of these mutated genes is reduced compared to the BCR‐FGFR1 parental kinase. In addition, we demonstrate that deletion of the FGFR1 tyrosine kinase domain abrogates transforming ability, which is not compensated for by BCR STK activity. Unbiased screening for proteins that are inactivated as a result of loss of the BCR STK identified activated S6 kinase and SHP2 kinase. Genetic and pharmacological inhibition of SHP2 function in SCLL cells expressing BCR‐FGFR1 in vitro leads to reduced viability and increased apoptosis. In vivo treatment of SCLL in mice with SHP099 leads to suppression of leukemogenesis, supporting an important role for SHP2 in FGFR1‐driven leukemogenesis. In combination with the BGJ398 FGFR1 inhibitor, cell viability in vitro is further suppressed and acts synergistically with SHP099 in vivo suggesting a potential combined targeted therapy option in this subtype of SCLL disease.
The knowledge - practice gap in physiotherapy practice: a clinical audit of the assessment and management of chronic low back pain within outpatient physiotherapy practice

Objective: The aim of this study was to investigate the extent of the knowledge – practice gap in the assessment and management of chronic low back pain (CLBP) within physiotherapy practice in a South Australian public hospital setting. Methods: Clinical audit of 78 patient records was undertaken to evaluate the level of documented compliance in physiotherapy practice with consensus evidence based guideline recommendations, during the period July 2012 to July 2013 Results: The clinical audit demonstrated variable levels of compliance with guideline recommendations for the assessment and management of CLBP. Documentation supporting the use of diagnostic triage, red flag screening and yellow flag screening in the physiotherapy assessment was identified in 4 (5%), 68 (87%) and 17 (22%) of the 78 medical records audited. Whilst documentation regarding the provision of advice and education, a supervised exercise program and a multidisciplinary approach to management was identified in 13 (17%), 78 (100%) and 3 (4%) medical records respectively. Conclusions: The results of this clinical audit suggest an important knowledge – practice gap between evidence based guidelines and clinical physiotherapy practices within this health care setting. These findings may have implications for clinicians and educators as they raise a number of questions about the acceptance of the biopsychosocial model and implementation of the evidence based practice regarding the assessment and management of CLBP into clinical physiotherapy practice.
Psychopharmacology of Antidepressants

1. Monoamine Hypothesis of Depression 2. Three Key Neurotransmitter Systems 3. Classical Antidepressants: MAO Inhibitors and Tricyclic Antidepressants 4. The Serotonin Selective Reuptake Inhibitors 5. Other Neurotransmitter Mechanisms 6. Antidepressant Summary 7. Antidepressant Combinations and Augmentation Strategies for Difficult Cases 8. Cytochrome P450 and Antidepressant Drug Interactions
Increase in Mitochondrial Mass in Human Fibroblasts under Oxidative Stress and during Replicative Cell Senescence

Abnormal proliferation of mitochondria generally occurs in muscle of aged individuals and patients with mitochondrial myopathy. An increase in the mitochondrial DNA (mtDNA) copy number has also been observed in aging human tissues. However, the molecular mechanism underlying the increase in mitochondrial mass and mtDNA is still unclear. In a previous study, we demonstrated that sublethal levels of oxidative stress caused an increase in mitochondrial mass in human lung cells. In this communication, we report our recent findings that the mitochondrial mass in human lung fibroblasts (MRC-5) in a later proliferation stage is significantly increased compared to that in the early stages of proliferation. The extent of the increase in mitochondrial mass in the senescent cells was similar to that in cells in the early stages of proliferation that had been treated with low concentrations (≤180 µM) of hydrogen peroxide (H2O2). Moreover, we found that the rate of reactive oxygen species (ROS) production was higher in cells in the later proliferation stage compared to cells in the early proliferation stages. A similar phenomenon was also observed in cells in the early proliferation stages under low levels of oxidative stress. On the other hand, the mRNA levels of many nuclear DNA-encoded proteins involved in mitochondrial biogenesis, particularly nuclear respiratory factor-1, were found to increase in cells in later proliferation stages and in cells in early proliferation stages that had been treated with 180 µM H2O2. Interestingly, the increase in mitochondrial mass in the cells under oxidative stress could be repressed by treatment with cycloheximide or m-chlorocarbonyl cyanide phenylhydrazone but not by chloramphenicol. Furthermore, the mitochondrial mass of mtDNA-less ρo cells was also significantly increased by exposure to low concentrations (e.g. 180 µM) of H2O2. These results suggest that the increase in mitochondrial mass in replicative senescent cells may result from an increase in ROS production, and that it is dependent on both de novo synthesis of nuclear DNA-encoded proteins and their import into mitochondria, dictated by the membrane potential of mitochondria.
Articles and Books · Neuigkeiten vom Buch- und Zeitschriftenmarkt

Abschließend wird ausführlich die psychodynamische Theorienbildung zum Somatisierungsgeschehen dargestellt. Verhaltenstheoretische Modelle kommen in diesem Zusammenhang nicht zur Sprache. Im 4. Kapitel über die Epidemiologie und gesundheitsökonomische Relevanz der somatoformen Störung wird kurz zusammengefasst die gesellschaftspolitische Bedeutung des Störungsbildes verdeutlicht. Der folgende Teil (11 Kapitel) widmet sich der Darstellung von Somatisierungssyndromen in verschiedenen medizinischen Fachgebieten. Ohne einer einheitlichen Ordnungssystematik zu folgen, kommen jeweils Epidemiologie, Erscheinungsformen, Fallbeispiele, differentialdiagnostische und diagnostische Überlegungen, prognostische Angaben sowie spezifische Therapieansätze zur Sprache. In jeweils eigenständigen Kapiteln werden abgehandelt: somatoforme Syndrome der Neurologie (psychogene Bewegungsstörungen, psychogene Gangstörungen, psychogener Tremor, Störungen der Sensibilität, pseudoepileptische Anfälle sowie Schwindel), Syndrome aus dem Bereich der Gynäkologie (chronische Unterbauchbeschwerden, Erkrankungen der Vulva mit somatoformem Bezug, urogynäkologische Beschwerden und Erkrankungen, prämenstruelles Syndrom) und der Dermatologie (somatoformer Juckreiz, somatoformes Brennen, somatoformer Schmerz, körperdysmorphe Störungen). Das Kapitel über Somatisierungssyndrome in der Kardiologie behandelt Patienten mit Herzangstneurosen, funktionell psychogenen atypischen Brustschmerzen sowie Angina-pectoris-Symptomen koronarer Genese, die bezüglich der Krankheitsbewältigung und der affektiven Belastung eine ähnliche Problematik aufweisen. Der Autor weist auf die besonderen Aspekte hin, die sich im therapeutischen Umgang mit Patienten ergeben, wenn der medizinische Apparat bei Nichtbestätigung eines subjektiv als lebensbedrohlich erlebten koronaren Ereignisses inadäquat reagiert und die Todesangst des Patienten nicht entsprechend aufgreift. Im folgenden Kapitel über somatoforme Syndrome in der Gastroenterologie werden nichtulzerative Dyspepsien sowie das Reizdarm-Syndrom behandelt. Das Chronische-Müdigkeits-Syndrom sowie das FibromyalgieSyndrom werden anschließend in je einem Kapitel ausführlich behandelt. Dem schließen sich Somatisierungssyndrome in der Urologie an (Prostatopathien, Miktionsstörungen, sexuelle Störungen, Reizblase, Urethralsyndrome, rezidivierende Zysten). Besprochen werden auch häufige Störungen aus dem Bereich der Zahnheilkunde (Burning Mouth-Syndrome, craniomandibuläre Dysfunktionen (Bruxismus), Allergien, elektrische Phänomene sowie Intoxikationsbefürchtungen (Amalgam). Ein weiteres interessantes Kapitel widmet sich SomatiKapfhammer, H. -P.; Gündel, H. Psychotherapie der Somatisierungsstörungen: Krankheitsmodelle und Therapiepraxis – störungsspezifisch und schulenübergreifend Stuttgart, Thieme, 2001, 333 S. , 49,95 EUR ISBN 3-13-126871-9
The acetylcholine receptor as a cellular receptor for rabies virus.

Characterization of specific host cell receptors for enveloped viruses is a difficult problem because many enveloped viruses bind to a variety of substrates which are not obviously related to tissue tropisms in the intact host. Viruses with a limited cellular tropism in infected animals present useful models for studying the mechanisms by which virus attachment regulates the disease process. Rabies virus is a rhabdovirus which exhibits a marked neuronotropism in infected animals. Limited data suggest that spread occurs by transsynaptic transfer of virus. The results of recent experiments at Yale suggest that viral antigen is localized very soon after injection at neuromuscular junctions, the motor nerve endings on muscle tissue. On cultured muscle cells, similar co-localization with the acetylcholine receptor is seen both before and after virus multiplication. Pretreatment of these cells with some ligands of the acetylcholine receptor results in reduced viral infection. These findings suggest that a neurotransmitter receptor or a closely associated molecule may serve as a specific host cell receptor for rabies virus and thus may be responsible for the tissue tropism exhibited by this virus. In addition to clarifying aspects of rabies virus pathogenesis, these studies have broad implications regarding the mechanism by which other viruses or viral immunizations might mediate autoimmune diseases such as myasthenia gravis. ImagesFIG. 1FIG. 2