Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel Mutation in Spectrin-like Repeat 1 of Dystrophin Central Domain Causes Protein Misfolding and Mild Becker Muscular Dystrophy*

Background: Knowledge of dystrophin modifications at the protein molecular level is required to understand genotype/phenotype link in muscular dystrophies. Results: A new mutation in DMD gene is accompanied with dystrophin structural and functional modifications. Conclusion: This Becker muscular dystrophy is due to misfolding of the dystrophin rod domain. Significance: We provide new insights in understanding the molecular bases of myopathy at the protein level. Mutations in the dystrophin gene without disruption of the reading frame often lead to Becker muscular dystrophy, but a genotype/phenotype correlation is difficult to establish. Amino acid substitutions may disrupt binding capacities of dystrophin and have a major impact on the functionality of this protein. We have identified two brothers (ages 8 and 10 years) with very mild proximal weakness, recurrent abdominal pain, and moderately elevated serum creatine kinase levels. Gene sequencing revealed a novel mutation in exon 11 of the dystrophin gene (c.1280T>C) leading to a L427P amino acid substitution in repeat 1 of the central rod domain. Immunostaining of skeletal muscle showed weak staining of the dystrophin region encoded by exons 7 and 8 corresponding to the end of the actin-binding domain 1 and the N-terminal part of hinge 1. Spectrofluorescence and circular dichroism analysis of the domain repeat 1-2 (R1-2) revealed partial misfolding of the L427P mutated protein as well as a reduced refolding rate after denaturation. Based on computational homology models of the wild-type and mutated R1-2, a molecular dynamics study showed an alteration in the flexibility of the structure, which also strongly affects the conformational space available in the N-terminal region of the fragment. Our results suggest that this missense mutation hinders the dynamic properties of the entire N-terminal region of dystrophin.
Tolerability of prophylactic Lariam regimens.

Three hundred and fifty-nine US Marines participated in a randomized double-blind clinical trial to assess tolerance of two prophylactic mefloquine regimens [250 mg salt weekly (n = 157) or 250 mg daily for 3 days followed by 250 mg weekly (n = 46)] compared with 300 mg weekly chloroquine (n = 156) over a 12-week period. The study participants were seen daily for four days, then weekly for 11 weeks. On each visit, the subject answered two computerized questionnaires (a review of body systems and an evaluation of mood states), participated in a physician interview, and was administered medications under supervision. A random sample of each group was assigned to either pharmacokinetic sampling or two wear a wrist watch size computerized sleep monitor (actigraph). The frequencies of intercurrent illness and other concomitant medications were tabulated. End study mefloquine plasma levels were obtained on all study participants. The results obtained showed no compromise in function due to dizziness or incoordination in the mefloquine groups. Overall, both weekly mefloquine and loading dose mefloquine were well tolerated. Sleep disturbance and increased dream activity were detected in the mefloquine groups. Depressive feelings were noted in two to three times more individuals in the mefloquine groups than in the chloroquine group early in the course of the study, and resolved in the majority of subjects as tolerance developed. Steady state mefloquine plasma levels were attained rapidly with the loading dose regimen in four days versus seven weeks with weekly mefloquine. (ABSTRACT TRUNCATED AT 250 WORDS)
The first pilot project of the consortium for top‐down proteomics: A status report

Pilot Project #1—the identification and characterization of human histone H4 proteoforms by top‐down MS—is the first project launched by the Consortium for Top‐Down Proteomics (CTDP) to refine and validate top‐down MS. Within the initial results from seven participating laboratories, all reported the probability‐based identification of human histone H4 (UniProt accession P62805) with expectation values ranging from 10−13 to 10−105. Regarding characterization, a total of 74 proteoforms were reported, with 21 done so unambiguously; one new PTM, K79ac, was identified. Inter‐laboratory comparison reveals aspects of the results that are consistent, such as the localization of individual PTMs and binary combinations, while other aspects are more variable, such as the accurate characterization of low‐abundance proteoforms harboring >2 PTMs. An open‐access tool and discussion of proteoform scoring are included, along with a description of general challenges that lie ahead including improved proteoform separations prior to mass spectrometric analysis, better instrumentation performance, and software development.
Body weight setpoint, metabolic adaption and human starvation

A biological setpoint for fatness has been proposed in the medical literature. This body weight setpoint functions as a point of stable equilibrium. In an underfed state, with resulting weight loss, the body will reduce the relative energy expenditure by metabolic adaption which reduces the rate of weight loss. Previous mathematical models of energy expenditure and weight loss dynamics have not addressed this setpoint mechanism. The setpoint model has been proposed to quantify this biological process and is unique in predicting energy expenditure during weight loss as a function of the setpoint fat-free mass ratio and setpoint energy expenditure, eliminating the various controlling characteristics such as age, gender and heredity. The model is applied to the seminal Minnesota human semistarvation experiment and is used to predict weight vs time on an individual basis and the caloric requirements for weight maintenance at the reduced weight. Comparison is made with the Harris-Benedict equations and the Brody-Kleiber. (W3/4) law.
Effects of respiratory physiotherapy on intracranial pressure and cerebral perfusion pressure in severe traumatic brain injury patients.

OBJECTIVE After brain injury intracranial hypertension is the major cause of mortality, in addition to the possibility of functional, behavioral and cognitive sequels. Scarcity of studies on the effects of respiratory physiotherapy on these patients may lead to contradictory performances. This study aimed to assess the effects of customary respiratory physiotherapy maneuvers on intracranial and cerebral perfusion pressures in patients with severe brain injury. METHODS Clinical, prospective trial with patients with severe traumatic brain injury, mechanically ventilated and with a continued measurement of intracranial pressure. The effects of manual vibrocompression maneuvers and intratracheal aspiration with or without saline infusion on the measurements of intracranial and cerebral perfusion pressures, between the first and third day after cerebral injury were evaluated. RESULTS Data were collected from 11 patients, 41 years of age (median) and APACHE II of 19.5 ± 5. The manual vibrocompression maneuver did not cause an increase of intracranial pressure on any of the days assessed. Intracranial pressure significantly increased after intratracheal aspiration maneuvers in relation to the basal measurement (day1, 9.5 ± 0.9 mm Hg vs 18.0 ± 3.2 mm Hg; day 2, 10.6 ± 1.7 mm Hg vs 21.4 ± 3.8 mm Hg; day 3, 14.4 ± 1.0 vs 24.9 ± 2.7 mm Hg; p<0.05 for all). However, these elevations were transient (about 27 seconds) and accompanied by compensatory increases of the cerebral perfusion pressure. CONCLUSION The manual vibrocompression maneuver did not increase intracranial pressure or cerebral perfusion pressure in patients with severe brain injury. Intratracheal aspiration induced a significant and transient increase of the intracranial and cerebral perfusion pressures.
Clinical Practice of Steroid Avoidance in Pediatric Kidney Transplantation

Steroid‐avoidance protocols have recently gained popularity in pediatric kidney transplantation. We investigated the clinical practice of steroid avoidance among 9494 kidney transplant recipients at 124 transplant centers between 2000 and 2012 in the Organ Procurement and Transplantation Network database. The practice of steroid avoidance increased during the study period and demonstrated significant variability among transplant centers. From 2008 to 2012, 39% of transplant centers used steroid avoidance in <10% of all discharged transplant recipients. Twenty‐one percent of transplant centers practiced steroid avoidance in 10–40% of transplant recipients, and 40% of transplant centers used steroid avoidance in >40% of discharged patients. Children receiving steroid avoidance more frequently received induction with lymphocyte‐depleting agents. Repeat kidney transplants were the least likely to receive steroid avoidance. Children who received a deceased donor kidney, underwent pretransplant dialysis, were highly sensitized, or had glomerular kidney disease or delayed graft function were also less likely to receive steroid avoidance. The variation in practice between centers remained highly significant (p < 0.0001) after adjustment for all patient‐ and center‐level factors in multivariate analysis. We conclude that significant differences in the practice of steroid avoidance among transplant centers remain unexplained and may reflect uncertainty about the safety and efficacy of steroid‐avoidance protocols.
The epidemiology of traumatic event exposure worldwide: results from the World Mental Health Survey Consortium

Background Considerable research has documented that exposure to traumatic events has negative effects on physical and mental health. Much less research has examined the predictors of traumatic event exposure. Increased understanding of risk factors for exposure to traumatic events could be of considerable value in targeting preventive interventions and anticipating service needs. Method General population surveys in 24 countries with a combined sample of 68 894 adult respondents across six continents assessed exposure to 29 traumatic event types. Differences in prevalence were examined with cross-tabulations. Exploratory factor analysis was conducted to determine whether traumatic event types clustered into interpretable factors. Survival analysis was carried out to examine associations of sociodemographic characteristics and prior traumatic events with subsequent exposure. Results Over 70% of respondents reported a traumatic event; 30.5% were exposed to four or more. Five types – witnessing death or serious injury, the unexpected death of a loved one, being mugged, being in a life-threatening automobile accident, and experiencing a life-threatening illness or injury – accounted for over half of all exposures. Exposure varied by country, sociodemographics and history of prior traumatic events. Being married was the most consistent protective factor. Exposure to interpersonal violence had the strongest associations with subsequent traumatic events. Conclusions Given the near ubiquity of exposure, limited resources may best be dedicated to those that are more likely to be further exposed such as victims of interpersonal violence. Identifying mechanisms that account for the associations of prior interpersonal violence with subsequent trauma is critical to develop interventions to prevent revictimization.
Hyperspectral Tree Species Classification of Japanese Complex Mixed Forest With the Aid of Lidar Data

The classification of tree species in forests is an important task for forest maintenance and management. With the increase in the spatial resolution of remote sensing imagery, individual tree classification is the next target of research area for the forest inventory. In this work, we propose a methodology involving the combination of hyperspectral and LiDAR data for individual tree classification, which can be extended to areas of shadow caused by the illumination of tree crowns with sunlight. To remove the influence of shadows in hyperspectral data, an unmixing-based correction is applied as preprocessing. Spectral features of trees are obtained by principal component analysis of the hyperspectral data. The sizes and shapes of individual trees are derived from the LiDAR data after individual tree-crown delineation. Both spectral and tree-crown features are combined and input into a support vector machine classifier pixel by pixel. This procedure is applied to data taken over Tama Forest Science Garden in Tokyo, Japan, to classify it into 16 classes of tree species. It is found that both shadow correction and tree-crown information improve the classification performance, which is further improved by postprocessing based on tree-crown information derived from the LiDAR data. Regarding the classification results in the case of 10% training data, when using the random sampling of pixels to select training samples, a classification accuracy of 82% was obtained, while the use of reference polygons as a more practical means of sample selection reduced the accuracy to 71%. These values are, respectively, 21.5% and 9% higher than those that are obtained using hyperspectral data only.
Post‐translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification

Summary. Background: Matrix Gla protein (MGP) is a small vitamin K‐dependent protein containing five γ‐carboxyglutamic acid (Gla) residues that are believed to be important in binding Ca2+, calcium crystals and bone morphogenetic protein. In addition, MGP contains phosphorylated serine residues that may further regulate its activity. In vivo, MGP has been shown to be a potent inhibitor of vascular calcification; however, the precise molecular mechanism underlying the function of MGP is not yet fully understood. Methods and results: We investigated the effects of MGP in human vascular smooth muscle cell (VSMC) monolayers that undergo calcification after exposure to an increase in Ca2+ concentration. Increased calcium salt deposition was found in cells treated with the vitamin K antagonist warfarin as compared to controls, whereas cells treated with vitamin K1 showed decreased calcification as compared to controls. With conformation‐specific antibodies, it was confirmed that warfarin treatment of VSMCs resulted in uncarboxylated (Gla‐deficient) MGP. To specifically test the effects of MGP on VSMC calcification, we used full‐length synthetic MGP and MGP‐derived peptides representing various domains in MGP. Full length MGP, the γ‐carboxylated motif (Gla) (amino acids 35–54) and the phosphorylated serine motif (amino acids 3–15) inhibited calcification. Furthermore, we showed that the peptides were not taken up by VSMCs but bound to the cell surface and to vesicle‐like structures. Conclusions: These data demonstrate that both γ‐glutamyl carboxylation and serine phosphorylation of MGP contribute to its function as a calcification inhibitor and that MGP may inhibit calcification via binding to VSMC‐derived vesicles.
Characterization of psychotic conditions. Use of the domains of psychopathology model.

BACKGROUND Previous factor analytic studies of patients with schizophrenia have consistently demonstrated the presence of 3 psychopathological domains labeled positive, negative, and disorganized. This study examined whether similar domains can be seen in disorders other than schizophrenia, and the degree to which such domains are independent of diagnostic categorization. METHODS Data from the Diagnostic and Statistical manual of Mental Disorders, Fourth Edition (DSM-IV) field trial involving 221 patients with schizophrenia and 189 patients with nonschizophrenia diagnoses were factor analyzed to study the nature of psychopathological domains in the 2 groups. Differential associations between each domain and selected clinical variables were assessed. RESULTS Factor analysis yielded a similar 3-factor model of positive, negative, and disorganization domains for patients with schizophrenia as well as other diagnoses. Differential associations found between individual domains and clinical variables (premorbid functioning and negative domain; absence of remissions and disorganization domain) were similar in both schizophrenia and nonschizophrenia groups. CONCLUSIONS The 3 psychopathological domains previously described in schizophrenia are not specific for that diagnosis. Differential associations found between individual domains and clinical variables were not limited by diagnostic categorization. The results suggest that these domains are not unique to schizophrenia and may each correspond to a discrete pathophysiologic condition.
Mitochondrial therapies for Parkinson's disease

Parkinson's disease (PD) is marked by widespread neurodegeneration in the brain in addition to a selective yet prominent and progressive loss of nigrostriatal dopaminergic neurons. Of the multiple theories suggested in the pathogenesis of PD, mitochondrial dysfunction takes a center stage in both sporadic and familial forms of illness. Deficits in mitochondrial functions due to impaired bioenergetics, aging associated increased generation of reactive oxygen species, damage to mitochondrial DNA, impaired calcium buffering, and alterations in mitochondrial morphology may contribute to improper functioning of the CNS leading to neurodegeneration. These mitochondrial alterations suggest that a potential target worth exploring for neuroprotective therapies are the ones that can preserve mitochondrial functions in PD. Here, we provide a recent update on potential drugs that are known to block mitochondrial dysfunctions in various experimental models and those that are currently under clinical trials for PD. We also review novel mitochondrial survival pathways that provide hope and promise for innovative neuroprotective therapies in the future that can be explored as possible therapeutic intervention for PD pathogenesis. © 2010 Movement Disorder Society
[Expression of CD1a, CD80, CD86 in dendritic cell of tumor tissue and regional lymph node in esophageal carcinoma].

BACKGROUND & OBJECTIVE Dendritic cells are the important antigen presenting cell, and take part in the anti-tumor immunoreaction. This study was designed to investigate the expression of CD1a (specific marker) and CD80, CD86 (costimulating molecules) in dendritic cell of tumor tissue and regional lymph node of esophageal carcinoma and to investigate the mechanisms by which tumors escape immune recognition. METHODS The expression of CD1a, CD80, CD86 in dendritic cells of tumor tissues and paratumor tissues from 58 patients with esophageal carcinoma (clinical period I-II:27 cases,III-IV: 31 cases;differentiation G(1-2): 37 cases,G3:21 cases;squamous cancer: 49 cases,adenoid cancer: 9 cases;lymph node metastases present: 37 cases,lymph node metastases absent: 21 cases), inflammatory tissues from 11 patients with esophagitis, 12 normal esophageal tissues (as control), 31 regional lymph nodes with tumor and 34 regional lymph nodes without tumor were determined using flow cytometry. RESULTS (1) The expression rates of CD1a, CD80, CD86 in tumor tissues (6.18+/-1.47, 5.37+/-1.13, 37.35+/-7.42) were less than those in normal tissues (10.28+/-2.11, 9.67+/-1.94, 48.76+/-10.23), the inflammatory tissues (11.89+/-2.65, 10.46+/-1.79, 51.55+/-10.60), and the paratumor tissue (11.79+/-2.41, 10.49+/-1.89, 9.78+/-12.31) (P< 0.01). (2) The expression rates of CD1a, CD80, CD86 in regional lymph node with tumor (8.34+/-1.66,6.78+/-1.42,41.70+/-8.71) were less than those in the lymph node without tumor (12.23+/-2.14, 10.82+/-2.11, 59.63+/-12.52)(P< 0.01). (3) There was no significant difference in the expression rates of CD1a, CD80, CD86 between paratumor tissue, inflammatory tissue and normal esophageal tissues (P >0.05). (4) The expression of CD1a, CD80, CD86 were not associated with the clinical period, pathological type, and the lymph node metastases (P >0.05); but were associated with pathological differentiation (grade1-2 were higher than grade 3)(P< 0.01). CONCLUSION (1) The number of dendritic cell of CD1a (+) decreases in tumor tissue and regional lymph node with tumor in esophageal carcinoma and the expression of CD80, CD86 are down-regulated. (2) The lower the tumor differentiation grade, the less the number of CD1a(+) dendritic cell in tumor tissue and regional lymph node and the lower the expression of CD80, CD86 in tumor tissue.
The retinal clock drives the expression of Kcnv2, a channel essential for visual function and cone survival.

PURPOSE The gene Kcnv2 codes for the voltage-gated potassium channel subunit Kv8.2, which can coassemble with Kv2.1 subfamily members to constitute functional voltage-gated potassium channels. Mutations in the Kcnv2 gene result in a retinal disorder designated "cone dystrophy with supernormal rod response (CDSRR)," revealing that Kcnv2 is essential for visual processing and cone survival. The aim of this study was to determine whether expression of Kcnv2 and Kv2.1 is under circadian regulation and may thus contribute to the clock-driven adjustment of photoreceptor function. METHODS Expression of the genes was recorded in preparations of the whole retina and microdissected retinal neurons by using quantitative polymerase chain reaction and Western blot. RESULTS The transcript levels of Kcnv2 and Kv2.1 in preparations of whole retina and photoreceptor cells were found to display daily rhythms, with elevated values during the night. For Kcnv2 this rhythm was shown to evoke a corresponding rhythm in Kv8.2, the protein product of this gene. The daily changes in retinal Kcnv2 and Kv2.1 mRNA levels persisted under constant darkness and are therefore driven by the endogenous retinal clock system, which itself is entrained by light. CONCLUSIONS The present data provide evidence that the transcriptional regulation of Kcnv2 and Kv2.1 is a way through which the retinal clock system drives the functional adaptation of visual function to the marked daily changes in environmental lighting conditions.
Deletion of the Dual Specific Phosphatase-4 (DUSP-4) Gene Reveals an Essential Non-redundant Role for MAP Kinase Phosphatase-2 (MKP-2) in Proliferation and Cell Survival*

Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP) implicated in a number of cancers. We examined the role of MKP-2 in the regulation of MAP kinase phosphorylation, cell proliferation, and survival responses in mouse embryonic fibroblasts (MEFs) derived from a novel MKP-2 (DUSP-4) deletion mouse. We show that serum and PDGF induced ERK-dependent MKP-2 expression in wild type MEFs but not in MKP-2−/− MEFs. PDGF stimulation of sustained ERK phosphorylation was enhanced in MKP-2−/− MEFs, whereas anisomycin-induced JNK was only marginally increased. However, marked effects upon cell growth parameters were observed. Cellular proliferation rates were significantly reduced in MKP-2−/− MEFs and associated with a significant increase in cell doubling time. Infection with adenoviral MKP-2 reversed the decrease in proliferation. Cell cycle analysis revealed a block in G2/M phase transition associated with cyclin B accumulation and enhanced cdc2 phosphorylation. MEFs from MKP-2−/− mice also showed enhanced apoptosis when stimulated with anisomycin correlated with increased caspase-3 cleavage and γH2AX phosphorylation. Increased apoptosis was reversed by adenoviral MKP-2 infection and correlated with selective inhibition of JNK signaling. Collectively, these data demonstrate for the first time a critical non-redundant role for MKP-2 in regulating cell cycle progression and apoptosis.