Miracle-dz/UniFAR-FTUs huggingface dataset:
Tandem Pore Domain Halothane-inhibited K+ Channel Subunits THIK1 and THIK2 Assemble and Form Active Channels*

Background: THIK1 and THIK2 are related leak K+ channel subunits. Results: Assembly of THIK1 with THIK2 was shown by dominant negative effects of pore-mutated subunits, in situ proximity ligation assay, FRET, and electrophysiology of covalent THIK1/THIK2 dimers. Conclusion: THIK1 and THIK2 assemble and form active channels. Significance: In cell and tissues co-expressing THIK1 and THIK2, heterodimeric channels may contribute to cell excitability. Despite a high level of sequence homology, tandem pore domain halothane-inhibited K+ channel 1 (THIK1) produces background K+ currents, whereas THIK2 is silent. This lack of activity is due to a unique combination of intracellular retention and weak basal activity in the plasma membrane. Here, we designed THIK subunits containing dominant negative mutations (THIK1DN and THIK2DN). THIK2DN mutant inhibits THIK1 currents, whereas THIK1DN inhibits an activated form of THIK2 (THIK2-A155P-I158D). In situ proximity ligation assays and Förster/fluorescence resonance energy transfer (FRET) experiments support a physical association between THIK1 and THIK2. Next, we expressed covalent tandems of THIK proteins to obtain expression of pure heterodimers. Td-THIK1-THIK2 (where Td indicates tandem) produces K+ currents of amplitude similar to Td-THIK1-THIK1 but with a noticeable difference in the current kinetics. Unlike Td-THIK2-THIK2 that is mainly detected in the endoplasmic reticulum, Td-THIK1-THIK2 distributes at the plasma membrane, indicating that THIK1 can mask the endoplasmic reticulum retention/retrieval motif of THIK2. Kinetics and unitary conductance of Td-THIK1-THIK2 are intermediate between THIK1 and THIK2. Altogether, these results show that THIK1 and THIK2 form active heteromeric channels, further expanding the known repertoire of K+ channels.
Obstetric brachial plexus injuries

Abstract This article presents a detailed review of the history, etiology, assessment protocols, and current treatment for children who suffer an obstetric birth palsy. In addition, new issues facing surgeons who deal with these patients and their families are discussed. Copyright © 2003 by the American Society for Surgery of the Hand
Exercise training attenuates cardiovascular adverse remodeling in adult ovariectomized spontaneously hypertensive rats

Objective:To study the combined effects of ovariectomy and regular exercise training on hypertension and on cardiac and aortic remodeling in spontaneously hypertensive rats (SHR). Design:Three-month-old female spontaneously hypertensive rats (SHR) were ovariectomized (ovx) or were left intact (int) and divided in four groups (n = 7): sedentary (sed-ovx), exercise-trained (ex-ovx), sedentary intact (sed-int), and exercise-trained intact (ex-int). The exercise protocol was performed on a motor treadmill for 13 weeks. Blood pressure (BP), left ventricular myocardium and aortic wall were studied by light microscopy and stereology. Results:Exercise-trained SHR showed a BP reduction of more than 15% compared with the matched sedentary SHR (sed-int: 210 ± 5 mm Hg, sed-ovx: 225 ± 4 mm Hg, ex-int: 178 ± 2 mm Hg, ex-ovx: 180 ± 3 mm Hg, P < 0.001). Ovariectomy caused adverse cardiac and aortic wall remodeling, including cardiomyocyte hypertrophy, myocardial interstitial reparative fibrosis and vascularization impairment with loss of cardiomyocytes, and aortic tunica media hypertrophy. Exercise training showed beneficial effects, mainly reduced BP, decreased cardiac hypertrophy due to hypertension, and increased myocardial vascularization. Ovariectomy accelerated cardiomyocyte loss in SHR while exercise training offset this process. Exercise training was the main factor influencing the improvement of intramyocardial arteries length density and significantly reduced the aortic wall thickness and increased the density of smooth muscle cell nuclei per tunica media unit area. Conclusions:In ovariectomized SHR, exercise training exerts beneficial effects diminishing adverse cardiac and aortic wall remodeling, mainly by reducing interstitial myocardial fibrosis, improving myocardial vascularization, and sustaining the number of cardiomyocytes.
Preventing Pressure Ulcers: A Multisite Randomized Controlled Trial in Nursing Homes.

BACKGROUND Pressure at the interface between bony prominences and support surfaces, sufficient to occlude or reduce blood flow, is thought to cause pressure ulcers (PrUs). Pressure ulcers are prevented by providing support surfaces that redistribute pressure and by turning residents to reduce length of exposure. OBJECTIVE We aim to determine optimal frequency of repositioning in long-term care (LTC) facilities of residents at risk for PrUs who are cared for on high-density foam mattresses. METHODS We recruited residents from 20 United States and 7 Canadian LTC facilities. Participants were randomly allocated to 1 of 3 turning schedules (2-, 3-, or 4-hour intervals). The study continued for 3 weeks with weekly risk and skin assessment completed by assessors blinded to group allocation. The primary outcome measure was PrU on the coccyx or sacrum, greater trochanter, or heels. RESULTS Participants were mostly female (731/942, 77.6%) and white (758/942, 80.5%), and had a mean age of 85.1 (standard deviation [SD] ± 7.66) years. The most common comorbidities were cardiovascular disease (713/942, 75.7%) and dementia (672/942, 71.3%). Nineteen of 942 (2.02%) participants developed one superficial Stage 1 (n = 1) or Stage 2 (n = 19) ulcer; no full-thickness ulcers developed. Overall, there was no significant difference in PrU incidence (P = 0.68) between groups (2-hour, 8/321 [2.49%] ulcers/group; 3-hour, 2/326 [0.61%]; 4-hour, 9/295 [3.05%]. Pressure ulcers among high-risk (6/325, 1.85%) versus moderate-risk (13/617, 2.11%) participants were not significantly different (P = 0.79), nor was there a difference between moderate-risk (P = 0.68) or high-risk allocation groups (P = 0.90). CONCLUSIONS Results support turning moderate- and high-risk residents at intervals of 2, 3, or 4 hours when they are cared for on high-density foam replacement mattresses. Turning at 3-hour and at 4-hour intervals is no worse than the current practice of turning every 2 hours. Less frequent turning might increase sleep, improve quality of life, reduce staff injury, and save time for such other activities as feeding, walking, and toileting.
The initiation of homologous chromosome synapsis in mouse fetal oocytes is not directly driven by centromere and telomere clustering in the bouquet

We investigated the behaviour of centromeres and distal telomeres during the initial phases of female meiosis in mice. In particular, we wished to determine whether clustering of centromeres and telomeres (bouquet formation) played the same crucial role in homologous chromosome pairing in female meiosis as it does in the male. We found that synapsis (intimate homologous chromosome pairing) is most frequently initiated in the interstitial regions of homologous chromosomes, apparently ahead of the distal regions. The proximal ends of the chromosomes appear to be disfavoured for synaptic initiation. Moreover, initiation of synapsis occurred in oocytes that showed little or no evidence of bouquet formation. A bouquet was present in a substantial proportion of cells at mid to late zygotene, and was still present in some pachytene oocytes. This pattern of bouquet formation and pairing initiation is in stark contrast to that previously described in the male mouse. We propose that although dynamic movements of centromeres and telomeres to form clusters may facilitate alignment of homologues or homologous chromosome segments during zygotene, in the female mouse positional control of synaptic initiation is dependent on some other mechanism.
Comprehensive study of Ga activation in Si, SiGe and Ge with 5 × 10−10 Ω·cm2 contact resistivity achieved on Ga doped Ge using nanosecond laser activation

Ga diffusion and activation in Si, SWGe<inf>0.6</inf> and Ge are studied comprehensively. Optimal Ga activation conditions for Si<inf>0.4</inf>Ge<inf>0.6</inf> and Ge feature a low thermal budget: Ga is highly activated at 400°C in Ge and at 500°C in SWGe<inf>0.6</inf> using a 1min rapid thermal annealing (RTA); the activation is further boosted using short-duration high-temperature nanosecond laser activation (NLA). A low Ti/p-Ge contact resistivity (pc) of 1.2×10<sup>−9</sup> Q-cm<sup>2</sup> is approached using Ga doping and 400°C RTA activation, while a record-low pc for p-Ge down to 5×10<sup>−10</sup> Qcm<sup>2</sup> is achieved using NLA for Ga activation.
Flavin monooxygenase 3 (FMO3) polymorphism in a white population: Allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism

The flavin‐containing monooxygenase 3 (FMO3) has been shown to be genetically polymorphic. In vitro, the enzyme contributes to the N‐oxidation of clozapine, caffeine, and several other drugs. We therefore wanted to analyze population frequencies and allelic linkage of FMO3 mutations and their functional effect on the metabolism of clozapine and caffeine.
Differential gene expression profiles in colon epithelium of two rat strains with distinct susceptibility to colon carcinogenesis after exposure to PhIP in combination with dietary high fat

Colon cancers develop through accumulation of multiple genetic and epigenetic alterations in colon epithelial cells, and the environment of the genetically altered epithelial cells may also have a substantial impact on their further development to cancer. In the present study, groups of 6‐week‐old F344 and ACI male rats, the former strain being susceptible to colon carcinogenesis induced by 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) and the latter being relatively resistant, were subjected to a long‐term carcinogenesis experiment using our intermittent feeding protocol of PhIP in combination with a high‐fat diet, which serves as a relevant risk factor that promotes the development of colon cancers. Animals were sacrificed at 60 weeks, and global gene expression analyses of normal parts of colon epithelial tissues were conducted using a high‐density oligonucleotide microarray to elucidate the differential gene expression profile (environment) in normal colonic regions between F344 and ACI strains. Of 8799 entries on the RatU34A array, 74 genes exhibited 3‐fold or greater variation. A subset of genes encoding ribosomal RNAs and proteins were highly preferentially expressed in the F344 strain. In addition, genes encoding fatty acid binding proteins and the peroxisome membrane protein 70 appeared up‐regulated in the susceptible F344 strain. In the ACI strain, a mismatch repair gene, Msh2, was preferentially expressed, at approximately 20‐fold the F344 level, along with a gene encoding a detoxification enzyme, catechol‐O‐methyltransferase. The combined effects of the repertoire of these differentially expressed genes in normal colon epithelial tissues may account for the distinct susceptibilities of F344 and ACI strains to colon carcinogenesis.
Low-dose γ-rays modify CD4+ T cell signalling response to simulated solar particle event protons in a mouse model

Purpose: Astronauts on missions are exposed to low-dose/low-dose-rate (LDR) radiation and could receive high doses during solar particle events (SPE). This study investigated T cell function in response to LDR radiation and simulated SPE (sSPE) protons, alone and in combination. Materials and methods: C57BL/6 mice received LDR γ-radiation (57Co) to a total dose of 0.01 Gray (Gy) at 0.179 mGy/h, either with or without subsequent exposure to 1.7 Gy sSPE protons delivered over 36 h. Mice were euthanised on days 4 and 21 post-exposure. T cells with cluster of differentiation 4 (CD4+) were negatively isolated from spleens and activated with anti-CD3 antibody. Cells and supernatants were evaluated for survival/signalling proteins and cytokines. Results: The most striking effects were noted on day 21. In the survival pathway, nuclear factor-kappaB (NF-κB; total and active forms) and p38 mitogen activated protein kinase (p38MAPK; total) were significantly increased and cJun N-terminal kinase (JNK; total and active) was decreased when mice were primed with LDR γ-rays prior to sSPE exposure (P < 0.001). Evaluation of the T cell antigen receptor (TCR) signalling pathway revealed that LDR γ-ray exposure normalised the high sSPE proton-induced level of lymphocyte specific protein tyrosine kinase (Lck; total and active) on day 21 (P < 0.001 for sSPE vs. LDR + sSPE), while radiation had no effect on active zeta-chain-associated protein kinase 70 (Zap-70). There was increased production of interleukin-2 (IL-2) and IL-4 and decreased transforming growth factor-β1 in the LDR + sSPE group compared to the sSPE group. Conclusion: The data demonstrate, for the first time, that protracted exposure to LDR γ-rays can significantly modify the effects of sSPE protons on critical survival/signalling proteins and immunomodulatory cytokines produced by CD4+ T cells.
Accurate CD4 T-cell enumeration and antiretroviral drug toxicity monitoring in primary healthcare clinics using point-of-care testing

Objective:To evaluate the accuracy of point-of-care tests (POCTs) for CD4 cell, clinical chemistry and hemoglobin in primary healthcare clinics in Mozambique. Design and methods:POCT and laboratory-based assays were conducted on adult HIV-positive patients enrolled consecutively at primary healthcare clinics in Mozambique. Patients were tested on-site with POCT CD4 (Pima), clinical chemistry (Reflotron) and hemoglobin (HemoCue) devices using finger prick blood. Results obtained on paired blood samples were used for agreement analysis (bias and limits of agreement). Repeatability analysis was also performed for POCT CD4 cell counting. Results:Primary health nurses operating the Pima, Reflotron and HemoCue POCT devices produced results with low levels of bias for CD4+ T-cell counts (−52.8 cells/μl), alanine aminotransferase (−0.2 U/l), aspartate aminotransferase (−4.0 U/l) and hemoglobin (0.95 g/dl). CD4+ T-cell counts in paired specimens of finger prick and venous blood tested on the POCT CD4 device were in close agreement (bias −9 cells/μl, coefficient of variation 10.6%). The repeatability of POCT CD4 cell counting was similar to that observed with laboratory instruments (bias −6.2 cells/μl, coefficient of variation 10.7% vs. bias −5.7 cells/μl, coefficient of variation 7.5%). Conclusion:Primary health clinic nurses generated accurate results for CD4+ T-cell counts, liver enzymes and hemoglobin using simple POC devices on finger prick samples at decentralized antiretroviral therapy (ART) clinics. POC diagnostics to monitor ART at primary healthcare level is technically feasible and should be utilized in efforts to decentralize HIV care and treatment.
Stress‐Induced Retrotranslocation of Clusterin/ApoJ into the Cytosol

Clusterin is a usually secreted glycoprotein with chaperone properties. Recently, it has been suggested that clusterin isoforms reside in the nuclear and cytosolic compartments of human cell types, where they can influence various cellular programs including DNA repair, transcription and apoptosis. Several mechanisms have been proposed to explain this atypical location, including alternative transcription initiation and alternative splicing. However, none of these have been unequivocally established as occurring in live cells. Here we provide direct experimental evidence that in live intact cells, under certain stress conditions, clusterin can evade the secretion pathway and reach the cytosol. This was demonstrated using several complementary approaches. Flow cytometry and selective permeabilization of U251 cell membranes with digitonin allowed detection of cytosolic clusterin in stressed U251 cells. In addition, a stringent enzymatic assay reliant upon the exclusively cytosolic deubiquitinase enzymes confirmed that clusterin synthesized with its hydrophobic secretion signal sequence can reach the cytosol of U251 cells. The retrotranslocation of clusterin is likely to occur through a mechanism similar to the endoplasmic reticulum (ER)‐associated protein degradation pathway and involves passage through the Golgi apparatus. We also report that the ER‐associated ubiquitin ligase Hrd1/synoviolin can interact with, and ubiquitinate clusterin. The possible biological functions of these novel behaviours of clusterin are discussed.
Mitochondrial COII Gene Sequences Provide New Insights into the Phylogeny of Marmoset Species Groups (Callitrichidae, Primates)

Mitochondrial cytochrome oxidase II (COII) gene sequences (549 base pairs) were used to investigate the taxonomic relationships among 12 marmoset (Callithrix, Cebuella and Mico) taxa. A large number of substitutions were found in the third base codon positions, providing a strong phylogenetic signal in a gene coding a conserved protein. Despite the significant affinity between the 2 Amazonian genera Cebuella and Mico, found in recent molecular studies, the analysis presented here did not resolve convincingly the phylogenetic relationships between the 3 genera. Mico nevertheless formed 3 distinct clades, reflecting a basic division of species groups based on geographic distribution (east or west of the Rio Tapajós) rather than morphology (presence or absence of auricular hair). This supports the taxonomic distinction of the allopatric emiliae forms. In Callithrix, Callithrix aurita forms a distinct clade, but the remaining morphotypes form a somewhat contradictory cluster, possibly resulting from an extremely rapid radiation.
Quality of parent communication about sex and its relationship to risky sexual behavior among youth in psychiatric care: a pilot study.

BACKGROUND The number of HIV infections among adolescents is increasing, and youth in psychiatric care are at particular risk because of their high rates of risky sexual behavior. METHODS As part of a larger longitudinal study examining AIDS-risk behavior among adolescents in psychiatric care, this pilot study investigated the relationship between parent communication about sex and sexual risk-taking among treatment-seeking adolescents. Adolescents reported their risky sexual behavior (e.g., inconsistent condom use, sex with multiple partners), and parents reported how frequently they bring up topics related to sex, HIV/AIDS, and birth control. Parents and adolescents participated together in videotaped discussions of fictional vignettes describing situations related to sex, birth control, and AIDS/HIV. Quality of the parent-teen discussions was coded based on a system developed by Whalen, Henker, Hollingshead, and Burgess (1996) to code AIDS-related discussions. RESULTS Quality but not frequency of parent-teen communication was associated with adolescent sexual risk-taking, and ethnic differences in communication were found. CONCLUSIONS Findings from this pilot investigation underscore the importance of studying the relationship between parent-teen communication and risky sexual behavior among troubled youth and provide direction for the development of family-based intervention programs that focus on parental behavior during conversations with teens.
Loop-Sheet Mechanism of Serpin Polymerization Tested by Reactive Center Loop Mutations*

The serpin mechanism of protease inhibition involves the rapid and stable incorporation of the reactive center loop (RCL) into central β-sheet A. Serpins therefore require a folding mechanism that bypasses the most stable “loop-inserted” conformation to trap the RCL in an exposed and metastable state. This unusual feature of serpins renders them highly susceptible to point mutations that lead to the accumulation of hyperstable misfolded polymers in the endoplasmic reticulum of secretory cells. The ordered and stable protomer-protomer association in serpin polymers has led to the acceptance of the “loop-sheet” hypothesis of polymerization, where a portion of the RCL of one protomer incorporates in register into sheet A of another. Although this mechanism was proposed 20 years ago, no study has ever been conducted to test its validity. Here, we describe the properties of a variant of α1-antitrypsin with a critical hydrophobic section of the RCL substituted with aspartic acid (P8–P6). In contrast to the control, the variant was unable to polymerize when incubated with small peptides or when cleaved in the middle of the RCL (accepted models of loop-sheet polymerization). However, when induced by guanidine HCl or heat, the variant polymerized in a manner indistinguishable from the control. Importantly, the Asp mutations did not affect the ability of the Z or Siiyama α1-antitrypsin variants to polymerize in COS-7 cells. These results argue strongly against the loop-sheet hypothesis and suggest that, in serpin polymers, the P8–P6 region is only a small part of an extensive domain swap.
Absorption , Dissociation , and Posttraumatic Stress : Differential Associations Among Constructs and Symptom Clusters

C in patterns of attention allocation following traumatic exposure have been implicated in the development and maintenance of posttraumatic stress symptoms (1-4). Attentional allocation is defined, in part, by absorption and dissociation, constructs which require further empirical investigation vis-à-vis posttraumatic stress (5). Dissociation is characterized as a process involving “disruption in the usually integrated functions of consciousness, memory, identity, or perception” (6), p. 519), with prominent presentations in trauma-related disorders such as posttraumatic stress disorder (PTSD). As a construct, Absorption, Dissociation, and Posttraumatic Stress: Differential Associations Among Constructs and Symptom Clusters
Air‐water gas exchange of chlorinated pesticides in four lakes spanning a 1,205 meter elevation range in the Canadian Rocky Mountains

Concentrations of selected persistent organic pollutants (POPs) in airand water were measured from four lakes that transect the Canadian Rocky Mountains. These data were used in combination with wind velocity and temperature‐adjusted Henry's law constants to estimate the direction and magnitude of chemical exchange across the air–water interface of these lakes. Bow Lake (1,975 m above sea level [masl]) was studied during the summers of 1998 through 2000; Donald (770 masl) was studied during the summer of 1999; Dixon Dam Lake (946 masl) and Kananaskis Lake (1,667 masl) were studied during the summer of 2000. Hexachlorobenzene (HCB) and dieldrin volatilized from Bow Lake in spring and summer of 1998 to 2000 at a rate of 0.92 ± 1.1 and 0.55 ± 0.37 ng m−2 d−1, respectively. The α‐endosulfan deposited to Bow Lake at a rate of 3.4 ± 2.2 ng m−2 d−1. Direction of gas exchange for γ‐hexachlorocyclohexane (γ‐HCH) changed from net deposition in 1998 to net volatilization in 1999, partly because of a surge in γ‐HCH concentrations in the water at Bow Lake in 1999. Average γ‐HCH concentrations in air declined steadily over the three‐year period, from 0.021 ng m−3 in 1998, to 0.0023 ng m−3 in 2000, and to volatilization in 1999 and 2000. Neither the concentrations of organochlorine compounds (OCs) in air and water, nor the direction and rate of air–water gas exchange correlate with temperature or elevation. In general, losses of pesticides by outflow were greater than the amount exchanged across the air–water interface in these lakes.