Miracle-dz/UniFAR-FTUs huggingface dataset:
Direct involvement of p53 in programmed cell death of oligodendrocytes.

A covalent dimer of interleukin (IL)‐2, produced in vitro by the action of a nerve‐derived transglutaminase, has been shown previously to be cytotoxic to mature rat brain oligodendrocytes. Here we report that this cytotoxic effect operates via programmed cell death (apoptosis) and that the p53 tumor suppressor gene is involved directly in the process. The apoptotic death of mature rat brain oligodendrocytes in culture following treatment with dimeric IL‐2 was demonstrated by chromatin condensation and internucleosomal DNA fragmentation. The peak of apoptosis was observed 16‐24 h after treatment, while the commitment to death was already observed after 3‐4 h. An involvement of p53 in this process was indicated by the shift in location of constitutively expressed endogenous p53 from the cytoplasm to the nucleus, as early as 15 min after exposure to dimeric IL‐2. Moreover, infection with a recombinant retrovirus encoding a C‐terminal p53 miniprotein, shown previously to act as a dominant negative inhibitor of endogenous wild‐type p53 activity, protected these cells from apoptosis.
Different and Divergent Regulation of the KIR2DL4 and KIR3DL1 Promoters1

The killer Ig-like receptors (KIR) are a family of highly related MHC class I receptors that show extreme genetic polymorphism both within the human population and between closely related primate species, suggestive of rapid evolutionary diversification. Most KIR are expressed in a variegated fashion by the NK population, giving rise to an NK repertoire of specificities for MHC class I. We compared the promoter for KIR3DL1, which exhibits variegated gene expression, with that for KIR2DL4, which is expressed by all NK cell clones. Maximum transcriptional activity of each was encoded within ∼270 bp upstream of the translation initiation codon. The KIR2DL4 promoter drove reporter gene expression only in NK cells, while the KIR3DL1 promoter was active in a range of cell types, suggesting that the latter requires other regulatory elements for physiological expression. In NK cells, reporter gene expression driven by the KIR2DL4 promoter was greater than that driven by the KIR3DL1 promoter. DNase I footprinting revealed that transcription factor binding sites differ between the two promoters. The data indicate that while the promoters of these two KIR genes share 67% nucleotide identity, they have evolved distinct properties consistent with different roles in regulating the generation of NK repertoire.
Scikit-ribo: Accurate estimation and robust modeling of translation dynamics at codon resolution

Ribosome profiling (Riboseq) is a powerful technique for measuring protein translation, however, sampling errors and biological biases are prevalent and poorly understand. Addressing these issues, we present Scikit-ribo (https://github.com/hanfang/scikit-ribo), the first open-source software for accurate genome-wide A-site prediction and translation efficiency (TE) estimation from Riboseq and RNAseq data. Scikit-ribo accurately identifies A-site locations and reproduces codon elongation rates using several digestion protocols (r = 0.99). Next we show commonly used RPKM-derived TE estimation is prone to biases, especially for low-abundance genes. Scikit-ribo introduces a codon-level generalized linear model with ridge penalty that correctly estimates TE while accommodating variable codon elongation rates and mRNA secondary structure. This corrects the TE errors for over 2000 genes in S. cerevisiae, which we validate using mass spectrometry of protein abundances (r = 0.81) and allows us to determine the Kozak-like sequence directly from Riboseq. We conclude with an analysis of coverage requirements needed for robust codon-level analysis, and quantify the artifacts that can occur from cycloheximide treatment.
The Dual Effects of B Cell Depletion on Antigen-Specific T Cells in BDC2.5NOD Mice

B cells play a critical role in the pathogenesis of autoimmune diabetes. To investigate the mechanisms by which B cell depletion therapy attenuates islet β cell loss and particularly to examine the effect of B cells on both diabetogenic and regulatory Ag-specific T cells, we generated a transgenic BDC2.5NOD mouse expressing human CD20 on B cells. This allowed us to deplete B cells for defined time periods and investigate the effect of B cell depletion on Ag-specific BDC2.5 T cells. We depleted B cells with anti-human CD20 Ab using a multiple injection protocol. We studied two time points, before and after B cell regeneration, to examine the effect on BDC2.5 T cell phenotype and functions that included antigenic response, cytokine profile, diabetogenicity, and suppressive function of regulatory T (Treg) cells. We found unexpectedly that B cell depletion induced transient aggressive behavior in BDC2.5 diabetogenic T cells and reduction in Treg cell number and function during the depletion period. However, after B cell reconstitution, we found that more regenerated B cells, particularly in the CD1d− fraction, expressed immune regulatory function. Our results suggest that the regenerated B cells are likely to be responsible for the therapeutic effect after B cell depletion. Our preclinical study also provides direct evidence that B cells regulate both pathogenic and Treg cell function, and this knowledge could explain the increased T cell responses to islet Ag after rituximab therapy in diabetic patients in a recent report and will be useful in design of future clinical protocols.
Guidelines for Screening of Extracranial Carotid Artery Disease: A Statement for Healthcare Professionals from the Multidisciplinary Practice Guidelines Committee of the American Society of Neuroimaging; Cosponsored by the Society of Vascular and Interventional Neurology

The aim of this new statement is to provide comprehensive and timely evidence‐based recommendations on the screening for asymptomatic carotid artery stenosis in the general population and selected subsets of patients. Recommendations are included for high‐risk persons in the general population; patients undergoing open heart surgery including coronary artery bypass surgery; patients with peripheral vascular diseases, abdominal aortic aneurysms, and renal artery stenosis; patients after radiotherapy for head and neck malignancies; patients following carotid endarterectomy, or carotid artery stent placement; patients with retinal ischemic syndromes; patients with syncope, dizziness, vertigo or tinnitus; and patients with a family history of vascular diseases and hyperhomocysteinemia. The recommendations are based on prevalence of disease, anticipated benefit, and concurrent guidelines from other professional organizations in selected populations.
Integrative taxonomy identifies new (and old) species in the Lasioglossum (Dialictus) tegulare (Robertson) species group (Hymenoptera, Halictidae)

An integrative taxonomic approach that utilizes the DNA barcode region of cytochrome c oxidase subunit 1 in conjunction with traditional morphological approaches identifies five distinct species previously recognized as Lasioglossum (Dialictus) tegulare (Robertson). Differences in DNA sequences and congruent, albeit minor, morphological variation support separation of L. tegulare into five species. Unique nucleotide substitution patterns for each species allows for character-based diagnostics using DNA barcodes. The names L. ellisiae (Sandhouse) and L. lepidii (Graenicher) are removed from synonymy. Two new species, L. puteulanum Gibbs sp. n. and L. carlinvillense Gibbs sp. n. , are described. A key is provided, which permits the identification of both males and females. The utility of the DNA barcode region as part of an integrative taxonomic framework is discussed.
Expression of K homology domain Containing protein Overexpressed in cancer in pancreatic FNA for diagnosing adenocarcinoma of pancreas

We evaluated the immunocytochemical (ICC) expression of K homology domain containing protein overexpressed in cancer (KOC) in pancreatic endoscopic ultrasound‐guided fine needle aspirates (EUS‐FNAs) to assess its potential use as an adjunct in differentiating nonneoplastic (GI epithelium) and benign neoplastic epithelia (benign epithelial pancreatic neoplasms) from pancreatic adenocarcinoma cells. Forty‐eight cases of EUS‐FNAs with histological and/or clinical follow‐up data were selected for this study. Alcohol‐fixed and PAP‐stained slides were stained with monoclonal antibody to KOC/L523S (clone 69.1). Results were recorded as negative or positive. KOC expression was present in 35/40 (88%) of adenocarcinomas (Ac) and was negative in all eight benign cases. The sensitivity and specificity were as follows: cytology 85 and 100%, KOC 88 and 100%; combination of cytology and KOC 95 and 100%. We conclude that KOC ICC expression on alcohol‐fixed smears along with cytology improves the sensitivity of EUS‐FNAs in the diagnosis of pancreatic Ac, and KOC reactivity is especially useful in differentiating Ac from nonneoplastic gastrointestinal epithelium and benign neoplastic epithelia. Diagn. Cytopathol. 2007;35:700–704. © 2007 Wiley‐Liss, Inc.
Roles for In Vitro Myelotoxicity Tests in Preclinical Drug Development and Clinical Trial Planning

Myelosuppression is the dose-limiting side effect for most anti-cancer and many anti-human immunodeficiency virus agents, which can be quantitated with optimized colony-forming assays (granulocyte-macrophage, late erythroid, and megakaryocytic [for murine only] colony-forming units and early erythroid burst-forming units (BFUs)). When applied to new drug development, the assays are used for therapeutic index-based screening (e.g., less myelosuppressive analogues, structure-toxicity studies, new drug leads), interpreting efficacy data from xenotransplant models, and selecting the most accurate animal model for human hematopoietic toxicity. However, other types of assays may be required to identify the mechanism underlying myelosuppression. In clinical trial planning, in vitro colony-forming assays can be used to elucidate schedule dependency of myelotoxicity (which in turn provides clues about mechanism of action), to plan cytokine support, and to estimate dose-escalation effects. The inhibition of colony formation can be measured relative to a compound with known clinical myelotoxicity and schedule dependency to provide some idea of the toxicity expected at particular doses, and the degree of heterogeneity between individuals, during clinical trials. The predictive accuracy of the in vitro data has been proven by validation studies with alkylating agents.
Sensations evoked by stimulation in the midbrain of man.

S EVERE pain evokes in man a variety of complex physiological and psychological events that are poorly understood. Our current knowledge of the neuroanatomica1 and physiological substrates for painful experiences have been gathered from clinical observations in humans or by inference from experiments with mute animals. This report concerns observations that have been made in persons suffering from severe chronic pain who were to undergo treatment for their pain by means of stereotaxic lesions localized in the dorsolateral tegmentum that would interrupt the ascending pain pathways. Before placement of the therapeutic lesions, fine electrodes were introduced into the midbrain and thalamus and electrical stimulation of these neural regions was carried out while the patient was alert. A group of 15 persons with intractable central pains was selected for stereotaxic mesencephalic tractotomy; in 12, chronic depth electrodes were implanted in the mesencephalon and thalamus preceding therapy (Table 1). Of the 12 patients who were electrically stimulated, three had phantom arm pain and one a severe causalgic arm pain. Eight persons suffered from central pain or dysesthesia. The selection of this latter group of patients was based on Riddoch's definition of central pain as "spontaneous pain and painful over-reaction to objective stimulation resulting from lesions confined to the substance of the central nervous system, including dysesthesia of any kind. ''1~ The cervical cord or the brachial plexus were the sites of pathologic involvement in the patients with phantom limb pain and the causalgia. In the eight patients with central dysesthesia, the pain was due to pathologic involvement at five sites in the central nervous system. These sites included the spinal cord, medulla, mesencephalon, thalamus,
Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene.

The distinguishing characteristics of familial cancer syndromes are an inherited predisposition to one or more characteristic types of tumors, early age at onset, and multiple synchronous or asynchronous tumors. Recently, the genes responsible for a number of inherited cancers have been identified.1–5 We describe a kindred with an increased risk of pancreatic cancers, melanomas, and possibly additional types of tumors. We provide strong evidence linking the predisposition to cancer in this kindred to an inherited mutation in the cyclin-dependent–kinase inhibitor 2 (CDKN2) tumor-suppressor gene. The results of our study of this family suggest that disruption of the .
Binocular Coordination in Fore/Aft Motion

Abstract: Stabilization of images on the fovea during either fore/aft translation of a subject or fore/aft movement of a visual target in front of a stationary observer imposes complex geometrical requirements that depend upon the eccentricity of the object of interest with respect to the eyes. Each eye needs to be rotated independently with varying proportions of conjugate (version) and disconjugate (vergence) eye movements to maintain fixation of the target. Here, we describe binocular coordination in the early response to translational movements of normal subjects along their naso‐occipital axis. We recorded the responses evoked by small (about 4 cm), abrupt (about 0.7 g), fore/aft translations in four normal subjects while they viewed a near target. In the forward and backward starting positions the target was 15 or 10.5 cm away, respectively. Each subject was tested with the target centered between the eyes, aligned on the right eye, and placed to the right of the right eye by ∼3 cm. The three conditions differed only in the lateral eccentricity of the target, yet the geometrical requirements for image stabilization are very different: pure vergence, one eye still, or mostly version. We found that the eye‐movement responses closely matched what was needed for visual stabilization of the target, though responses to stimuli calling for divergence were less accurate than those for convergence. The latency of these responses ranged from 40 to 65 ms and achieved about 80% of the ideal response by 90 to 100 ms after the onset of the stimulus. Next, we asked whether these eye movements were generated by the vestibular system or by high‐level strategies for image stabilization, such as pursuit. Thus, in a second set of experiments we used the mean profile of foreaft body motion computed for each subject to drive a small visual target across the same distances and in the same eccentricities used during body translations. We found that visually driven responses had longer latencies (by at least 80 ms, ranging from 144 to 155 ms) and slower dynamics (with significantly lower peak eye velocities), highlighting the different subsystems producing the two types of responses. Saccades were also an important component of the response to both visual and vestibular stimuli, less frequent during the centered‐target configuration and more frequent during viewing of eccentric targets. Visual stimuli evoked saccadic corrections more often and at shorter latencies than did vestibular stimuli. Both smooth and saccadic eye movements were appropriately disconjugate and their pattern depended on whether the eyes were converging or diverging.
Behavioral pharmacology of two novel substituted quinoxalinedione glutamate antagonists

Two novel quinoxalinedione glutamatergic antagonists, with in vitro selectivity for the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor, were evaluated in a number of behavioral tests primarily designed to compare their effects to those of the noncomperitive NMDA antagonist phencyclidine (PCP). The compounds evaluated were 5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) and 5-nitro-6,7-dichloro-l,4-dihydro-2,3-quinoxalinedione (ACEA-1021). In rats, both ACEA-1011 and ACEA-1021 were completely devoid of PCP-like discriminative stimulus effects, although behavioral activity, in the form of response rate suppression, was seen at the higher doses tested (6–25 mg/kg, i.p.). ACEA-1011 and ACEA-1021 were also ineffective as antagonists of PCP discrimination in rats. ACEA-1021 failed to substitute in rhesus monkeys trained to discriminate PCP from sham injection, although in the monkeys minimal effects were observed on rates of responding even at the highest dose tested (10.2 mg/kg, i.v.). ACEA-1021 also failed to produce ethanol-like discriminative stimulus effects in rats under test conditions where PCP has been shown to produce substantial levels of substitution for ethanol. Both ACEA-1011 and ACEA-1021 were also evaluated as antagonists of NMDA discrimination in rats. ACEA-1011 produced some decreases in NMDA-lever responding, with the largest effect at one intermediate dose (3 mg/kg, i.p.). ACEA-1021 was ineffective as an antagonist of NMDA discrimination. Unlike results reported for PCP-like NMDA antagonists, neither ACEA-1011 nor ACEA-1021 disrupted prepulse inhibition of the acoustic startle reflex in rats. It was not possible to establish ACEA-1021 (10 or 15.6 mg/kg) as a discriminative stimulus in rats. In conclusion, the novel glutamate antagonists ACEA-1011 and ACEA-1021 did not produce a profile of behavioral effects similar to that of PCP-like noncomperitive NMDA antagonists. These results are consistent with an emerging body of evidence showing differences in the behavioral effects of different classes of glutamate antagonists.
Acupuncture for depression: a randomized controlled trial.

OBJECTIVE To assess the efficacy of acupuncture as an intervention for major depressive disorder (MDD). METHOD Acupuncture was examined in 151 patients with MDD (DSM-IV) who were randomly assigned to 1 of 3 groups in a double-blind randomized controlled trial. The specific intervention involved Traditional Chinese Medicine (TCM)-style acupuncture with manual stimulation for depression; the control conditions consisted of (1) a nonspecific intervention using a comparable number of legitimate acupuncture points not specifically targeted to depressive symptoms and (2) a waitlist condition, which involved waiting without intervention for 8 weeks. After 8 weeks, all patients received the depression-specific acupuncture. Each 8-week intervention regimen consisted of 12 acupuncture sessions delivered in an acupuncturist's office in the community. The primary outcome measure was the 17-item Hamilton Rating Scale for Depression. The study was conducted from February 1998 to April 2002. RESULTS Twenty patients terminated treatment before the completion of the 8-week intervention (13%) but not differentially by study group. Random regression models of the intent-to-treat sample revealed that although patients receiving acupuncture improved more than those awaiting intervention, no evidence of differential efficacy of the depression-specific over nonspecific intervention was found. Response rates in acupuncture-treated patients were relatively low after 8 weeks (22% and 39% for specific and nonspecific intervention groups, respectively), with the response rate after the entire 16-week trial reaching 50%. CONCLUSION Although TCM manual acupuncture is a well-tolerated intervention, results fail to support its efficacy as a monotherapy for MDD. It can't be ruled out that factors unique to the implementation of acupuncture in this research study may have limited the efficacy of interventions compared to those provided in naturalistic settings. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov identifier NCT00010517.
Reported analgesic administration to rabbits, pigs, sheep, dogs and non-human primates undergoing experimental surgical procedures

Reported analgesic use following experimental surgery is low in rodents and there has been little published information on the frequency of analgesic use in other laboratory species. A structured literature review was conducted to examine analgesic administration in larger laboratory animals. The Scirus search engine was used to identify studies published in peer-reviewed journals that reported carrying out experimental surgery on ‘large’ laboratory animals, specifically rabbits, pigs, sheep, dogs and non-human primates. Seventy-four studies between 2000 and 2001 and 75 studies between 2005 and 2006 were included in the review. There was an increase in the reported administration of systemic analgesics to these species from 50% in 2000–2001 to 63% in 2005–2006. When all agents with analgesic properties were considered (systemic analgesics, local anaesthetics and anaesthetics with analgesic components), the proportion of papers that reported some form of analgesic administration to ‘large’ laboratory animals increased from 86% in 2000–2001 to 89% in 2005–2006. Overall rabbits, pigs, sheep, dogs and non-human primates were more likely to receive analgesics following potentially painful experimental procedures than has been reported in laboratory rodents but analgesic administration to ‘large’ laboratory species is still not optimal.
A multisample study of longitudinal changes in brain network architecture in 4–13‐year‐old children

Recent advances in human neuroimaging research have revealed that white‐matter connectivity can be described in terms of an integrated network, which is the basis of the human connectome. However, the developmental changes of this connectome in childhood are not well understood. This study made use of two independent longitudinal diffusion‐weighted imaging data sets to characterize developmental changes in the connectome by estimating age‐related changes in fractional anisotropy (FA) for reconstructed fibers (edges) between 68 cortical regions. The first sample included 237 diffusion‐weighted scans of 146 typically developing children (4–13 years old, 74 females) derived from the Pediatric Longitudinal Imaging, Neurocognition, and Genetics (PLING) study. The second sample included 141 scans of 97 individuals (8–13 years old, 62 females) derived from the BrainTime project. In both data sets, we compared edges that had the most substantial age‐related change in FA to edges that showed little change in FA. This allowed us to investigate if developmental changes in white matter reorganize network topology. We observed substantial increases in edges connecting peripheral and a set of highly connected hub regions, referred to as the rich club. Together with the observed topological differences between regions connecting to edges showing the smallest and largest changes in FA, this indicates that changes in white matter affect network organization, such that highly connected regions become even more strongly imbedded in the network. These findings suggest that an important process in brain development involves organizing patterns of inter‐regional interactions. Hum Brain Mapp 39:157–170, 2018. © 2017 Wiley Periodicals, Inc.
Quality‐adjusted time without symptoms or toxicity analysis of pazopanib versus sunitinib in patients with renal cell carcinoma

In a phase 3, randomized, open‐label trial (Pazopanib versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma, COMPARZ; NCT00720941), pazopanib was found to be noninferior to sunitinib in terms of progression‐free survival in patients with metastatic renal cell carcinoma with no prior therapy. Overall treatment differences were evaluated in a post hoc analysis with a quality‐adjusted time without symptoms or toxicity (Q‐TWiST) methodology.