Miracle-dz/UniFAR-FTUs huggingface dataset:
WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.
Serum markers of lipid peroxidation, antioxidant enzymatic defense, and collagen degradation in an experimental (Pond-Nuki) canine model of osteoarthritis.

BACKGROUND Chondrocyte lipid peroxidation is strongly suggested to mediate collagen degradation and thus, to be involved in the pathogenesis of cartilage degradation and osteoarthritis (OA). OBJECTIVES The objective of this study was to evaluate early changes in serum biochemical indicators of oxidative stress during the development of OA in a canine model. METHODS Experimental OA was induced in 7 dogs by transection of the anterior cruciate ligament (Pond-Nuki model). Venous blood samples were obtained prior to the operation and on postoperative days 30, 60, and 105. The activity of serum catalase (an antioxidant enzyme), malondialdehyde (MDA) concentration (a marker of lipid peroxidation), and serum C2C neoepitope concentration (a marker of collagen type II degradation) were measured. RESULTS A statistically significant increase in all parameters as early as the 30th postoperative day was observed, compared with preoperative values. Serum catalase activity peaked on day 60, whereas MDA and C2C concentrations increased continuously until the end of the experimental period. A significant positive correlation was found between MDA and C2C concentrations, but not between catalase activity and MDA or C2C concentrations. CONCLUSIONS The results support the hypothesis that oxidative stress is involved in the pathogenesis of OA in the dog based on the Pond-Nuki model. The correlation between MDA and C2C concentrations suggests a possible association between oxidative stress and cartilage degeneration.
Gain of 1q and loss of 9q21.3‐q32 are associated with a less favorable prognosis in papillary thyroid carcinoma

In order to approach the genetic mechanisms behind initiation and progression of papillary thyroid carcinoma (PTC) tumorigenesis, we characterized numerical chromosomal imbalances in a panel of 25 PTCs with varying histopathological and clinical features using comparative genomic hybridization (CGH). The most frequently detected imbalance was gain of 9q33‐qter, which was seen in close to 30% of the cases. The commonly occurring regions of loss were assigned to 22q (12%) and 9q21.3‐q32 (12%), while gains preferentially involved the entire X chromosome (20%), 1q (16%), 17q (16%), and 22q (12%). The distribution of CGH alterations supports the idea of a progression of genetic events in the development of PTC, where gain of 9q33‐qter would represent a relatively early event that is followed by loss of 22q and gain of X, 1q, 17q, and 22q. When the detected CGH alterations were compared with the clinical outcome and the histopathological features of the 25 PTC cases, several statistically significant correlations were revealed. The total number of genetic alterations was higher in tumors from patients with aggressive disease as compared to those without signs of aggressiveness. Gain of 1q and loss of 9q21.3‐q32 were exclusively seen in tumors from patients with aggressive disease, and the presence of distant metastases was associated with gain of 1q. A sex‐dependent distribution was also evident for one of the common alterations, with gain of X exclusively seen in male cases. Taken together, the findings identify several candidate locations for tumor suppressor genes and oncogenes that are potentially involved in the establishment and progression of papillary thyroid carcinogenesis. © 2001 Wiley‐Liss, Inc.
Identification and localization of 5-hydroxytryptamine receptor sites in macaque visual cortex

Abstract The two main receptor subtypes for 5-hydroxytryptamine (5HT) were measured and localized in visual cortical areas of macaque monkey. [3H]5HT was used to label all 5HT-1 receptor subtypes and [3H]ketanserin was used to label 5HT-2 receptors. Both receptor types could be demonstrated in membranes prepared from macaque primary visual cortex. The specificity of these ligands for 5HT-1 or 5HT-2 receptors was demonstrated by the pharmacological profile of inhibitors of the specific binding. 5HT-1A receptor sites were detected by displacement experiments and by direct labeling with [3H]8-hydroxy-2(di-n-propylamino) tetralin 8OH-DPAT. Receptor autoradiography showed that the distribution of these receptor subtypes varied from one part of visual cortex to another. 5HT-1 receptors, labeled with [3H]5HT were present in several bands through layer IV of primary visual cortex with the densest band seen in and above layer IVA: another band was in lower layer VI. The band in layer VI was predominantly 5HT-1A sites. There were two main bands of 5HT-2 receptor sites, the most prominent around the IV/V boundary, and the other extending from layer IVA upwards. Adjacent areas showed 5HT receptors in a broad band corresponding to layer IV. 5HT-1A sites were found in superficial layers of adjacent areas, except V2. These layering patterns did not correspond precisely with cytoarchitectonic layering, nor with the pattern of 5HT-containing presynaptic fibres in published reports. It is important, therefore, in considering the role of the 5HT-containing neurons in cortical function to take account not only of the anatomy of the presynaptic terminals, but also of the postsynaptic receptors upon which the released transmitter will act, and their location within the cortex.
Distinct patterns of calcium transients during early and delayed afterdepolarizations induced by isoproterenol in ventricular myocytes.

BACKGROUND The relation between early afterdepolarizations (EADs) and changes in intracellular Ca2+ concentration ([Ca2+]i) is still unclear. In the present study, we compared spatiotemporal changes in [Ca2+]i related to EADs and delayed afterdepolarizations (DADs) induced by isoproterenol. METHODS AND RESULTS Isolated patch-clamped guinea pig ventricular myocytes, loaded with fluo-3 acetoxymethyl ester (fluo-3 AM), were paced at 0.1 to 2 Hz. Isoproterenol (100 nmol/L) caused alterations in both phase 2 and phase 4 of the action potential (AP), consistent with EADs and DADs, respectively. During EADs (n = 16), similar to driven APs, increases in [Ca2+]i occurred simultaneously throughout the cell, whereas during DADs (n = 25), they originated in discrete cell sites and propagated as a wave. This difference was confirmed by analysis of eight EADs and DADs coupled to the same beat. Ca2+ transient linked to EADs reached a peak relative fluorescence level (expressed as percentage of the maximal level reached during the last stimulated beat) that was always higher than that reached during the DADs (77 +/- 3% versus 64 +/- 2%, P < .001). Spatial heterogeneity of Ca2+ transients was assessed by the maximal time interval between peaks monitored in different cell regions; this time lag was always greater during DADs than during EADs (290 versus 40 milliseconds, P = .006). CONCLUSIONS The present study had two main findings. First, even very modest notches occurring during the plateau of the AP may be accompanied by a marked secondary increase in [Ca2+]i. Second, these Ca2+ transients occurring during EADs are synchronous throughout the cell and differ significantly from those observed under identical conditions during DADs.
Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis

Background Cannabinoids modulate fibrogenesis in scleroderma. Ajulemic acid (AjA) is a non-psychoactive synthetic analogue of tetrahydrocannabinol that can bind the peroxisome proliferator-activated receptor-γ (PPAR-γ). Recent evidence suggests a key role for PPAR-γ in fibrogenesis. Objective To determine whether AjA can modulate fibrogenesis in murine models of scleroderma. Material and methods Bleomycin-induced experimental fibrosis was used to assess the antifibrotic effects of AjA in vivo. In addition, the efficacy of AjA in pre-established fibrosis was analysed in a modified model of bleomycin-induced dermal fibrosis and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor I. Skin fibrosis was evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation, α-smooth muscle actin was examined. To study the direct effect of AjA in collagen neosynthesis, skin fibroblasts from patients with scleroderma were treated with increasing concentrations of AjA. Protein expression of PPAR-γ, and its endogenous ligand 15d-PGJ2, and TGFβ were assessed before and after AjA treatment. Results AjA significantly prevented experimental bleomycin-induced dermal fibrosis and modestly reduced its progression when started 3 weeks into the disease. AjA strongly reduced collagen neosynthesis by scleroderma fibroblasts in vitro, an action which was reversed completely by co-treatment with a selective PPAR-γ antagonist. Conclusions AjA prevents progression of fibrosis in vivo and inhibits fibrogenesis in vitro by stimulating PPAR-γ signalling. Since therapeutic doses of AjA are well tolerated in humans, it is suggested that AjA as an interesting molecule targeting fibrosis in patients with scleroderma.
Pathogen Specificity and Autoimmunity Are Distinct Features of Antigen-Driven Immune Responses in Neuroborreliosis

ABSTRACT Neuroborreliosis (NB) is a chronic infectious disease of the central nervous system (CNS) caused by a tick-borne spirochete, Borrelia burgdorferi. In addition to direct effects of the causative infectious agent, additional immunity-mediated mechanisms are thought to play a role in the CNS pathology of NB. In order to further understand the involvement of humoral immune mechanisms in NB, we dissected the intrathecal antibody responses down to the single-plasma-cell level. Starting with single-cell reverse transcription-PCR of fluorescence-activated cell sorter-sorted cerebrospinal fluid plasma cells from an NB patient, we identified expanded clones and resurrected the antigen specificity of their secreted antibodies through recombinant expression of the correctly paired immunoglobulin heavy- and light-chain genes as monoclonal antibodies (MAbs). As expected, we found specificity for the causative infectious agent, B. burgdorferi, among the clonally expanded plasma cell (cePC)-derived MAbs. However, from an independent cePC of the same patient, we could derive MAbs specific for human CNS myelin, without detectable cross-reactivity with B. burgdorferi antigens. While reactivity against B. burgdorferi is a known feature of humoral immune responses in NB, we show (i) that immune responses specific for self antigens may be a distinct feature of CNS infections independent of pathogen reactivity and (ii) that humoral autoimmunity in NB (since found in cePC) is the result of a truly antigen-driven immune response. Our findings indicate that in NB mechanisms may be at play that induce distinct immune responses specific for pathogen and self antigens independent from “molecular mimicry. ”
Smoking habit, immune suppression, oral contraceptive use, and hormone replacement therapy use and cervical carcinogenesis: a review of the literature

High-risk human papillomaviruses (HPVs) are involved in the etiopathogenesis of cervical intraepithelial neoplasia (CIN) and cervical cancer. After taking HPV into account, smoking habit appears to be the most significant environmental risk factor, and the risk of this malignancy increases significantly with intensity and duration of smoking. Women with human immunodeficiency virus (HIV) infection experience a higher incidence of CIN and invasive cervical cancer. Among HIV+ women, the highly active antiretroviral therapy increases the regression rate of CIN, but the majority of these lesions do not regress to normal. As far as oral contraceptives (OCs), a systematic review of 28 studies found that, compared with never pill users, the relative risk (RR) of cervical cancer increased with increasing duration of OC use. The results were similar for squamous cell carcinoma and adenocarcinoma, and the RRs decreased after pill discontinuation. However, by weighing risks and benefits, the World Health Organization does not recommend any change in OC practice. There is no correlation between hormone replacement therapy and cervical cancer. Experimental data have shown that estradiol and progesterone can modulate the host immune response to HPV16. Prophylactic vaccination in conjunction with cervical screening is the best prevention strategy for cervical cancer.
An 8-year follow-up of 450 sons of alcoholic and control subjects.

BACKGROUND Between 1978 and 1988, 453 sons (age range, 18-29 years) of alcoholic and control subject were evaluated for their level of reaction (LR) to alcohol. This article presents the results of the 8.2-year follow-up of 450 of these men. The three goals were (1) to attempt to replicate results of the follow-up of the first 223 subjects, (2) to evaluate the potential impact of the quantity and frequency of drinking at the time of the original study on the relationship between LR and alcoholic outcome (ALC), and, most importantly, (3) to test if the relationship between family history (FH) and ALC might be mediated by LR in a subset of the sample. METHODS Face-to-face structured follow-up interviews were carried out with the subjects and separately with an additional informant, and blood samples, as well as urine specimens, were obtained for determination of state markers of heavy drinking and drug toxicology screens. RESULTS First, the rate of development of DSM-III-R abuse and dependence on alcohol was 14.1% and 28.6%, respectively, for family history positive (FHP) subjects, compared with 6.6% and 10.8%, respectively, for family history negative (FHN) men. Second, neither consideration of the quantity nor the frequency of drinking at the time of the original study, nor their combination, effectively diminished the relationships between LR and ALC. Third, among men who drank and demonstrated the 15% highest and lowest scores of LR at about the age of 20 years (ie, 30% of the relevant population), the correlation between FH and ALC was greatly reduced when LR was considered, but the correlation between LR and ALC was not greatly diminished when the impact of FH was evaluated. CONCLUSIONS In this sample of moderately functional white men, the development of alcoholism occurred in relationship to an FH of alcoholism, but alcohol abuse or dependence was unrelated to prior psychiatric disorders. For this group, LR at the age of 20 years was associated with future alcoholism in a manner that was independent of the drinking practices at the time of the original study. At least among those men with clearly high and low LR scores, these data are consistent with the conclusion that LR might be a mediator of the alcoholism risk.
Impaired expression of CYP2D6 in intermediate metabolizers carrying the *41 allele caused by the intronic SNP 2988G>A: evidence for modulation of splicing events

We investigated the molecular basis for low expression and activity of CYP2D6 associated with the CYP2D6*41 allele in about 10–15% of Caucasians with intermediate metabolizer phenotype. With respect to two previously described polymorphisms in the promoter (−1584C>G) and in intron 6 (2988G>A; c.985+39G>A), the three most frequent functional alleles have the distinct haplotypes 2D6*1[CG], 2D6*2[GG] and 2D6*41[CA], respectively. Reporter gene analyses in transiently transfected HepG2 and Huh7 hepatoma cells did not indicate changes in transcription rate by these polymorphisms. By reverse-transcription polymerase chain reaction analysis of liver RNA of genotyped patients, however, we discovered that the 2988G>A change was associated with increased levels of a nonfunctional splice variant lacking exon 6. Quantification by denaturing high-performance liquid chromatography revealed up to 7.3-fold increased levels of the splice variant and up to 2.9-fold less functional transcript in carriers of 2D6*41, in good concordance with concomitant changes in immunoquantified CYP2D6 protein. Recombinant expression of the entire genomic sequence coding for 2D6*41, 2D6*2 and 2D6*1 alleles but lacking the upstream region in COS-1 and Huh7 cell lines resulted in two-fold to five-fold reduced levels of CYP2D6 mRNA containing exon 6, apoprotein and enzyme activity of 2D6*41. These experiments establish the causal relationship between the intron 6 single-nucleotide polymorphism 2988G>A and the low expression phenotype associated with allele 2D6*41. These data improve the CYP2D6 genotype–phenotype relationship and they demonstrate that major phenotype changes occurring in large population subgroups can be caused by intronic polymorphisms outside of splice site consensus sequences.
Children's auditory working memory performance in degraded listening conditions.

PURPOSE The objectives of this study were to determine (a) whether school-age children with typical hearing demonstrate poorer auditory working memory performance in multitalker babble at degraded signal-to-noise ratios than in quiet; and (b) whether the amount of cognitive demand of the task contributed to differences in performance in noise. It was hypothesized that stressing the working memory system with the presence of noise would impede working memory processes in real time and result in poorer working memory performance in degraded conditions. METHOD Twenty children with typical hearing between 8 and 10 years old were tested using 4 auditory working memory tasks (Forward Digit Recall, Backward Digit Recall, Listening Recall Primary, and Listening Recall Secondary). Stimuli were from the standardized Working Memory Test Battery for Children. Each task was administered in quiet and in 4-talker babble noise at 0 dB and -5 dB signal-to-noise ratios. RESULTS Children's auditory working memory performance was systematically decreased in the presence of multitalker babble noise compared with quiet. Differences between low-complexity and high-complexity tasks were observed, with children performing more poorly on tasks with greater storage and processing demands. There was no interaction between noise and complexity of task. All tasks were negatively impacted similarly by the addition of noise. CONCLUSIONS Auditory working memory performance was negatively impacted by the presence of multitalker babble noise. Regardless of complexity of task, noise had a similar effect on performance. These findings suggest that the addition of noise inhibits auditory working memory processes in real time for school-age children.
La responsabilidad social de la empresa

Desde mediados de los 80, en simultaneo con el agotamiento del modelo de Estado de Bienestar y el auge del neoliberalismo, la sociedad comenzo a demandar a las empresas mayor responsabilidad social y ambiental, ademas de un comportamiento mas etico y transparente. La sociologia de la empresa permite analizar desde un nuevo angulo estas problematicas, ya que la concibe no solo como un instrumento para obtener ganacias, sino como un actor social dotado de una cultura propia, capaz de crear identidad. Esto es clave en la coyuntura actual, en que la empresa ya no se limita a administrar recursos economicos, tecnicos y humanos, como ocurria hasta hace algunos anos. Hoy, la creacion y el desarrollo permanente de nuevos recursos se imponen como exigencias para la supervivencia economica.
Collaborative Governance in the Management of Village Owned Enterprises Ponggok Sub District Polanharjo District Klaten Central Java 2016

The Law No. 6 of 2014 article 1 mention about the village-owned enterprises as the business entity which the capital is owned by the village in order to be managed for community welfare. The government of village should be able to see the potential of the village to be managed along with the community and private sector to maintain its sustainability. The successful of Ponggok village to establish and run the village-owned enterprises Tirta Mandiri brings the Ponggok village as one of the richest village in Indonesia with the 9.6 billion rupiah income per year. This research aims to see how the ability of the collaborative governance to push accountability and transparency factors in managing the village-owned enterprises in 2016. This research used the method of collaborative governance through the data collection and interview towards the related actors. According to the data, the collaborative governance in the management of Ponggok village-owned enterprises involved three actors such as the government of the village, community and private sector. Collaborative governance be able to push the accountability and transparency in the management of village-owned enterprises by those collaborative actors. The result of collaborative governance can be felt by the villagers in form of welfare.
Crystal structure of a plant ribonuclease, RNase LE.

Ribonuclease LE (RNase LE) from cultured tomato (Lycopersicon esculentum) cells is a member of the RNase T(2) family showing broad base specificity. The crystal structure of RNase LE has been determined at 1.65 A resolution. The structure consists of seven alpha-helices and seven beta-strands, belonging to an alpha+beta type structure. Comparison of the structure of RNase LE with that of RNase Rh, a microbial RNase belonging to the RNase T(2) family, reveals that while the overall folding topologies are similar to each other, major insertions and deletions are found at the N-terminal regions. The structural comparison, an amino acid sequence alignment of the RNase T(2) enzymes, and comparison of the disulfide-bonding pattern of these enzymes show that the structure of RNase LE shown here is the basic framework of the animal/plant subfamily of RNase T(2) enzymes (including a self-incompatibility protein called S-RNase), and the structure of RNase Rh is that of the fungal subfamily of RNase T(2) enzymes (including RNase T(2)). Subsequently, we superposed the active-site of the RNase LE with that of RNase Rh and found that (1) His39, Trp42, His92, Glu93, Lys96, and His97 of RNase LE coincided exactly with His46, Trp49, His104, Glu105, Lys108, and His109, respectively, of RNase Rh, and (2) two conserved water molecules were found at the putative P(1) sites of both enzymes. These facts suggest that plant RNase LE has a very similar hydrolysis mechanism to that of fungal RNase Rh, and almost all the RNase T(2) enzymes widely distributed in various species share a common catalytic mechanism. A cluster of hydrophobic residues was found on the active-site face of the RNase LE molecule and two large hydrophobic pockets exist. These hydrophobic pockets appear to be base binding sites mainly by hydrophobic interactions and are responsible for the base non-specificity of RNase LE.