Miracle-dz/UniFAR-FTUs huggingface dataset:
Mutation patterns in small cell and non-small cell lung cancer patients suggest a different level of heterogeneity between primary and metastatic tumors

Several studies have shown heterogeneity in lung cancer, with parallel existence of multiple subclones characterized by their own specific mutational landscape. The extent to which minor clones become dominant in distinct metastasis is not clear. The aim of our study was to gain insight in the evolution pattern of lung cancer by investigating genomic heterogeneity between primary tumor and its distant metastases. Whole exome sequencing (WES) was performed on 24 tumor and five normal samples of two small cell lung carcinoma (SCLC) and three non-SCLC (NSCLC) patients. Validation of somatic variants in these 24 and screening of 33 additional samples was done by single primer enrichment technology. For each of the three NSCLC patients, about half of the mutations were shared between all tumor samples, whereas for SCLC patients, this percentage was around 95. Independent validation of the non-ubiquitous mutations confirmed the WES data for the vast majority of the variants. Phylogenetic trees indicated more distance between the tumor samples of the NSCLC patients as compared to the SCLC patients. Analysis of 30 independent DNA samples of 16 biopsies used for WES revealed a low degree of intra-tumor heterogeneity of the selected sets of mutations. In the primary tumors of all five patients, variable percentages (19-67%) of the seemingly metastases-specific mutations were present albeit at low read frequencies. Patients with advanced NSCLC have a high percentage of non-ubiquitous mutations indicative of branched evolution. In contrast, the low degree of heterogeneity in SCLC suggests a parallel and linear model of evolution.
Effect of seasonal changes on fertility parameters of Holstein dairy cows in subtropical climate of Taiwan

Objective The purpose of this retrospective study was to investigate the relationship between temperature–humidity index (THI), season, and conception rate (CR) of Holstein cows in central Taiwan. Methods The mean performance and number of observations were statistically evaluated for various parameters, including age at first service, number of days open, gestation length, CR, and calving interval for different parities. Results The results indicate that the mean age at first service was 493.2 days; the gestation length was similar across all cows of different parities, ranging from 275.1 to 280.7 days. The overall CR of all inseminations was significantly lower in multiparous cows (47.26%±0.22%) than in heifers (57.14%±0.11%) (p<0.05). At THI>72 and during the hot season (from June to November), CRs for multiparous cows were significantly reduced compared to that for heifers, while the ratio remained unchanged among heifers for all seasons. Conclusion To achieve a high CR, lactating cows should be bred in winter and spring (from December to May) from the start of the seasonal breeding program, whereas the heifer should be allowed to breed in summer and fall under the subtropical climate in Taiwan.
The unfolded protein response regulator ATF6 promotes mesodermal differentiation

The proteostasis stress-response protein ATF6 directs the mesodermal lineage during vertebrate embryogenesis and early development. A primitive role for ATF6 The endoplasmic reticulum (ER) mediates and monitors the folding, packaging, and transport of proteins in cells. The unfolded protein response (UPR) preserves ER homeostasis in the adult organism; however, inactivating mutations in the UPR-associated transcription factor ATF6 cause congenital vision defects, suggesting an embryonic role as well. Kroeger et al. found that ATF6 was critical to the differentiation of stem cells to the mesodermal lineage, at least in part, by promoting the growth and maturation of the ER, which presumably enables cells to stably produce the abundance of proteins necessary for development. Thus, the ER homeostasis protein in adult cells first directs ER development in embryonic cells. Activating ATF6 promoted the development of functional vascular endothelial cells from stem cells in culture dishes, suggesting that manipulating ATF6 may facilitate the production of mesodermal tissues for research or therapy. ATF6 encodes a transcription factor that is anchored in the endoplasmic reticulum (ER) and activated during the unfolded protein response (UPR) to protect cells from ER stress. Deletion of the isoform activating transcription factor 6α (ATF6α) and its paralog ATF6β results in embryonic lethality and notochord dysgenesis in nonhuman vertebrates, and loss-of-function mutations in ATF6α are associated with malformed neuroretina and congenital vision loss in humans. These phenotypes implicate an essential role for ATF6 during vertebrate development. We investigated this hypothesis using human stem cells undergoing differentiation into multipotent germ layers, nascent tissues, and organs. We artificially activated ATF6 in stem cells with a small-molecule ATF6 agonist and, conversely, inhibited ATF6 using induced pluripotent stem cells from patients with ATF6 mutations. We found that ATF6 suppressed pluripotency, enhanced differentiation, and unexpectedly directed mesodermal cell fate. Our findings reveal a role for ATF6 during differentiation and identify a new strategy to generate mesodermal tissues through the modulation of the ATF6 arm of the UPR.
Sequencing and analysis of the complete mitochondrial genome of Rufous-tailed Shrike, Lanius isabellinus (Passeriformes, Laniidae)

Abstract The complete mitochondrial genome of the Rufous-tailed Shrike (Lanius isabellinus) was 16 819 bp in length. The GenBank accession number is KP995437 and the contents of A, T, C, and G are 31.1% (5234 bp), 25.5% (4293 bp), 28.7% (4826 bp), and 14.7% (2466 bp), respectively. Gene organization and length are similar to other species of birds. It comprises 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a control region. All protein-coding genes use the typical initiation codon ATG, except for COX1 that uses GTG. All the complete stop codons were co-incident with the Black-headed Gull (Chroicocephalus ridibundus) and the Grey-backed Shrike (Lanius tephronotus), except for ND2 that was terminated with TAG. In addition, the phylogenetic relationships of Passeriformes based on complete mitochondrial genome showed that genetic distance of Laniidae and Corvidae was closer than other species.
Structural features of Cas2 from Thermococcus onnurineus in CRISPR‐cas system type IV

CRISPR‐Cas is RNA‐based prokaryotic immune systems that defend against exogenous genetic elements such as plasmids and viruses. Cas1 and Cas2 are highly conserved components that play an essential part in the adaptation stage of all CRISPR‐Cas systems. Characterization of CRISPR‐Cas genes in Thermococcus onnurineus reveals the association of the Cas2 gene with the putative type IV system that lacks Cas1 or its homologous genes. Here, we present a crystal structure of T. onnurineus Cas2 (Ton_Cas2) that exhibits a deep and wide cleft at an interface lined with positive residues (Arg16, Lys18, Lys19, Arg22, and Arg23). The obvious DNA recognizing loops in Cas2 from E. coli (Eco_Cas2) are absent in Ton_Cas2 and have significantly different shapes and electrostatic potential distributions around the putative nucleotide binding region. Furthermore, Ton_Cas2 lacks the hairpin motif at the C‐terminus that is responsible for Cas1 binding in Eco_Cas2. These structural features could be a unique signature and indicate an altered functional mechanism in the adaptation stage of Cas2 in type IV CRISPR‐Cas systems.
MAdCAM‐1 costimulates T cell proliferation exclusively through integrin α4β7, whereas VCAM‐1 and CS‐1 peptide use α4β1: evidence for “remote” costimulation and induction of hyperresponsiveness to B7 molecules

We have analyzed the effects of the α4 integrin ligands mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1), and the fibronectin CS‐1 splice variant on T cell activation. Immobilized MAdCAM‐1 and VCAM‐1 IgG‐Fc chimeras and a fibronectin CS‐1 peptide efficiently costimulate T cell proliferation when antigen presentation is mimicked by anti‐CD3 antibody. VCAM‐1‐Fc and fibronectin CS‐1, which are adhesive ligands for both the α4 β1 and α4 β7 integrins, medicate T cell costimulation exclusively through integrin α4 β1, but not through α4 β7. The inability of VCAM‐1‐Fc to costimulate via α4 β7 suggests that cell adhesion per se is insufficient, and that exquisite recognition and activation events must be triggered. MAdCAM‐1‐Fc mediates costimulation exclusively via α4 β7, and can both synergize with and induce hyperresponsiveness to the classical costimulator B7‐2. MAdCAM‐1‐Fc and VCAM‐1‐Fc, but not B7‐2, effectively costimulate when immobilized on sites spatially distant from the anti‐CD3 antibody (“remote” costimulation). In vitro, the relative potencies of the CAM were VCAM‐1‐Fc > ICAM‐1‐Fc > MAdCAM‐1‐Fc > B7‐Fc, except at high concentrations where ICAM‐1 was the most potent. Features of costimulatory CAM revealed by this study have important implications for the design of immunotherapeutic vaccine strategies to combat cancer and infection.
Role of nerve growth factor in a mouse model of allergic airway inflammation and asthma

The role of nerve growth factor (NGF), a potent mediator acting in the development and differentitation of both neuronal and immune cells, was examined in a mouse model of allergic asthma. NGF‐positive cells were detected in the inflammatory infiltrate of the lung and enhanced levels of NGF were detected in serum and broncho‐alveolar lavage fluids. Mononuclear cells in inflamed airway mucosa as well as broncho‐alveolar macrophages were identified as one source of NGF production. Splenic mononuclear cells from allergen‐sensitized mice produced NGF in response to allergen. They responded to exogenously added NGF with a dose‐dependent increase in IL‐4 and IL‐5 production and augmented IgE and IgG1 synthesis. In contrast, IFN‐γ and IgG2a levels remained unaffected. The effects were NGF specific, since they could be blocked by an anti‐NGF‐antibody. Nasal application of anti‐NGF to allergen‐sensitized mice significantly reduced IL‐4 and prevented development of airway hyperreactivity. These results show that allergic airway inflammation is accompanied by enhanced local NGF production that acts as an amplifier for Th2 effector functions and plays an important role in the development of airway hyperreactivity. Therefore it is suggested that NGF may serve as a link between the immune and nerve system.
Extent and divergence of heteroplasmy of the DNA barcoding region in Anapodisma miramae (Orthoptera: Acrididae)

Abstract A partial sequence of the mitochondrial cytochrome oxidase subunit I (COI) gene is widely used as a molecular marker for species identification in animals, also termed a DNA barcode. However, the presence of more than one sequence type in a single individual, also known as heteroplasmy, is one of the shortcomings of barcode identification. In this study, we examined the extent and divergence of COI heteroplasmy, including nuclear-encoded mitochondrial pseudogenes (NUMTs), at the genomic-DNA level from 13 insect species including orthopteran Anapodisma miramae, and a long fragment of mitochondrial DNA and cDNA from A. miramae as templates. When multiple numbers of clones originated from genomic DNA were sequenced, heteroplasmy was prevalent in all species and NUMTs were observed in five species. Long fragment DNA (∼13.5 kb) also is a source of heteroplasmic amplification, but the divergent haplotypes and NUMTs obtained from genomic DNA were not detected in A. miramae. On the other hand, cDNA was relatively heteroplasmy-free. Consistently, one dominant haplotype was always obtained from the genomic DNA-origin clones in all species and also from the long fragment- and cDNA-origin clones in the two tested individuals of A. miramae. Furthermore, the dominant haplotype was identical in sequence, regardless of the DNA source in A. miramae. Thus, one possible solution to avoid the barcoding problem in relationship to heteroplasmy could be the acquisition of multiple numbers of barcoding sequences to determine a dominant haplotype that can be assigned as barcoding sequence for a given species.
Implications of Left-sided Gallbladder in the Emergency Setting: Retrospective Review and Top Tips for Safe Laparoscopic Cholecystectomy

Background: Left-sided gallbladder without situs viscerum inversus (LSG-woSVI) is a rare congenital anomaly. Clinical features and routine presurgical imaging could miss the anomalous position, thereby producing complications during surgery. Laparoscopic cholecystectomy can be performed safely, but the risk of bile duct injury (BDI) is greater than in cholecystectomy of the orthotopic gallbladder. We present a retrospective review of all scientific literature for diagnosed cases of LSG-woSVI undergoing cholecystectomy from 1996 to 2014. Our objectives were to outline empirical top tips for a safe cholecystectomy in incidentally diagnosed LSG-woSVI. Methods: We carried a comprehensive search of PubMed using medical subject headings “left-sided gallbladder,” “right-sided ligamentum teres” “situs viscerun inversus,” “preoperative diagnoses,” “cholecystectomy,” and “bile duct injury. ” We considered a classification of the LSG-woSVI in 2 groups: True LSG-woSVI and LSG-woSVI in patients with right-sided ligamentum teres. Results: Our retrospective review revealed 55 cases of LSG-woSVI. The mean age was 51 years ±17 SD, male/female ratio was 2:1, clinical presentation was pain in the right upper abdominal quadrant in 75.5%, preoperative diagnosis was reached in 16.3%, True LSG was diagnosed in 83%, acute cholecystitis was found in 50%, laparoscopic cholecystectomy was performed in 79.6%, fundus-first dissection technique was used in 16.7%, intraoperative cholangiography was performed in 39.1%, and BDI occurred in 7.3% of the reported cases. Conclusions: Increased awareness of the anatomic aberrations in LSG-woSVI associated with improved preoperative diagnosis and a good knowledge about safe surgical techniques for cholecystectomy could indubitably reduce the incidence of BDI.
Elementary Teachers' Experiences and Perceptions of Departmentalized Instruction: A Case Study.

This case study investigated elementary teachers’ experiences and perceptions during a trial year of departmentalized instruction in a rural south Georgia elementary school. To inform their decision about whole-school departmentalization for the future, school administrators appointed twelve first through third grade teachers to pilot the instructional model for one school year. This case study utilized data collected from focus group interviews, individual interviews with departmentalized teachers, teacher journals, and questionnaires. The experiences and perceptions of the departmentalized teachers informed the study about perceived positive and negative attributes of departmentalized instruction, self-efficacy beliefs, and experiences of a shift in instructional models. Aligning with related literature, findings revealed teacher preference for the departmentalized instructional model over the self-contained model due to lighter workload, more focused and higher quality instruction, and increased self-efficacy.
Intraorbital Arteriovenous Fistula Secondary to Penetrating Injury

Purpose: To describe the clinical and radiologic features and management of an intraorbital arteriovenous fistula secondary to penetrating injury. Method: Interventional case report and literature review. Results: We describe a 13-year-old girl with a history of penetrating orbital injury who presented with proptosis, eyelid hyperemia, and orbital venous congestion. Computed tomography showed a large foreign body in the superiormedial orbit and an enlarged superior ophthalmic vein (SOV). Doppler ultrasonography revealed arterialized flow in the SOV. Removal of the foreign body did not alter the orbital symptoms. Carotid angiography disclosed a fistula between the ophthalmic artery and the SOV. The patient underwent an attempted coil embolization of the fistula through the femoral vein, which was unsuccessful, but she developed profound thrombosis of the SOV, which propagated through the orbital venous system. Although orbital venous congestive symptoms were acutely exacerbated, they regressed spontaneously within 1 month. The patient was followed for 23 months without recurrence. Conclusions: Penetrating injury of the orbital apex may lead to the formation of an arteriovenous fistula, transvenous embolization of which may be complicated by thrombosis of the SOV. In our case, this unintentional result facilitated the resolution of the fistula.
Reward System Activation in Response to Alcohol Advertisements Predicts College Drinking.

OBJECTIVE In this study, we assess whether activation of the brain's reward system in response to alcohol advertisements is associated with college drinking. Previous research has established a relationship between exposure to alcohol marketing and underage drinking. Within other appetitive domains, the relationship between cue exposure and behavioral enactment is known to rely on activation of the brain's reward system. However, the relationship between neural activation to alcohol advertisements and alcohol consumption has not been studied in a nondisordered population. METHOD In this cross-sectional study, 53 college students (32 women) completed a functional magnetic resonance imaging scan while viewing alcohol, food, and control (car and technology) advertisements. Afterward, they completed a survey about their alcohol consumption (including frequency of drinking, typical number of drinks consumed, and frequency of binge drinking) over the previous month. RESULTS In 43 participants (24 women) meeting inclusion criteria, viewing alcohol advertisements elicited activation in the left orbitofrontal cortex and bilateral ventral striatum-regions of the reward system that typically activate to other appetitive rewards and relate to consumption behaviors. Moreover, the level of self-reported drinking correlated with the magnitude of activation in the left orbitofrontal cortex. CONCLUSIONS Results suggest that alcohol cues are processed within the reward system in a way that may motivate drinking behavior.
Foucault Retires to the Gym: Understanding Embodied Aging in the Third Age

RÉSUMÉ Des pressions sociales récentes ont amené une nouvelle conception du « troisième âge », qui est maintenant vu comme une période d’activité constante, et non de repos ou de relaxation. Cet article explore les pressions exercées sur les individus, qui sont poussés vers le vieillissement « réussi » à travers la pratique d’activités physiques, malgré leur avancée en âge. Il examine, par l’intermédiaire d’entretiens semi-directifs avec 15 personnes à la retraite ou en préretraite fréquentant les gyms (8 femmes, 7 hommes), comment cet appel à une activité accrue influence la perception que des adultes d’âge moyen et avancé ont d’eux-mêmes et des autres. En prenant appui sur la nature productive du pouvoir, tel que conçu par Foucault, cet article fait valoir que les individus qui se perçoivent comme des adeptes du vieillissement actif et réussi se considèrent en opposition à leurs pairs inactifs. Dans un cadre néolibéral, ces participants se définissent comme des citoyens moralement responsables qui, par leur engagement dans des activités de mise en forme physique, sont autorisés à juger et à discipliner les corps de ces « autres » qui ne peuvent pratiquer ou qui ne pratiqueront pas une activité physique régulière. ABSTRACT In light of recent social pressures leading to a reimagining of the “Third Age” as a time of constant activity rather than repose and relaxation, this article explores the pressure on individuals to age “successfully” by engaging in physical activity in later life. Through semi-structured interviews with 15 retired or semi-retired gym-goers (eight women and seven men), the article examines how this call to increased activity impacts the ways active mid-life and older adults understand themselves and others. Drawing on Foucault’s understandings of the productive nature of power, we argue that those who perceive themselves as successfully heeding the call to active aging position themselves in contrast to inactive peers. Within a neoliberal framework, these participants self-identify as morally responsible citizens who, as a result of engagement in fitness activities, are authorized to survey and discipline the bodies of those “others” who will not or cannot engage in regular exercise.
Current Ptosis Management: A National Survey of ASOPRS Members

Purpose: To assess current practice patterns for management of ptosis by current ASOPRS members. Methods: An invitation to participate in a web-based, anonymous survey was sent to current members of the American Society of Ophthalmic Plastic and Reconstructive Surgeons (ASOPRS) via e-mail. The survey consisted of 4 sections: preoperative testing of ptosis patients, surgical preferences, dry eye evaluation in ptosis patients, and length of postfellowship practice. Responses were analyzed using standard statistical methods. Results: Fifty percent of ASOPRS members performed more than 100 ptosis procedures in the past year. Most ASOPRS members performed preoperative photography, automated perimetry testing, and phenylephrine testing in evaluation of ptosis patients. A slight majority of ASOPRS members did not use preoperative Schirmer testing as the primary screening tool for dry eye disease. Most ASOPRS members performed internal levator aponeurosis advancement surgery, although most surgeons performing concurrent ptosis repair and blepharoplasty preferred an external approach. Frontalis sling surgery was performed using a wide variety of materials for suspension. Conclusion: Current trends in the management and preoperative evaluation of blepharoptosis by ASOPRS members revealed a number of interesting common practices that are of value to current practitioners.
Inhibition of retrograde transport modulates misfolded protein accumulation and clearance in motoneuron diseases

ABSTRACT Motoneuron diseases, like spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS), are associated with proteins that because of gene mutation or peculiar structures, acquire aberrant (misfolded) conformations toxic to cells. To prevent misfolded protein toxicity, cells activate a protein quality control (PQC) system composed of chaperones and degradative pathways (proteasome and autophagy). Inefficient activation of the PQC system results in misfolded protein accumulation that ultimately leads to neuronal cell death, while efficient macroautophagy/autophagy-mediated degradation of aggregating proteins is beneficial. The latter relies on an active retrograde transport, mediated by dynein and specific chaperones, such as the HSPB8-BAG3-HSPA8 complex. Here, using cellular models expressing aggregate-prone proteins involved in SBMA and ALS, we demonstrate that inhibition of dynein-mediated retrograde transport, which impairs the targeting to autophagy of misfolded species, does not increase their aggregation. Rather, dynein inhibition correlates with a reduced accumulation and an increased clearance of mutant ARpolyQ, SOD1, truncated TARDBP/TDP-43 and expanded polyGP C9ORF72 products. The enhanced misfolded protein clearance is mediated by the proteasome, rather than by autophagy and correlates with the upregulation of the HSPA8 cochaperone BAG1. In line, overexpression of BAG1 increases the proteasome-mediated clearance of these misfolded proteins. Our data suggest that when the misfolded proteins cannot be efficiently transported toward the perinuclear region of the cells, where they are either degraded by autophagy or stored into the aggresome, the cells activate a compensatory mechanism that relies on the induction of BAG1 to target the HSPA8-bound cargo to the proteasome in a dynein-independent manner.