Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of Germline Mutations in Upper Tract Urothelial Carcinoma With Suspected Lynch Syndrome

Objective Whole-exon sequencing (WES) is a commercially available tool for hereditary disease testing. However, little is known about hereditary upper-tract urothelial carcinoma (UTUC) in the Chinese population. This study aims to investigate the prevalence of Lynch syndrome (LS) in UTUC patients with high-risk features and identify the germline mutations of genetic predisposition gene mutations in those patients. Methods In total, 354 consecutive UTUC patients undergoing surgery were universally recruited, of whom 108 patients under 60 years old or with a personal/family history of cancer underwent universal immunohistochemistry staining to detect the expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). Patients with deficient or weak MMR protein staining or meeting the Amsterdam II criterion were defined as suspected LS patients, who further experienced microsatellite instability (MSI) (BAT25, BAT26, BAT40, D2S123, D5S346, D17S250) detection and performed WES analysis to explore germline pathogenic/likely pathogenic (P/LP) alterations. Results Of 108 patients, 90 (83.3%) cases were included due to younger than 60 years, and 18 cases due to personal/family history. IHC staining identified 21 patients with deficient MMR protein staining and 15 cases with weak MMR protein staining. Three cases met the Amsterdam II criterion but with proficient MMR protein staining. Finally, WES analysis was performed in 38 suspected LS patients and P/LP germline mutations were identified in 22 individuals. Genetic testing confirmed 5 LS cases, including 3 cases with novel mutations. MSI-harboring tumor was discovered in 4 LS cases, one of whom had weak MMR protein staining. Germline P/LP variants in DNA damage repair genes were found in 11 cases. In addition, we found that 11 patients had high- or moderate- penetrance P/LP mutations other than MMR genes. The common P/LP variants in high- or moderate-penetrance genes were 4 in ATM, 3 in MSH6 and KIT, and 2 in APC, NF1 and DICER. Conclusions We identified approximately 11% of UTUC cases as suspected LS and at least 1.4% patients with confirmed LS-associated UTUC. In addition, broader germline genetic testing could be considered to screen for cancer severity in hereditary UTUC patients.
Feasibility of Systemically Applied dsRNAs for Pest-Specific RNAi-Induced Gene Silencing in White Oak

The efficacy of double-stranded RNA (dsRNA) in inducing host specific gene knockdown and mortality has been demonstrated in a multitude of insects and dsRNAs are being integrated for pest suppression in a variety of agricultural and horticultural crops. However, less attention has been applied to their use in forest settings, despite the demonstrated susceptibility of multiple forest pests to RNAi. Prior to implementation for forest pest suppression, characterization of the specificity, efficacy, and behavior of dsRNAs in the environment is essential. Therefore, we investigated the translocation and retention of exogenously applied dsRNA in an economically and ecologically significant hardwood tree when applied hydroponically. White oak (Quercus alba, L.) seedlings were exposed to dsRNAs as a root soak, and at 1, 3, 5, and 7 days post-exposure were destructively sampled, divided into stem and leaf tissue, and the RNA extracted. Gel electrophoresis was used to visualize the presence of exogenous dsRNA in treated seedling material and Sanger sequencing was used to further verify recovery of treatment dsRNAs. Both techniques confirmed the presence of the exogenously applied dsRNAs in each tissue type at each sample interval, demonstrating successful uptake and translocation of dsRNAs through white oak tissues. Our findings support root uptake as a viable delivery method for dsRNAs in hardwood seedlings, which could provide single tree protection from selected tree feeding pests or pathogens.
Functional Investigation of a Neuronal Microcircuit in the CA1 Area of the Hippocampus Reveals Synaptic Dysfunction in Dravet Syndrome Mice

Dravet syndrome is severe childhood-onset epilepsy, caused by loss of function mutations in the SCN1A gene, encoding for the voltage-gated sodium channel NaV1.1. The leading hypothesis is that Dravet is caused by selective reduction in the excitability of inhibitory neurons, due to hampered activity of NaV1.1 channels in these cells. However, these initial neuronal changes can lead to further network alterations. Here, focusing on the CA1 microcircuit in hippocampal brain slices of Dravet syndrome (DS, Scn1aA1783V/WT) and wild-type (WT) mice, we examined the functional response to the application of Hm1a, a specific NaV1.1 activator, in CA1 stratum-oriens (SO) interneurons and CA1 pyramidal excitatory neurons. DS SO interneurons demonstrated reduced firing and depolarized threshold for action potential (AP), indicating impaired activity. Nevertheless, Hm1a induced a similar AP threshold hyperpolarization in WT and DS interneurons. Conversely, a smaller effect of Hm1a was observed in CA1 pyramidal neurons of DS mice. In these excitatory cells, Hm1a application resulted in WT-specific AP threshold hyperpolarization and increased firing probability, with no effect on DS neurons. Additionally, when the firing of SO interneurons was triggered by CA3 stimulation and relayed via activation of CA1 excitatory neurons, the firing probability was similar in WT and DS interneurons, also featuring a comparable increase in the firing probability following Hm1a application. Interestingly, a similar functional response to Hm1a was observed in a second DS mouse model, harboring the nonsense Scn1aR613X mutation. Furthermore, we show homeostatic synaptic alterations in both CA1 pyramidal neurons and SO interneurons, consistent with reduced excitation and inhibition onto CA1 pyramidal neurons and increased release probability in the CA1-SO synapse. Together, these results suggest global neuronal alterations within the CA1 microcircuit extending beyond the direct impact of NaV1.1 dysfunction.
Intralymphatic Immunotherapy (ILIT) With Bee Venom Allergens: A Clinical Proof-of-Concept Study and the Very First ILIT in Humans

Background Subcutaneous venom immunotherapy (VIT) represents an effective treatment against bee venom allergy. However, it involves long treatment times, high costs, and the risk of adverse events (AEs). Shorter, safer, and cheaper treatment options are therefore pursued. Objective To determine the safety, immunogenicity, and efficacy of bee venom intralymphatic immunotherapy (ILIT). Methods In an open pilot study, 12 patients received bee venom ILIT in three sessions with 14-day intervals: 0.1–5 μg/dose. Ultrasound imaging was applied to guide an injection and to document the lymph node structure. In a second study, 67 patients from 15 centers in Europe and Australia were randomized to receive four doses of either 10- or 20-μg bee venom ILIT with 28-day intervals. Clinical endpoints included specific IgE and IgG and protection after a bee sting challenge. These studies were performed in the years 2000–2003. Results In a proof-of-concept study, no serious AEs were observed. An increase in allergen-specific IgG1 but no IgG4 and IgE was observed. ILIT induced the protection against a bee sting challenge in 7 out of 8 challenged patients. In a multicenter study, an increase in allergen-specific IgG and IgE was observed, with the highest increase in patients receiving a higher ILIT dose. The study was terminated due to several serious AEs upon the sting challenge provocation after the completion of treatment. However, out of 45 patients challenged, 15 (65%) and 18 (82%) patients in the 10- and 20-μg group, respectively, showed an improvement of two grades or more. No correlation was observed between antibody levels and sting protection. Conclusions While a pilot study suggested the safety and efficacy of bee venom ILIT, a high number of AEs seen after the sting challenge following a randomized study indicate that the immunology protection offered by bee venom ILIT is insufficient. Of note, the bee venom allergen extract used in the two studies were from the two different providers. While the first study used a formulation approved for use in subcutaneous VIT, the second study used a nonapproved formulation never tested in humans. Further studies on approved formulations should be performed to generate conclusive results regarding the safety and efficacy of bee venom ILIT.
Proteomic Signatures of Microbial Adaptation to the Highest Ultraviolet-Irradiation on Earth: Lessons From a Soil Actinobacterium

In the Central Andean region in South America, high-altitude ecosystems (3500–6000 masl) are distributed across Argentina, Chile, Bolivia, and Peru, in which poly-extremophilic microbes thrive under extreme environmental conditions. In particular, in the Puna region, total solar irradiation and UV incidence are the highest on Earth, thus, restraining the physiology of individual microorganisms and the composition of microbial communities. UV-resistance of microbial strains thriving in High-Altitude Andean Lakes was demonstrated and their mechanisms were partially characterized by genomic analysis, biochemical and physiological assays. Then, the existence of a network of physiological and molecular mechanisms triggered by ultraviolet light exposure was hypothesized and called “UV-resistome”. It includes some or all of the following subsystems: (i) UV sensing and effective response regulators, (ii) UV-avoidance and shielding strategies, (iii) damage tolerance and oxidative stress response, (iv) energy management and metabolic resetting, and (v) DNA damage repair. Genes involved in the described UV-resistome were recently described in the genome of Nesterenkonia sp. Act20, an actinobacterium which showed survival to high UV-B doses as well as efficient photorepairing capability. The aim of this work was to use a proteomic approach together with photoproduct measurements to help dissecting the molecular events involved in the adaptive response of a model High-Altitude Andean Lakes (HAAL) extremophilic actinobacterium, Nesterenkonia sp. Act20, under artificial UV-B radiation. Our results demonstrate that UV-B exposure induced over-abundance of a well-defined set of proteins while recovery treatments restored the proteomic profiles present before the UV-challenge. The proteins involved in this complex molecular network were categorized within the UV-resistome subsystems: damage tolerance and oxidative stress response, energy management and metabolic resetting, and DNA damage repair.
Psychophysical Impact of COVID-19 Pandemic and Same-Sex Couples’ Conflict: The Mediating Effect of Internalized Sexual Stigma

Research on the effects of the COVID-19 pandemic on same-sex relationships is limited. The present study aimed at analyzing the association between the psychophysical impact of the COVID-19 pandemic and same-sex couples’ conflict, also considering the potential mediating effect of internalized sexual stigma (ISS). For this purpose, psychophysical challenges and couples’ conflict during the COVID-19 pandemic, ISS, age, biological sex, sexual orientation, relationship duration, religiosity, involvement in lesbian, gay, and bisexual (LGB) associations, sexual satisfaction, and interpersonal partner violence were assessed in an Italian sample of 232 LGB people engaged in a same-sex relationship (aged 18–45 years; Mage = 28.68, SD = 6.91). The results indicated that the psychophysical impact of the COVID-19 pandemic was significantly associated with couples’ conflict, and ISS mediated this relationship. Among the covariates considered, only sexual satisfaction was associated with couples’ conflict. The findings suggest that ISS, over and above the adverse effects of the COVID-19 pandemic on psychophysical health, triggered conflict within same-sex relationships. Studying the role of ISS in various relational and social contexts is important, as ISS may have an adverse effect on the mental health of sexual minority people. We recommend that more efforts be made to improve research on the LGB population during the public health response to the COVID-19 emergency, because the paucity of studies underlines the invisibility of this population in many domains, including the domain of romantic relationships. Implications and directions for future research are discussed.
Emerging MR Imaging and Spectroscopic Methods to Study Brain Tumor Metabolism

Proton magnetic resonance spectroscopy (1H-MRS) provides a non-invasive biochemical profile of brain tumors. The conventional 1H-MRS methods present a few challenges mainly related to limited spatial coverage and low spatial and spectral resolutions. In the recent past, the advent and development of more sophisticated metabolic imaging and spectroscopic sequences have revolutionized the field of neuro-oncologic metabolomics. In this review article, we will briefly describe the scientific premises of three-dimensional echoplanar spectroscopic imaging (3D-EPSI), two-dimensional correlation spectroscopy (2D-COSY), and chemical exchange saturation technique (CEST) MRI techniques. Several published studies have shown how these emerging techniques can significantly impact the management of patients with glioma by determining histologic grades, molecular profiles, planning treatment strategies, and assessing the therapeutic responses. The purpose of this review article is to summarize the potential clinical applications of these techniques in studying brain tumor metabolism.
HLA-B*13, B*35 and B*39 Alleles Are Closely Associated With the Lack of Response to ART in HIV Infection: A Cohort Study in a Population of Northern Brazil

Introduction Immune reconstitution failure after HIV treatment is a multifactorial phenomenon that may also be associated with a single polymorphism of human leukocyte antigen (HLA); however, few reports include patients from the Brazilian Amazon. Our objective was to evaluate the association of the immunogenic profile of the “classical” HLA-I and HLA-II loci with treatment nonresponse in a regional cohort monitored over 24 months since HIV diagnosis. Materials and Methods Treatment-free participants from reference centers in the state of Pará, Brazil, were enrolled. Infection screening was performed using enzyme immunoassays (Murex AG/AB Combination DiaSorin, UK) and confirmed by immunoblots (Bio-Manguinhos, FIOCRUZ). Plasma viral load was quantified by real-time PCR (ABBOTT, Chicago, Illinois, USA). CD4+/CD8+ T lymphocyte quantification was performed by immunophenotyping and flow cytometry (BD Biosciences, San Jose, CA, USA). Infection was monitored via test and logistics platforms (SISCEL and SICLOM). Therapeutic response failure was inferred based on CD4+ T lymphocyte quantification after 1 year of therapy. Loci A, B and DRB1 were genotyped using PCR-SSO (One Lambda Inc., Canoga Park, CA, USA). Statistical tests were applied using GENEPOP, GraphPad Prism 8.4. 3 and BioEstat 5.3. Results Of the 270 patients monitored, 134 responded to treatment (CD4+ ≥ 500 cells/µL), and 136 did not respond to treatment (CD4+ < 500 cells/µL). The allele frequencies of the loci were similar to heterogeneous populations. The allelic profile of locus B was statistically associated with treatment nonresponse, and the B*13, B*35 and B*39 alleles had the greatest probabilistic influence. The B*13 allele had the highest risk of treatment nonresponse, and carriers of the allele had a detectable viral load and a CD4+ T lymphocyte count less than 400 cells/µL with up to 2 years of therapy. The B*13 allele was associated with a switch in treatment regimens, preferably to efavirenz (EFZ)-based regimens, and among those who switched regimens, half had a history of coinfection with tuberculosis. Conclusions The allelic variants of the B locus are more associated with non-response to therapy in people living with HIV (PLHIV) from a heterogeneous population in the Brazilian Amazon.
Equal Representation Does Not Mean Equal Opportunity: Women Academics Perceive a Thicker Glass Ceiling in Social and Behavioral Fields Than in the Natural Sciences and Economics

In the study of women in academia, the focus is often particularly on women’s stark underrepresentation in the math-intensive fields of natural sciences, technology, and economics (NTE). In the non-math-intensive of fields life, social and behavioral (LSB) sciences, gender issues are seemingly less at stake because, on average, women are well-represented. However, in the current study, we demonstrate that equal gender representation in LSB disciplines does not guarantee women’s equal opportunity to advance to full professorship—to the contrary. With a cross-sectional survey among N = 2,109 academics at mid-level careers (i.e., assistant and associate professors) in the Netherlands, we test the hypothesis that in LSB (more than NTE), female academics perceive to hit a “thicker” glass ceiling—that is, they see a sharper contrast between the high representation of women at the lower compared to the top levels. We test whether this predicts female academics’ lower estimated chances to reach full professorship relative to men in LSB (but not NTE). We introduce a novel perceived glass ceiling index (GCI), calculated based on academics’ perceptions of the share of women and men in their direct work environment minus their perceptions of gender ratio among full professors in their field. Results confirm that the perceived glass ceiling is thicker in the non-math-intensive LSB compared to math-intensive NTE fields. Furthermore, only in LSB (but not NTE), women perceived a thicker glass ceiling than men. Moreover, only among female academics, the thicker the perceived glass ceiling, the lower their estimated chances to become full professor 1 day. Combined, a moderated mediation showed that for women only, a thicker perceived glass ceiling in LSB compared to NTE disciplines predicted their lower estimated chances to advance to full professor level. No such mediation occurred for men. We conclude that women’s higher numerical representation in LSB disciplines does not negate a male-dominant normative standard about academic leadership and success. Paradoxically, the perceived odds for female academics to reach the top of their field are lower in fields where they are relatively highly represented, and this may pose unique barriers to women’s perceived opportunities for career success.
Creating Extraordinary From Ordinary: High Resource Efficiency of Underdog Entrepreneurs and Its Mechanism

Existing theory has not documented the potential benefits of facing the challenges of underdog entrepreneurs, who may succeed unexpectedly. This research explains why, and under what circumstances, the underdog status of entrepreneurs can promote entrepreneurial success rather than just hinder it. We predict that the underdog effect has the potential to boost entrepreneurial resource efficiency when entrepreneurs hold an incremental (vs. entity) theory, enter a low-barrier (vs. high-barrier) industry, and are in a favorable (vs. unfavorable) business environment. Study 1 provides support for the positive relationship between underdog status and resource efficiency through an ordinary least squares (OLS) regression analysis, which is accompanied by a moderating effect of the implicit theory, industry context, and business environment. The data was obtained from two nationwide surveys. By extending a qualitative comparative analysis (QCA) of multiple case studies, Study 2 reveals support for a synergistic effect of the above factors. Our research results examine the assumption that perceiving underdog status is detrimental and offer meaningful insights into why and when underdog entrepreneurs have good performance in entrepreneurial resource efficiency. We provide a psychological and behavioral explanation for the underdog effect, extending the underdog effect theory to the field of entrepreneurship for the first time from the perspective of the actors. Finally, theoretical contributions and practical implications are discussed by indicating the limitations of the research.
The Forgotten (Invisible) Healthcare Heroes: Experiences of Canadian Medical Laboratory Employees Working During the Pandemic

Objective The purpose of this qualitative study was to understand the stressors and coping strategies of medical laboratory technologists (MLTs) and assistants (MLAs) working during the COVID-19 pandemic in Ontario, Canada. Methods In this descriptive qualitative study, we held two focus groups with MLTs and MLA who were working during the COVID-19 pandemic. The focus group sessions were transcribed verbatim followed by thematic analysis to develop codes and themes. Findings A total of 13 participants across Ontario were involved in our study, which included one MLT (n = 7) group and one MLA (n = 6) MLA. Overall, the stressors and coping methods identified between both focus groups were consistent. Our results revealed four main themes: (1) COVID-19 contributing to the notable and existing staff shortage; (2) the pandemic reinforced that medical laboratory employees are forgotten within the healthcare system; (3) a poor work environment exacerbated by the pandemic; and (4) a resilient and passionate group. Rich descriptions explained the underlying issues related to the themes. Conclusions MLTs and MLAs are critical members of the healthcare team and provide vital patient care services. This study explored their experiences working during the pandemic and offers timely recommendations to mitigate against occupational stressors.
Physiological Response to Heat Stress in Immune Phenotyped Canadian Holstein Dairy Cattle in Free-Stall and Tie-Stall Management Systems

The climate in northern latitude countries, such as Canada, are changing twice as fast as in lower latitude countries. This has resulted in an increased frequency of hot days and longer more frequent heat waves. Canadian dairy cattle are therefore at increased risk of heat stress, especially those in management systems without the infrastructure to properly cool animals. Cattle experiencing heat stress undergo numerous physiological changes. Previous research has shown dairy cattle classified as high immune responders have lower incidence of disease. Therefore, the objective of this study was to evaluate the variation in respiration rate, rectal temperature, and rumination activity in immune phenotyped dairy cattle during a natural heat stress challenge. Additionally, the relationship between physiological response and temperature humidity index was compared between free-stall and tie-stall management systems. A total of 27 immune phenotyped (nine high, nine average and nine low) lactating dairy cattle were housed in a free-stall during the summer months for a duration of 27 days. Concurrently, two groups of six (three high and three low) immune phenotyped lactating dairy cattle were housed in a tie-stall for a duration of 12 days. Rumination was measured for the duration of the study for all cattle using SCR Heatime rumination collars. Respiration was measured using EMKA respiration bands for cattle housed in the tie-stalls, and manually [once in the morning (a.m.) and once in the afternoon (p.m.)] for cattle in free-stall management. Rectal temperature was measured using a digital thermometer twice daily (a.m. and p.m.) in both free-stall and tie-stall management systems. The temperature humidity index was recorded every 15 min in both management systems for the duration of the study. The results showed that high responders had significantly lower respiration rates compared to low responders when the temperature humidity index was high in both free-stall and tie-stall management systems, but there was no difference in rectal temperature, or rumination activity between phenotypes. Temperature humidity index values in the free-stall were significantly lower than the tie-stall. These findings increase the evidence that high immune responders are more likely to be tolerant to heat stress than low immune responders.