Miracle-dz/UniFAR-FTUs huggingface dataset:
Loss of TDP-43 in astrocytes leads to motor deficits by triggering A1-like reactive phenotype and triglial dysfunction

Significance Aberrant TDP-43 aggregation is one of the defining pathological hallmark proteins of two overlapping adult-onset neurodegenerative diseases, amyotrophic lateral sclerosis and frontotemporal dementia. While TDP-43 aggregates are also found in astrocytes, it is not known how loss of astroglial TDP-43 affects neuronal function and disease pathogenesis. Herein, we show that TDP-43 is required for maintaining the protective properties of astrocytes, such that loss of astroglial TDP-43 causes triglial abnormalities that result in motor deficits. These findings establish that TDP-43–mediated dysfunction in different cell types uniquely contributes to neurodegenerative disease through cell-type–specific mechanisms. Delineating these etiologies could facilitate the discovery of novel strategies to treat neurological disorders caused by TDP-43 proteinopathy. Patients with amyotrophic lateral sclerosis (ALS) can have abnormal TDP-43 aggregates in the nucleus and cytosol of their surviving neurons and glia. Although accumulating evidence indicates that astroglial dysfunction contributes to motor neuron degeneration in ALS, the normal function of TDP-43 in astrocytes are largely unknown, and the role of astroglial TDP-43 loss to ALS pathobiology remains to be clarified. Herein, we show that TDP-43–deleted astrocytes exhibit a cell-autonomous increase in GFAP immunoreactivity without affecting astrocyte or microglia proliferation. At the transcriptomic level, TDP-43–deleted astrocytes resemble A1-reactive astrocytes and induce microglia to increase C1q expression. These astrocytic changes do not cause loss of motor neurons in the spinal cord or denervation at the neuromuscular junction. In contrast, there is a selective reduction of mature oligodendrocytes, but not oligodendrocyte precursor cells, suggesting triglial dysfunction mediated by TDP-43 loss in astrocytes. Moreover, mice with astroglial TDP-43 deletion develop motor, but not sensory, deficits. Taken together, our results demonstrate that TDP-43 is required to maintain the protective functions of astrocytes relevant to the development of motor deficits in mice.
Can increased dietary fibre level and a single enrichment device reduce the risk of tail biting in undocked growing-finishing pigs in fully slatted systems?

This study evaluated the effectiveness of combined dietary and enrichment strategies to manage tail biting in pigs with intact tails in a conventional fully-slatted floor housing system. A 2 × 2 × 2 factorial design was used. Pigs had either a high fibre (weaner 5.3% and finisher 11.6% of crude fibre) or standard fibre diet (weaner 3.7% and finisher 5.9% of crude fibre). In the weaner stage, pigs had either a spruce wooden post (supplied in a wall-mounted dispenser) or a rubber floor toy as a enrichment device, and in the finisher stage, they had either the same or alternate enrichment item. Six hundred and seventy-two pigs were assigned to 48 pens of 14 pigs and followed from weaning until slaughter. Individual tail lesion scores and pen level behaviours were directly recorded every 2 weeks. Twenty-six pens had tail biting outbreaks and 161 injured pigs needed removal for treatment. Pigs fed with the high fibre diet performed more tail biting (p < 0.05) and tended to have a worse tail damage scores than those fed the standard fibre diet (p = 0.08). Pigs which had the floor toy as weaners and wood as finishers tended to have fewer tail lesions in the finisher stage than their counterparts (p = 0.06). Pigs receiving the floor toy as enrichment interacted with the enrichment more frequently overall (p < 0.001) and performed fewer harmful behaviours in the weaner stage (p < 0.05). Overall, higher fibre in the diet in a relatively barren environment did not help reduce tail biting or tail lesions. Altering the fibre level in the pigs’ diet and providing a single enrichment device to undocked pigs on fully slatted floors resulted in a high level of tail biting and a large proportion of pigs with partial tail amputation.
Systemic Glycosaminoglycan Clearance by HARE/Stabilin-2 Activates Intracellular Signaling

Scavenger receptors perform essential functions, critical to maintaining mammalian physiologic homeostasis by continuously clearing vast numbers of biomolecules from blood, interstitial fluid and lymph. Stabilin-2 (Stab2) and the Hyaluronic Acid Receptor for Endocytosis (HARE), a proteolytic isoform of Stab2, are important scavenger receptors responsible for the specific binding and internalization (leading to degradation) of 22 discrete molecules, macromolecular complexes and cell types. One-third of these ligands are glycosaminoglycans (GAGs). Full-length Stab2, but not HARE, mediates efficient phagocytosis of apoptotic cells and bacteria via binding to target surface ligands. HARE, the C-terminal half of Stab2, mediates endocytosis of all the known soluble ligands. HA was the first ligand identified, in 1981, prior to receptor purification or cloning. Seven other GAG ligands were subsequently identified: heparin, dermatan sulfate, chondroitin and chondroitin sulfates A, C, D and E. Synthetic dextran sulfate is also a GAG mimic and ligand. HARE signaling during HA endocytosis was first discovered in 2008, and we now know that activation of HARE/Stab2 signaling is stimulated by receptor-mediated endocytosis or phagocytosis of many, but not all, of its ligands. This review focuses on the HARE-mediated GAG activation of intracellular signaling, particularly the Extracellular Signal-Regulated Kinase 1/2 pathway.
Associations between Intake of Dietary Flavonoids and 10-Year Incidence of Age-Related Hearing Loss

Dietary flavonoids are vasoactive phytochemicals with promising anti-inflammatory properties. We aimed to assess the associations between baseline intakes of six commonly consumed flavonoid subclasses and 10-year incidence of age-related hearing loss. At baseline, 1691 participants aged 50+ years had information on dietary intakes and hearing status. Hearing loss was defined as the pure-tone average of frequencies 0.5, 1.0, 2.0, and 4.0 kHz > 25 dB hearing level (HL). Dietary data were collected through a semi-quantitative food frequency questionnaire. The flavonoid content of foods was estimated using US databases. During the 10-year follow-up, 260 (31.6%) new cases of hearing loss (incident) were observed. After multivariable adjustment, participants in the fourth versus first quartile (reference group) of intake of dietary isoflavone had 36% lower risk of incident hearing loss after 10 years: odds ratios (OR) 0.64 (95% confidence intervals, CI, 0.42–0.99); p-value for trend = 0.03. Nonsignificant associations were observed between the other five flavonoid subclasses and 10-year incidence of hearing loss. Our findings do not support the hypothesis that the intake of dietary flavonoids protect against long-term risk of hearing loss. The association with isoflavone intake needs to be confirmed by other population-based studies.
The small GTPase Arf6 is dysregulated in a mouse model for fragile X syndrome

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, results from silencing of the fragile X mental retardation gene 1 (FMR1). The analyses of FXS patients’ brain autopsies revealed an increased density of immature dendritic spines in cortical areas. We hypothesize that the small GTPase Arf6, an actin regulator critical for the development of glutamatergic synapses and dendritic spines, is implicated in FXS. Here, we determined the fraction of active, GTP‐bound Arf6 in cortical neuron cultures and synaptoneurosomes from Fmr1 knockout mice, measured actin polymerization in neurons expressing Arf6 mutants with variant GTP‐ or GDP‐binding properties, and recorded hippocampal long‐term depression induced by metabotropic glutamate receptors (mGluR‐LTD) in acute brain slices. We detected a persistently elevated Arf6 activity, a loss of Arf6 sensitivity to synaptic stimulation and an increased Arf6‐dependent dendritic actin polymerization in mature Fmr1 knockout neurons. Similar imbalances in Arf6‐GTP levels and actin filament assembly were caused in wild‐type neurons by RNAi‐mediated depletion of the postsynaptic Arf6 guanylate exchange factors IQSEC1 (BRAG2) or IQSEC2 (BRAG1). Targeted deletion of Iqsec1 in hippocampal neurons of 3‐week‐old mice interfered with mGluR‐LTD in wild‐type, but not in Fmr1 knockout mice. Collectively, these data suggest an aberrant Arf6 regulation in Fmr1 knockout neurons with consequences for the actin cytoskeleton, spine morphology, and synaptic plasticity. Moreover, FXS and syndromes caused by genetic variants in IQSEC1 and IQSEC2 share intellectual disabilities and developmental delay as main symptoms. Therefore, dysregulation of Arf6 may contribute to the cognitive impairment in FXS.
Effect of phenotypic detection of circulating tumor cells marked by epithelial-mesenchymal transformation on the prognosis of lung cancer

Abstract Background: To explore the significance of phenotype detection of circulating tumor cells (CTCs) based on epithelial-mesenchymal transition (EMT) labeling to evaluate the prognosis of lung cancer. Methods: Database was retrieved from China National Knowledge Infrastructure (CNKI), Chinese Biomedical literature Database (CBM), Chinese Scientific and Journal Database (VIP), Wan Fang database, PubMed, and EMBASE. Based on EMT on overall survival (OS) and disease-free survival (DFS), hazard ratios (HRs) and its 95% of confidence intervals (CIs) were applied to assess the prognostic effect of CTCs. RevMan 5.3 and STATA 16.0 software were adopted to perform the meta-analysis. Results: Based on EMT in terms of the prognosis of patients suffering from lung cancer, this study comprehensively reviewed and evaluated the available evidence of phenotype detection of CTCs. Conclusion: Based on EMT in the prognosis of patients who developed with lung cancer, our findings proved the effect of phenotype detection of CTCs. Such studies may reveal a new prognostic marker for lung cancer patients and help clinicians and health professionals make clinical decisions. OSF Registration Number: DOI 10.17605/OSF.IO/E7KAZ.
Feeding ecological knowledge: the underutilised power of faecal DNA approaches for carnivore diet analysis

Feeding ecological knowledge: the underutilised power of faecal DNA approaches for carnivore diet analysis Pedro MONTERROSO* CIBIO/InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Universidade do Porto. Campus de Vairão, R. Padre Armando Quintas, Vairão, 4485-661, Portugal. Email: pmonterroso@cibio.up. pt Raquel GODINHO CIBIO/InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Universidade do Porto. Campus de Vairão, R. Padre Armando Quintas, Vairão, 4485-661, Portugal Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, R. Campo Alegre s/n, Porto, 4169-007, Portugal. Email: rgodinho@cibio.up. pt Teresa OLIVEIRA CIBIO/InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Universidade do Porto. Campus de Vairão, R. Padre Armando Quintas, Vairão, 4485-661, Portugal Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, R. Campo Alegre s/n, Porto, 4169-007, Portugal. Email: mteresaoliveira92@gmail.com Pablo FERRERAS Instituto de Investigación en Recursos Cinegéticos (IREC, CSIC-UCLM-JCCM), Ronda de Toledo 12, Ciudad Real, 13071, Spain. Email: Pablo.Ferreras@uclm.es Marcella J. KELLY Department of Fish and Wildlife Conservation, Virginia Tech, 146 Cheatham Hall, Blacksburg, VA, 24061-0321, USA. Email: makelly2@vt.edu Dana J. MORIN Cooperative Wildlife Research Laboratory, Southern Illinois University, 251 Lincoln Drive, Carbondale, IL, 62901, USA. Email: dana.morin@siu.edu Lisette P. WAITS Department of Fish and Wildlife Sciences, University of Idaho, 875 Perimeter Drive MS 1136, Moscow, ID, 83844-1136, USA. Email: lwaits@uidaho.edu Paulo C. ALVES† CIBIO/InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Universidade do Porto. Campus de Vairão, R. Padre Armando Quintas, Vairão, 4485-661, Portugal Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, R. Campo Alegre s/n, Porto, 4169-007, Portugal Wildlife Biology Program, University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA. Email: pcalves@fc.up. pt L. Scott MILLS† Wildlife Biology Program, University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA Office of Research and Creative Scholarship, University of Montana, 32 Campus Drive, Missoula, MT, 59812, USA. Email: scott.mills@mso.umt. edu
Diet of tropical insectivorous birds in lowland Malaysian rainforest

ABSTRACT Despite the importance of diet in avian ecology, knowledge of bird diet in tropical regions, particularly South-East Asia, is limited. Assessing predator–prey relationships of how energy flows across ecosystems provides insight into niche segregation of sympatric species. We examined induced-regurgitation samples from 15 species of insectivorous birds – 12 babblers and three flycatcher-like species – from the Krau Wildlife Reserve, central Peninsular Malaysia. The main objective of this study was to compare and characterise the diet of similar trophically insectivorous birds so as to examine the occurrence of dietary overlap or segregation. The majority of identified prey items belong to the following arthropod taxa: Coleoptera (53%), Hymenoptera (19%), Blattodea (11%), and Araneae (11%). The diet of all bird species slightly overlapped (p = 0.070) but network analysis yielded a relatively low value (Ro = 0.53), indicating dietary divergence may have occurred among the studied bird species, possibly reflected by the variation in proportion of arthropod groups. A high proportion of Coleoptera and three other arthropod groups (i.e. Hymenoptera, Blattodea and Araneae) in the diet of studied birds could be related to their richness and abundance in aerial leaf-litter, the substrate preferred by most babblers. Dietary differences may further be explained by variations in bill shapes and sizes, likely corresponding to prey size. Unique foraging strategies (utilising different vertical strata, microhabitats, and attack manoeuvres) could also lead to dietary separation among sympatric species. Flycatcher-like species were expected to flycatch different prey items (families or lower taxa) versus the gleaning birds (most babblers). This study successfully discerned more details on the diets of insectivorous birds inhabiting Malaysian forests, providing a foundation for future studies on the ecology and biology of understorey birds.
Overweight Women with Breast Cancer on Chemotherapy Have More Unfavorable Inflammatory and Oxidative Stress Profiles

Chronic inflammation and redox imbalance are strongly influenced by diet and nutritional status, and both are risk factors for tumor development. This prospective study aimed to explore the associations between inflammatory and antioxidant markers and nutritional status in women with breast cancer undergoing chemotherapy. The women were evaluated at three times: T0, after the infusion of the first cycle; T1, after infusion of the intermediate cycle; and T2, after the infusion of the last chemotherapy cycle. The consumption of antioxidant nutrients and the Total Dietary Antioxidant Capacity reduced between T0 and T2 and the Dietary Inflammatory Index scores increased throughout the chemotherapy. Blood samples taken at the end of the chemotherapy showed lower levels of glutathione reductase and reduced glutathione, with greater quantification of the transcripts for Interleukin-6 and Tumor Necrosis Factor α. It should be emphasized that the Total Dietary Antioxidant Capacity is lower and the Dietary Inflammatory Index is higher in the group of overweight patients at the end of the follow-up, besides showing lower levels of the redox status, especially the plasma levels of glutathione reductase (p = 0.039). In addition, trends towards higher transcriptional levels of cytokines in peripheral blood were observed more often in overweight women than in non-overweight women. In this study of 55 women with breast cancer, nine (16%) with metastases, diet became more pro-inflammatory with fewer antioxidants during the chemotherapy. Briefly, we have shown that chemotherapy is critical for high-risk overweight women due to their reduced intake of antioxidant nutrients, generating greater inflammatory and oxidative stress profiles, suggesting the adoption of healthier dietary practices by women with breast cancer throughout their chemotherapy.
Sex Specific Expression of Interleukin 7, 8 and 15 in Placentas of Women with Gestational Diabetes

Gestational diabetes mellitus (GDM) is known to increase the risk for feto-maternal complications during pregnancy. A state of low-grade inflammation, with elevated levels of proinflammatory molecules, similar to patients with obesity or diabetes mellitus type 2 has also been partly described in GDM. The placenta, as unique interface between mother and fetus, is not only passively affected by changes in one of these organisms, but also acts as a modulator by expressing hormones and cytokines. This study aimed to investigate the expression of the proinflammatory cytokines Interleukin (IL) 7, 8 and 15 in GDM in placental tissue. A total number of 80 placentas were included (40 GDM/40 control group). The expression of IL-7, 8 and 15 was investigated in extravillous trophoblast (EVT) and syncytiotrophoblast (SCT) by immunohistochemistry and immunofluorescence double staining. The immunohistochemical staining was evaluated with the semiquanitfied immunoreactive score (IRS). While the expression IL-15 was significantly upregulated in EVTs of women with GDM. The expression of IL-8 was significantly decreased in EVT of the GDM group. Furthermore, significant fetal sex specific differences were detectable in all three cytokines. Our findings suggest an involvement of the investigated cytokines in the maintenance of a state of chronic low-grade inflammation on placental level in patients suffering from GDM.
Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy

Pathogenic mutations in A-type nuclear lamins cause dilated cardiomyopathy, which is postulated to result from dysregulated gene expression due to changes in chromatin organization into active and inactive compartments. To test this, we performed genome-wide chromosome conformation analyses (Hi-C) in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with a haploinsufficient mutation for lamin A/C. Compared to gene-corrected cells, mutant hiPSC-CMs have marked electrophysiological and contractile alterations, with modest gene expression changes. While large-scale changes in chromosomal topology are evident, differences in chromatin compartmentalization are limited to a few hotspots that escape inactivation during cardiogenesis. These regions exhibit upregulation of multiple non-cardiac genes including CACNA1A, encoding for neuronal P/Q-type calcium channels. Pharmacological inhibition of the resulting current partially mitigates the electrical alterations. On the other hand, A/B compartment changes do not explain most gene expression alterations in mutant hiPSC-CMs. We conclude that global errors in chromosomal compartmentation are not the primary pathogenic mechanism in heart failure due to lamin A/C haploinsufficiency. Summary Bertero et al. observe that lamin A/C haploinsufficiency in human cardiomyocytes markedly alters electrophysiology, contractility, gene expression, and chromosomal topology. Contrary to expectations, however, changes in chromatin compartments involve just few regions, and most dysregulated genes lie outside these hotspots. Condensed title Genomic effects of lamin A/C haploinsufficiency
Diagnostic validation of a rapid and field-applicable PCR-lateral flow test system for point-of-care detection of cyprinid herpesvirus 3 (CyHV-3)

Koi herpesvirus disease (KHVD) is a highly infectious disease leading to outbreaks and mass mortality in captive and free-ranging common carp and koi carp. Outbreaks may result in high morbidity and mortality which can have a severe economic impact along the supply chain. Currently, control and prevention of KHVD relies on avoiding exposure to the virus based on efficient hygiene and biosecurity measures. An early diagnosis of the disease is crucial to prevent its spread and to minimize economic losses. Therefore, an easy-to-handle, sensitive, specific and reliable test prototype for a point-of-care detection of KHV was developed and evaluated in this study. We used a multiplex-endpoint-PCR followed by a specific probe hybridization step. PCR-products/hybridization-products were visualized with a simple and universal lateral flow immunoassay (PCR-LFA). Fifty-four gill tissue samples (KHV-positive n = 33, KHV-negative n = 21) and 46 kidney samples (KHV-positive n = 24, KHV-negative n = 22) were used to determine diagnostic sensitivity and specificity of the PCR-LFA. In addition, the usability of PCR-LFA to detect CyHV-3-DNA in gill swabs taken from 20 perished common carp during a KHVD-outbreak in a commercial carp stock was examined. This assay gave test results within approximately 60 min. It revealed a detection limit of 9 KHV gene copies/μl (95% probability), a diagnostic specificity of 100%, and diagnostic sensitivity of 94.81% if samples were tested in a single test run only. PCR inhibition was noticed when examining gill swab samples without preceding extraction of DNA or sample dilution. Test sensitivity coud be enhanced by examining samples in five replicates. Overall, our PCR-LFA proved to be a specific, easy-to-use and time-saving point-of-care-compatible test for the detection of KHV-DNA. Regarding gill swab samples, further test series using a higher number of clinical samples should be analyzed to confirm the number of replicates and the sample processing necessary to reveal a 100% diagnostic sensitivity.
Effect of 1α,25(OH)2 Vitamin D3 in Mutant P53 Glioblastoma Cells: Involvement of Neutral Sphingomyelinase1

Simple Summary The active form of vitamin D3 slows proliferation and stimulates differentiation of glioblastoma cells with mutated p53 by acting via neutral sphingomyelinase 1 and not by classical via vitamin D receptor-mediated Abstract Glioblastoma is one the most aggressive primary brain tumors in adults, and, despite the fact that radiation and chemotherapy after surgical approaches have been the treatments increasing the survival rates, the prognosis of patients remains poor. Today, the attention is focused on highlighting complementary treatments that can be helpful in improving the classic therapeutic approaches. It is known that 1α,25(OH)2 vitamin D3, a molecule involved in bone metabolism, has many serendipidy effects in cells. It targets normal and cancer cells via genomic pathway by vitamin D3 receptor or via non-genomic pathways. To interrogate possible functions of 1α,25(OH)2 vitamin D3 in multiforme glioblastoma, we used three cell lines, wild-type p53 GL15 and mutant p53 U251 and LN18 cells. We demonstrated that 1α,25(OH)2 vitamin D3 acts via vitamin D receptor in GL15 cells and via neutral sphingomyelinase1, with an enrichment of ceramide pool, in U251 and LN18 cells. Changes in sphingomyelin/ceramide content were considered to be possibly responsible for the differentiating and antiproliferative effect of 1α,25(OH)2 vitamin D in U251 and LN18 cells, as shown, respectively, in vitro by immunofluorescence and in vivo by experiments of xenotransplantation in eggs. This is the first time 1α,25(OH)2 vitamin D3 is interrogated for the response of multiforme glioblastoma cells in dependence on the p53 mutation, and the results define neutral sphingomyelinase1 as a signaling effector.