Miracle-dz/UniFAR-FTUs huggingface dataset:
Fat-regulating phosphatidic acid phosphatase: a review of its roles and regulation in lipid homeostasis

Phosphatidic acid (PA) phosphatase is an evolutionarily conserved enzyme that plays a major role in lipid homeostasis by controlling the cellular levels of its substrate, PA, and its product, diacylglycerol. These lipids are essential intermediates for the synthesis of triacylglycerol and membrane phospholipids; they also function in lipid signaling, vesicular trafficking, lipid droplet formation, and phospholipid synthesis gene expression. The importance of PA phosphatase to lipid homeostasis and cell physiology is exemplified in yeast, mice, and humans by a host of cellular defects and lipid-based diseases associated with loss or overexpression of the enzyme activity. In this review, we focus on the mode of action and regulation of PA phosphatase in the yeast Saccharomyces cerevisiae. The enzyme Pah1 translocates from the cytosol to the nuclear/endoplasmic reticulum membrane through phosphorylation and dephosphorylation. Pah1 phosphorylation is mediated in the cytosol by multiple protein kinases, whereas dephosphorylation is catalyzed on the membrane surface by an integral membrane protein phosphatase. Posttranslational modifications of Pah1 also affect its catalytic activity and susceptibility to degradation by the proteasome. Additional mechanistic understanding of Pah1 regulation should be instrumental for the identification of small-molecule inhibitors or activators that can fine-tune PA phosphatase function and thereby restore lipid homeostasis. Graphical Abstract
Yeast and human P4-ATPases transport glycosphingolipids using conserved structural motifs

Lipid transport is an essential process with manifest importance to human health and disease. Phospholipid flippases (P4-ATPases) transport lipids across the membrane bilayer and are involved in signal transduction, cell division, and vesicular transport. Mutations in flippase genes cause or contribute to a host of diseases, such as cholestasis, neurological deficits, immunological dysfunction, and metabolic disorders. Genome-wide association studies have shown that ATP10A and ATP10D variants are associated with an increased risk of diabetes, obesity, myocardial infarction, and atherosclerosis. Moreover, ATP10D SNPs are associated with elevated levels of glucosylceramide (GlcCer) in plasma from diverse European populations. Although sphingolipids strongly contribute to metabolic disease, little is known about how GlcCer is transported across cell membranes. Here, we identify a conserved clade of P4-ATPases from Saccharomyces cerevisiae (Dnf1, Dnf2), Schizosaccharomyces pombe (Dnf2), and Homo sapiens (ATP10A, ATP10D) that transport GlcCer bearing an sn2 acyl-linked fluorescent tag. Further, we establish structural determinants necessary for recognition of this sphingolipid substrate. Using enzyme chimeras and site-directed mutagenesis, we observed that residues in transmembrane (TM) segments 1, 4, and 6 contribute to GlcCer selection, with a conserved glutamine in the center of TM4 playing an essential role. Our molecular observations help refine models for substrate translocation by P4-ATPases, clarify the relationship between these flippases and human disease, and have fundamental implications for membrane organization and sphingolipid homeostasis.
Atomically thin van der Waals tunnel field-effect transistors and its potential for applications

Power dissipation is a crucial problem as the packing density of transistors increases in modern integrated circuits. Tunnel field-effect transistors (TFETs), which have high energy filtering provided by band-to-band tunneling (BTBT), have been proposed as an alternative electronics architecture to decrease the energy loss in bias operation and to achieve steep switching at room temperature. Very recently, the BTBT behavior has been demonstrated in van der Waals heterostructures by using unintentionally doped semiconductors. The reason of the BTBT formation is attributed to a significant band bending near the heterointerface, resulting in carrier accumulations. In this work, to investigate charge transport in type-III transistors, we adopted the same band-bending concept to fabricate van der Waals BP/MoS2 heterostructures. Through analyzing the temperature dependence of their electrical properties, we carefully ruled out the contribution of metal-semiconductor contact resistances and improved our understanding of carrier injection in 2D type-III transistors. The BP/MoS2 heterostructures showed both negative differential resistance and 1/f2 current fluctuations, strongly demonstrating the BTBT operation. Finally, we also designed a TFET based on this heterostructure with an ionic liquid gate, and this TFET demonstrated an subthreshold slope can successfully surmount the thermal limit of 60 mV/decade. This work improves our understanding of charge transport in such layered heterostructures and helps to improve the energy efficiency of next-generation nanoscale electronics.
The β4 subunit of Cav1.2 channels is required for an optimal interferon response in cardiac muscle cells

A regulatory subunit of a voltage-gated calcium channel translocates to the nucleus to promote an antiviral response. Channeling antiviral immunity? The intracellular β4 subunit of the voltage-gated calcium channel Cav1.2 plays a major role in the proper localization and function of the pore-forming α subunit, but it has also been implicated in regulating gene expression in neurons and lymphocytes. Tammineni et al. found that β4 abundance and nuclear localization were increased in a cardiac cell line in response to treatment with type I interferon (IFN) or infection with dengue virus. The β4 subunit physically interacted with the transcriptional regulator IRF7 and was associated with the increased expression of IFN-stimulated genes. In cells overexpressing the β4 subunit, dengue virus replication was inhibited. Together, these data suggest that the β4 subunit may play a channel-independent role in the antiviral response. The auxiliary β4 subunit of the cardiac Cav1.2 channel plays a poorly understood role in gene transcription. Here, we characterized the regulatory effects of the β4 subunit in H9c2 rat cardiac cells on the abundances of Ifnb mRNA [which encodes interferon-β (IFN-β)] and of the IFN-β–related genes Ddx58, Ifitm3, Irf7, Stat2, Ifih1, and Mx1, as well as on the abundances of the antiviral proteins DDX58, IRF7, STAT2, and IFITM3. Knocking down the β4 subunit in H9c2 cells reduced the expression of IFN-β–stimulated genes. In response to inhibition of the kinase JAK1, the abundances of β4 subunit mRNA and protein were decreased. β4 subunit abundance was increased, and it translocated to the nucleus, in cells treated with IFN-β, infected with dengue virus (DENV), or transfected with poly(I:C), a synthetic analog of double-stranded RNA. Cells that surrounded the virus-infected cells showed translocation of β4 subunit proteins to nuclei in response to spreading infection. We showed that the β4 subunit interacted with the transcriptional regulator IRF7 and that the activity of an Irf7 promoter–driven reporter was increased in cells overexpressing the β4 subunit. Last, overexpressing β4 in undifferentiated and differentiated H9c2 cells reduced DENV infection and decreased the abundance of the viral proteins NS1, NS3, and E-protein. DENV infection and poly(I:C) also increased the concentration of intracellular Ca2+ in these cells. These findings suggest that the β4 subunit plays a role in promoting the expression of IFN-related genes, thereby reducing viral infection.
Interglial Crosstalk in Obesity-Induced Hypothalamic Inflammation

Glial cells have recently gained particular attention for their close involvement in neuroinflammation and metabolic disorders including obesity and diabetes. In the central nervous system (CNS), different types of resident glial cells have been documented to express several signaling molecules and related receptors, and their crosstalks have been implicated in physiology and pathology of the CNS. Emerging evidence illustrates that malfunctioning glia and their products are an important component of hypothalamic inflammation. Recent studies have suggested that glia–glia crosstalk is a pivotal mechanism of overnutrition-induced chronic hypothalamic inflammation, which might be intrinsically associated with obesity/diabetes and their pathological consequences. This review covers the recent advances in the molecular aspects of interglial crosstalk in hypothalamic inflammation, proposing a central role of such a crosstalk in the development of obesity, diabetes, and related complications. Finally, we discuss the possibilities and challenges of targeting glial cells and their crosstalk for a better understanding of hypothalamic inflammation and related metabolic dysfunctions.
Inactivation of RUNX3 protein expression in tongue squamous cell carcinoma and its association with clinicopathological characteristics

The function of runt-related transcription factor 3 (RUNX3) in oral cancer remains controversial. The present study aimed to determine the status of RUNX3 protein expression and its association with clinicopathological characteristics in tongue squamous cell carcinomas (SCC). The present study used three pairs of tongue SCC and non-cancerous tissues to assess RUNX3 protein expression by western blot analysis, and two tongue SCC cell lines to determine RUNX3 protein localization by immunofluorescence and immunocytochemistry. Tissue microarray immunohistochemistry was performed to detect the clinical relevance of RUNX3 in 79 patients with tongue SCC. The results demonstrated that RUNX3 protein expression was reduced in tongue SCC tissues compared with in paired non-cancerous tissues. Similarly, the expression of RUNX3 was low in SCC25 and Cal27 cells, and was predominantly localized to the cytoplasm. In the 79 patients with tongue SCC, RUNX3 protein expression was presented in different manners in carcinoma nests and tumor stroma. RUNX3 in carcinoma nests (nRUNX3) exhibited nuclear positive staining in 24/79 samples, cytoplasmic mislocalization in 41/79 samples and was undetectable in 14/79 samples. RUNX3 in stroma (sRUNX3) exhibited nuclear positive staining in 40/79 samples and nuclear negative staining in 39/79 samples. Negative nRUNX3 expression was significantly associated with lymph node metastasis (P=0.014), clinical stage (P=0.027), and overall and disease-free survival (P=0.008 and P=0.007, respectively). In addition, negative sRUNX3 expression was associated with lymph node metastasis (P=0.003) and clinical stage (P=0.003); however, not with overall survival. The findings of the present study preliminarily suggested that cytoplasmic mislocalization of RUNX3 protein may be a common event in tongue SCC, and that sRUNX3 protein expression may be a potential prognostic biomarker.
A validated algorithm to identify recurrence of bladder cancer: a register-based study in Denmark

Purpose Recurrence of cancer is not routinely registered in the national registers in Denmark. The aim of this study was to develop and validate a register-based algorithm to identify patients diagnosed with recurrence of invasive bladder cancer (BC). Materials and methods We performed a cohort study based on data from Danish national health registers. Diagnosis codes and procedural codes in the Danish National Patient Register and Systematized Nomenclature of Medicine codes in the Danish National Pathology Register were used as indicators of cancer recurrence. Status and date of recurrence as registered in the Danish Bladder Cancer Database (DaBlaCa-data) were used as the gold standard of BC recurrence to ascertain the accuracy of the algorithm. Results The algorithm reached a sensitivity of 85% (95% CI: 78–91), a specificity of 90% (95% CI: 79–96), and a positive predictive value of 95% (95% CI: 89–98). The algorithm demonstrated superior performance in patients undergoing cystectomy compared to patients undergoing radiotherapy as primary BC treatment. The concordance correlation coefficient for the agreement between the recurrence dates generated by the algorithm and the gold standard was 0.96 (95% CI: 0.95–0.98), and the estimated date was set within 90 days of the gold standard date for 90% of patients. Conclusion The proposed algorithm to identify patients diagnosed with BC recurrence from Danish national registries showed excellent performance in terms of ascertaining occurrence and the timing of BC recurrence.
Individualized Homeopathic Therapy in a Case of Obesity, Dysfunctional Uterine Bleeding, and Autonomic Dystonia

Patient: Female, 39 Final Diagnosis: Vegetovascular dystonia • dysfunctional uterine bleeding Symptoms: Bleeding per vaginum • loss of consciousness • weakness Medication: — Clinical Procedure: Oral medication Specialty: General and Internal Medicine Objective: Unusual clinical course Background: Obesity is one of the leading causes of morbidity and mortality globally and challenging to treat because of the multifactorial etiology and presentation. Individualized homeopathy takes into account factors that led to a patient’s health condition and hence may have a role in the treatment of obesity and related co-morbidities; co-morbidities that may arising from the same etiology may respond as a whole to homeopathy treatment. Case Report: A 39-year-old Russian female who developed multiple problems after severe emotional stress was treated with individualized classical homeopathic therapy. Obesity, dysfunctional uterine bleeding, and dysautonomia were pathologies that showed improvement. Conclusions: The response in this patient’s case, supports the need for further investigation on the relevance of individualized homeopathy in these related conditions.
Direct activation of G-protein-gated inward rectifying K+ channels promotes nonrapid eye movement sleep

STUDY OBJECTIVES A major challenge in treating insomnia is to find effective medicines with fewer side effects. Activation of G-protein-gated inward rectifying K+ channels (GIRKs) by GABAB agonists baclofen or γ-hydroxybutyric acid (GHB) promotes nonrapid eye movement (NREM) sleep and consolidates sleep. However, baclofen has poor brain penetration, GHB possesses abuse liability, and in rodents both drugs cause spike-wave discharges (SWDs), an absence seizure activity. We tested the hypothesis that direct GIRK activation promotes sleep without inducing SWD using ML297, a potent and selective GIRK activator. METHODS Whole-cell patch-clamp recordings from hypocretin/orexin or hippocampal neurons in mouse brain slices were made to study neuronal excitability and synaptic activity; spontaneous activity, locomotion, contextual and tone-conditioned memory, and novel object recognition were assessed. Electroencephalogram/electromyogram (EEG/EMG) recordings were used to study GIRK modulation of sleep. RESULTS ML297, like baclofen, caused membrane hyperpolarization, decreased input resistance, and blockade of spontaneous action potentials. Unlike baclofen, ML297 (5-10 µM) did not cause significant depression of postsynaptic excitatory and inhibitory currents (EPSCs-IPSCs), indicating preferential postsynaptic inhibition. ML297 (30 mg/kg, i.p.) inhibited wake activity and locomotion, and preferentially increased NREM sleep without altering EEG delta power, REM sleep, inducing SWDs, or impairing conditioned memory and novel object recognition. CONCLUSIONS This study finds that direct activation of neuronal GIRK channels modulates postsynaptic membrane excitability and prolongs NREM sleep without changing sleep intensity, inducing SWDs, or impairing memory in rodents. These results suggest that direct GIRK activation with a selective compound may present an innovative approach for the treatment of chronic insomnia.
A 9-Week Nordic and Free Walking Improve Postural Balance in Parkinson’s Disease

Abstract Aerobic training has a neuroprotective effect in people with Parkinson’s disease. Recent evidence indicates that Nordic walking seems a promising alternative due to positive outcomes in functional mobility. However, the effects of Nordic walking compared to free walking on static and functional balance parameters are still unknown. The aim of this study was to evaluate the effects of nine weeks of Nordic and free walking training on static and functional balance. The sample size was 33 individuals with eight dropouts, leaving 25 individuals in the final sample (Nordic Walking, n=14, Free Walking, n=11). The participants underwent two evaluations in the present randomized clinical trial, pre- and post-training, to determine average velocity and root-mean-square values from center of pressure with eyes open and eyes closed. The functional balance showed approximately 5% improvement for the two groups (p=0.04). The results indicate that nine weeks of Nordic and free walking training were enough to induce improvements in the proprioceptive system and functional balance.
The Expressing Patterns of Opioid Peptides, Anti-opioid Peptides and Their Receptors in the Central Nervous System Are Involved in Electroacupuncture Tolerance in Goats

To investigate dynamic processes of enkephalin (ENK), cholecystokinin octapeptide (CCK-8), orphanin FQ (OFQ) and their receptors (μ opioid receptor, MOR; CCK B type receptor, CCKBR and opioid receptor-like 1 receptor, OPRL1) in the central nerve system (CNS) during electroacupuncture (EA) tolerance, EA of Sixty Hz was used to stimulate goats for 6 h. Pain threshold was measured using potassium iontophoresis. The expression levels of ENK, CCK-8, and OFQ and their receptors were determined with ELISA and qPCR, respectively. The results showed that the change rates of pain threshold in EA-treated goats decreased from 89.9 ± 11.7% at 0.5 h to –11.4 ± 8.9% at 6 h. EA induced the decreased ENK and increased CCK-8 and OFQ in the most measured nuclei. EA caused decreased preproenkephalin mRNAs in ACB, CAU, PVH, and PAG at 4 h, and decreased or unchanged MOR mRNAs at 2–6 h, but increased CCK mRNAs in CAU, PVT, PVH, PAG, and SCD at 4–12 h. Increased prepronociceptin mRNAs and fluctuated CCKBR and OPLR1 mRNAs were found in the most measured nuclei. ENK levels were positively correlated (p < 0.01) with the change rates of pain thresholds in the measured nuclei or areas while CCK-8 levels (or OFQ levels) were negatively correlated (p < 0.01) with the pain thresholds in CAU (or CAU and ACB). These results suggest that the development and recovery of EA tolerance may be associated with the specific expression patterns of opioid peptides, anti-opioid peptides and their receptors in the analgesia-related nuclei or areas.
Cofactors are essential constituents of stable and seeding-active tau fibrils

Significance The tau protein is involved in Alzheimer’s and other neurodegenerative diseases, where the location, morphology, and quantity of amyloid fibrils composed of tau correlate with the disease type and stage. While tau fibrillary aggregates have been colocalized in brains together with several cofactors, their role in fibril formation, structure, and seeding has been largely neglected. We show that seeding of tau aggregation is facilitated by polyanionic cofactors, and that seeded or recombinant mature fibrils depolymerize into monomers when their cofactor is removed. We show that cofactor-assisted seeding with mouse brain-derived tau fibrils yielded tau fibrils with distinct and narrowed structural properties compared with heparin-induced fibrils, suggesting that the fibrillar templates tuned the structure of the seeded fibril. Amyloid fibrils are cross-β–rich aggregates that are exceptionally stable forms of protein assembly. Accumulation of tau amyloid fibrils is involved in many neurodegenerative diseases, including Alzheimer’s disease (AD). Heparin-induced aggregates have been widely used and assumed to be a good tau amyloid fibril model for most biophysical studies. Here we show that mature fibrils made of 4R tau variants, prepared with heparin or RNA, spontaneously depolymerize and release monomers when their cofactors are removed. We demonstrate that the cross-β-sheet assembly formed in vitro with polyanion addition is unstable at room temperature. We furthermore demonstrate high seeding capacity with transgenic AD mouse brain-extracted tau fibrils in vitro that, however, is exhausted after one generation, while supplementation with RNA cofactors resulted in sustained seeding over multiple generations. We suggest that tau fibrils formed in brains are supported by unknown cofactors and inhere higher-quality packing, as reflected in a more distinct conformational arrangement in the mouse fibril-seeded, compared with heparin-induced, tau fibrils. Our study suggests that the role of cofactors in tauopathies is a worthy focus of future studies, as they may be viable targets for diagnosis and therapeutics.
Child and Adolescent Psychosocial Care Center service use profile in Brazil: 2008 to 2012

Objective: To describe the service use profile of Child and Adolescent Psychosocial Care Centers (Centro de Atenção Psicossocial Infanto-Juvenil [CAPSi]) in Brazil regarding diagnostic categories, sociodemographic aspects, and care modalities between 2008 and 2012. Methods: A descriptive, ecological study was performed using data from the Unified Health System regarding high-complexity procedure authorizations (Autorização de Procedimentos de Alta Complexidade [APAC]) for the period from 2008-2012. The variables sex, age, diagnosis (F00-F99 of ICD-10), and type of care provided were examined. The data were processed using TabWin and STATA version 12. Results: A total of 837,068 records were examined, each representing one visit to CAPSi. Most visits were by male users (68.8%). The most common diagnoses were hyperkinetic disorders (13%), pervasive developmental disorders (12.4%), and conduct disorders (8.4%). Conclusions: Behavioral and emotional disorders that usually appear during childhood or adolescence and psychological development disorders were frequent, with more than 50% of the latter comprising autism spectrum disorders. Regional differences were observed, with a higher presence of this diagnosis in the Southeast, while the North and Northeast had a high percentage of visits due to mental retardation.
The Genetic Landscape of Diamond-Blackfan Anemia

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 1 in 100,000 to 200,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this genetically heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole exome sequencing (WES). Overall, we identified rare and predicted damaging mutations in likely causal genes for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and in one of 19 previously reported genes encoding for a diverse set of ribosomal proteins (RPs). Using WES exon coverage estimates, we were able to identify and validate 31 deletions in DBA associated genes. We also observed an enrichment for extended splice site mutations and validated the diverse effects of these mutations using RNA sequencing in patientderived cell lines. Leveraging the size of our cohort, we observed several robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. In addition to comprehensively identifying mutations in known genes, we further identified rare mutations in 7 previously unreported RP genes that may cause DBA. We also identified several distinct disorders that appear to phenocopy DBA, including 9 individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain > 5% of DBA cases. Overall, this comprehensive report should not only inform clinical practice for DBA patients, but also the design and analysis of future rare variant studies for heterogeneous Mendelian disorders.