Miracle-dz/UniFAR-FTUs huggingface dataset:
Rare missense variants in the human cytosolic antibody receptor preserve antiviral function

The genetic basis of most human disease cannot be explained by common variants. One solution to this ‘missing heritability problem’ may be rare missense variants, which are individually scarce but collectively abundant. However, the phenotypic impact of rare variants is under-appreciated as gene function is normally studied in the context of a single ‘wild-type’ sequence. Here, we explore the impact of naturally occurring missense variants in the human population on the cytosolic antibody receptor TRIM21, using volunteer cells with variant haplotypes, CRISPR gene editing and functional reconstitution. In combination with data from a panel of computational predictors, the results suggest that protein robustness and purifying selection ensure that function is remarkably well-maintained despite coding variation.
Anemia of Inflammation with An Emphasis on Chronic Kidney Disease

Iron is vital for a vast variety of cellular processes and its homeostasis is strictly controlled and regulated. Nevertheless, disorders of iron metabolism are diverse and can be caused by insufficiency, overload or iron mal-distribution in tissues. Iron deficiency (ID) progresses to iron-deficiency anemia (IDA) after iron stores are depleted. Inflammation is of diverse etiology in anemia of chronic disease (ACD). It results in serum hypoferremia and tissue hyperferritinemia, which are caused by elevated serum hepcidin levels, and this underlies the onset of functional iron-deficiency anemia. Inflammation is also inhibitory to erythropoietin function and may directly increase hepcidin level, which influences iron metabolism. Consequently, immune responses orchestrate iron metabolism, aggravate iron sequestration and, ultimately, impair the processes of erythropoiesis. Hence, functional iron-deficiency anemia is a risk factor for several ailments, disorders and diseases. Therefore, therapeutic strategies depend on the symptoms, severity, comorbidities and the associated risk factors of anemia. Oral iron supplements can be employed to treat ID and mild anemia particularly, when gastrointestinal intolerance is minimal. Intravenous (IV) iron is the option in moderate and severe anemic conditions, for patients with compromised intestinal integrity, or when oral iron is refractory. Erythropoietin (EPO) is used to treat functional iron deficiency, and blood transfusion is restricted to refractory patients or in life-threatening emergency situations. Despite these interventions, many patients remain anemic and do not respond to conventional treatment approaches. However, various novel therapies are being developed to treat persistent anemia in patients.
Inflammation and depressive phenotypes: evidence from medical records from over 12 000 patients and brain morphology

Abstract Background Preclinical and human studies suggest an association between chronic inflammation and the development of depressive behaviors. This is proposed to occur through downstream effects of inflammatory cytokines on neuroplasticity, neurogenesis and neurotransmitter function, although the neural correlates remain poorly understood in humans. Methods In Study 1, structural magnetic resonance imaging and serum inflammatory cytokine data were analyzed from 53 psychiatrically healthy female participants. Correlational analyses were conducted between interleukin-6 (IL-6) and volume in a priori regions implicated in the pathophysiology of major depressive disorder (MDD). In Study 2, medical data [including serum inflammatory acute phase reactants (C-reactive protein)] were analyzed for 12 589 participants. Participants were classified as having (n = 2541) v. not having (n = 10 048) probable lifetime MDD using phenotypes derived using machine-learning approaches. Non-parametric analyses compared inflammation between groups, whereas regression analyses probed whether inflammation predicted probable MDD classification while accounting for other variables. Results In Study 1, significant negative correlations emerged between IL-6 and hippocampal, caudate, putamen and amygdalar volume. In Study 2, the MDD group showed a higher probability of elevated inflammation than the non-MDD group. Moreover, elevated inflammation was a significant predictor of probable MDD classification. Conclusions Findings indicate that inflammation is cross-sectionally related to reduced volume in brain regions implicated in MDD phenotypes among a sample of psychiatrically healthy women, and is associated with the presence of probable MDD in a large clinical dataset. Future investigations may identify specific inflammatory markers predicting first MDD onset.
Biological Assessment of Zn–Based Absorbable Metals for Ureteral Stent Applications

The use of ureteral stents to relieve urinary tract obstruction is still challenged by the problems of infection, encrustation, and compression, leading to the need for early removal procedures. Biodegradable ureteral stents, commonly made of polymers, have been proposed to overcome these problems. Recently, absorbable metals have been considered as potential materials offering both biodegradation and strength. This work proposed zinc-based absorbable metals by firstly evaluating their cytocompatibility toward normal primary human urothelial cells using 2D and 3D assays. In the 2D assay, the cells were exposed to different concentrations of metal extracts (i.e., 10 mg/mL of Zn–1Mg and 8.75 mg/mL of Zn–0.5Al) for up to 3 days and found that their cytoskeletal networks were affected but were recovered at day 3, as observed by immunofluorescence. In the 3D ureteral wall tissue construct, the cells formed a multilayered urothelium, as found in native tissue, with the presence of tight junctions at the superficial layer and laminin at the basal layer, indicating a healthy tissue condition even with the presence of the metal samples for up to 7 days of exposure. The basal cells attached to the metal surface as seen in a natural spreading state with pseudopodia and fusiform morphologies, indicating that the metals were non-toxic.
Are intestinal helminths playing a positive role in tuberculosis risk? A systematic review and meta-analysis

Background Co-infection of intestinal helminthic infections (IHIs) and tuberculosis (TB) has appeared as a public health issue, especially in developing countries. Some recent studies have been carried out on the possible relevance of IHIs to TB. The current systematic review and meta-analysis was conducted to assess the prevalence and odds ratio (OR) of IHIs among TB patients and clarify the relationship between IHIs and TB disease. Methods For the purpose of the study, five English databases including PubMed, Science Direct, Scopus, Web of Science (ISI), and Google scholar were searched (up to January 30, 2019) in order to find the related studies. Random-effects meta-analysis model was used to estimate the pooled prevalence, odds ratio (OR), and 95% confidence interval (CI). Inclusion and exclusion criteria were applied. Results A total of 20 studies including 10 studies with case-control design (2217 patients and 2520 controls) and 10 studies with cross-sectional design (a total of 2415 participants) met the eligibility criteria. As shown by the random-effects model, the pooled prevalence of IHIs in TB patients was estimated to be 26% (95% CI, 17–35%; 1249/4632). The risk of IHI was higher in TB patients compared to controls but this was not statistically significant. However, according to genus/species, the pooled OR of Strongyloides stercoralis (S. stercoralis) (OR, 2.68; 95% CI, 1.59–4.54) had a significantly higher risk in TB patients compared to controls. Nevertheless, the results of random effects model showed no statistically significant association between overall pooled OR of IHIs in TB patients compared to controls in case-control studies (OR, 1; 95% CI, 0–1). Conclusions It is highly recommended that more precise studies should be carried out by researchers in order to better understand this association. Also, it is of great importance to include the periodic screenings for IHIs in the routine clinical care of these patients.
Associations of Meal Timing and Frequency with Obesity and Metabolic Syndrome among Korean Adults

Emerging studies indicate that meal timing is linked to cardiometabolic risks by deterioration of circadian rhythms, however limited evidence is available in humans. This large-scale cross-sectional study explored the associations of meal timing and frequency with obesity and metabolic syndrome among Korean adults. Meal timing was defined as nightly fasting duration and morning, evening, and night eating, and meal frequency was estimated as the number of daily eating episodes using a single-day 24-hour dietary recall method. Meal frequency was inversely associated with prevalence of abdominal obesity, elevated blood pressure, and elevated triglycerides in men only. Independent of the nightly fasting duration and eating episodes, morning eating was associated with a lower prevalence of metabolic syndrome (odds ratio (OR), 0.73; 95% confidence interval (CI), 0.57–0.93 for men and OR, 0.69; 95% CI, 0.54–0.89 for women) than no morning eating, whereas night eating was associated with a 48% higher prevalence of metabolic syndrome (OR, 1.48; 95% CI, 1.15–1.90) than no night eating in men only. Longer fasting duration and less sleep were associated with obesity and metabolic syndrome. These findings suggest that overall eating patterns, including energy distribution across the day, eating frequency, and sleep duration, rather than fasting duration alone, are related to cardiometabolic risks in free-living Korean adults.
Toward Real-Time Monitoring and Control of Single Nanoparticle Properties with a Microbubble Resonator Spectrometer

Optical microresonators have widespread application at the frontiers of nanophotonic technology, driven by their ability to confine light to the nanoscale and enhance light–matter interactions. Microresonators form the heart of a recently developed method for single-particle photothermal absorption spectroscopy, whereby the microresonators act as microscale thermometers to detect the heat dissipated by optically pumped, nonluminescent nanoscopic targets. However, translation of this technology to chemically dynamic systems requires a platform that is mechanically stable, solution compatible, and visibly transparent. We report microbubble absorption spectrometers as a versatile platform that meets these requirements. Microbubbles integrate a two-port microfluidic device within a whispering gallery mode microresonator, allowing for the facile exchange of chemical reagents within the resonator’s interior while maintaining a solution-free environment on its exterior. We first leverage these qualities to investigate the photoactivated etching of single gold nanorods by ferric chloride, providing a method for rapid acquisition of spatial and morphological information about nanoparticles as they undergo chemical reactions. We then demonstrate the ability to control nanorod orientation within a microbubble through optically exerted torque, a promising route toward the construction of hybrid photonic-plasmonic systems. Critically, the reported platform advances microresonator spectrometer technology by permitting room-temperature, aqueous experimental conditions, which may be used for time-resolved single-particle experiments on non-emissive, nanoscale analytes engaged in catalytically and biologically relevant chemical dynamics.
CLASP promotes microtubule bundling in metaphase spindle independently of Ase1/PRC1 in fission yeast

ABSTRACT Microtubules in the mitotic spindle are organised by microtubule-associated proteins. In the late stage of mitosis, spindle microtubules are robustly organised through bundling by the antiparallel microtubule bundler Ase1/PRC1. In early mitosis, however, it is not well characterised as to whether spindle microtubules are actively bundled, as Ase1 does not particularly localise to the spindle at that stage. Here we show that the conserved microtubule-associated protein CLASP (fission yeast Peg1/Cls1) facilitates bundling of spindle microtubules in early mitosis. The peg1 mutant displayed a fragile spindle with unbundled microtubules, which eventually resulted in collapse of the metaphase spindle and abnormal segregation of chromosomes. Peg1 is known to be recruited to the spindle by Ase1 to stabilise antiparallel microtubules in late mitosis. However, we demonstrate that the function of Peg1 in early mitosis does not rely on Ase1. The unbundled spindle phenotype of the peg1 mutant was not seen in the ase1 mutant, and Peg1 preferentially localised to the spindle even in early mitosis unlike Ase1. Moreover, artificial overexpression of Ase1 in the peg1 mutant partially suppressed unbundled microtubules. We thus conclude that Peg1 bundles microtubules in early mitosis, in a distinct manner from its conventional Ase1-dependent functions in other cell cycle stages. Summary: The conserved microtubule-associated protein CLASP/Peg1/Cls1 bundles microtubules of the metaphase spindle in fission yeast. Unlike its conventional role in anaphase, this CLASP function does not depend upon Ase1/PRC1.
Preservative-free versus preserved brimonidine %0.15 preparations in the treatment of glaucoma and ocular hypertension: short term evaluation of efficacy, safety, and potential advantages

Abstract Purpose: To compare the efficacy, safety, and potential advantages of the preservative-free versus preserved brimonidine %0.15 preparations in patients with primer open-angle glaucoma (POAG) or ocular hypertension (OHT). Methods: Forty-two eyes of the 21 treatment-naive patients with POAG or OHT were enrolled in this study. Eyes were randomly assigned to receive brimonidine-purite 0.15% or preservative-free brimonidine 0.15% two times daily. Efficacy of the two eye drops was assessed by measuring the intraocular pressure (IOP) at 9–10 am at baseline and week 4. Safety and potential advantages of the drops were evaluated at weeks 4 in terms of ocular symptoms and tear parameters. Ocular symptom values of the patients were evaluated with a scale of 0–4 (0 = no discomfort and 4 = severe discomfort). Results: Both of the brimonidine tartrate formulations resulted in statistically similar IOP reduction (preserved formulation; −5.2 mmHg [22.9% reduction] preservative-free formulation; −5.7 mmHg [24.1% reduction], p = 0.37). It was found that brimonidine tartrate formulations with and without topical preservatives did not produce a statistically significant difference in pain, stinging, and blurred vision at the upon instillation (p > 0.05). However, the burning sensation was significantly higher in the preservative-free formulation at the first instillation compared to the preserved formulation (p = 0.01). Also, there was no statistically significant difference between the two formulations in terms of symptoms (itching, burning, tearing, stinging, and photophobia) and tear parameters during the day (p > 0.05). Conclusions: Although topical preservative-free brimonidine tartrate treated eyes had a more burning sensation at the first drop, the two formulations were similar in terms of ocular tolerability in the short term period. Also, both formulations were found to reduce IOP at a similar rate.
Nitroxyl (HNO) as a potential theranostic in the cancer arena.

SIGNIFICANCE As one-electron reduced molecule of nitric oxide (NO), nitroxyl (HNO) has gained enormous attention because its novel physiological or pharmacological properties, ranging from cardiovascular protective actions to anti-tumoricidal effects. Recent Advances: HNO is emerging as a new entity with therapeutic advantages over its redox sibling, NO. The interests in the chemical, pharmacological and biological characteristics of HNO have broadened our current understanding of its role in physiology and pathophysiology. CRITICAL ISSUES In particular, the experimental evidence suggests the therapeutic potential of HNO in tumor pharmacology, such as neuroblastoma, gastrointestinal tumor, ovarian, lung and breast cancers. Indeed, HNO donors have been demonstrated to attenuate tumor proliferation and angiogenesis. FUTURE DIRECTIONS In this review, the generation and detection of HNO are outlined, and the roles of HNO in cancer progression are further discussed. We anticipate that the completion of this review might give novel insights into the roles of HNO in cancer pharmacology and open up a novel field of cancer therapy based on HNO. Key words: nitroxyl, nitric oxide; hydrogen sulfide; anti-cancer; cancer therapy.
Chronic myelogenous leukemia stem cells require cell-autonomous pleiotrophin signaling.

Tyrosine kinase inhibitors (TKIs) induce molecular remission in the majority of patients with chronic myelogenous leukemia (CML), but persistence of CML stem cells hinders cure and necessitates indefinite TKI therapy. We report that CML stem cells upregulate expression of pleiotrophin (PTN) and require cell-autonomous PTN signaling for CML pathogenesis in BCR/ABL+ mice. Constitutive PTN deletion substantially reduced the numbers of CML stem cells capable of initiating CML in vivo. Hematopoietic cell-specific deletion of PTN suppressed CML development in BCR/ABL+ mice, suggesting that cell-autonomous PTN signaling was necessary for CML disease evolution. Mechanistically, PTN promoted CML stem cell survival and TKI resistance via induction of Jun and the unfolded protein response. Human CML cells were also dependent on cell-autonomous PTN signaling and anti-PTN antibody suppressed human CML colony formation and CML repopulation in vivo. Our results suggest that targeted inhibition of PTN has therapeutic potential to eradicate CML stem cells.
Non‐canonical AUX/IAA protein IAA33 competes with canonical AUX/IAA repressor IAA5 to negatively regulate auxin signaling

The phytohormone auxin controls plant growth and development via TIR1‐dependent protein degradation of canonical AUX/IAA proteins, which normally repress the activity of auxin response transcription factors (ARFs). IAA33 is a non‐canonical AUX/IAA protein lacking a TIR1‐binding domain, and its role in auxin signaling and plant development is not well understood. Here, we show that IAA33 maintains root distal stem cell identity and negatively regulates auxin signaling by interacting with ARF10 and ARF16. IAA33 competes with the canonical AUX/IAA repressor IAA5 for binding to ARF10/16 to protect them from IAA5‐mediated inhibition. In contrast to auxin‐dependent degradation of canonical AUX/IAA proteins, auxin stabilizes IAA33 protein via MITOGEN‐ACTIVATED PROTEIN KINASE 14 (MPK14) and does not affect IAA33 gene expression. Taken together, this study provides insight into the molecular functions of non‐canonical AUX/IAA proteins in auxin signaling transduction.
Effects of ketamine on circadian rhythm and synaptic homeostasis in patients with treatment‐resistant depression: A protocol for mechanistic studies of its rapid and sustained antidepressant actions in humans

The breakthrough discovery has been made that a single dose of ketamine, an N‐methyl‐D‐aspartate receptor antagonist, achieves rapid and sustained (~7 days) antidepressant activity in patients with major depressive disorder (MDD). This discovery has ushered in an exciting era of research and brought new hope for patients with MDD. However, the mechanisms underlying the specific antidepressant actions of ketamine in humans remain to be elucidated.
Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis.

Previous work has reported the important links between cellular bioenergetics and the development of chronic kidney disease, highlighting the potential for targeting metabolic functions to regulate disease progression. More recently, it has been shown that alterations in fatty acid oxidation (FAO) can have an important impact on the progression of kidney disease. In this work, we demonstrate that loss of miR-33, an important regulator of lipid metabolism, can prevent the repression of FAO in fibrotic kidneys and reduce lipid accumulation. These changes were associated with a dramatic reduction in the extent of fibrosis induced in two different mouse models of kidney disease. These effects were not related to changes in circulating leukocytes, as bone marrow transplant from miR-33 deficient animals did not have a similar impact on disease progression. Most importantly, targeted delivery of miR-33 peptide nucleic acid (PNA) inhibitors to the kidney and other acidic microenvironments was accomplished using pH low insertion peptides (pHLIP) as a carrier. This was effective at both increasing the expression of factors involved in FAO and reducing the development of fibrosis. Together, these findings suggest that miR-33 may be an attractive therapeutic target for the treatment of chronic kidney disease.
Protective behaviours of near work and time outdoors in myopia prevalence and progression in myopic children: a 2-year prospective population study

Aim To investigate the protective behaviours of longer near work distance, discontinuing near work and more time outdoors in recess from parent self-report in the myopia prevalence and progression among myopic children aged 9–11 years. Methods Myopia Investigation study in Taipei is a longitudinal population-based study that enrolled elementary school students in Taipei. We provided vision and refraction examination every 6 months. Spherical equivalent (SE) of cycloplegic refraction ≤−0.50 Diopter (D) is defined as myopia. Total 10 743 (70.4%) students completed 2-year refraction data and questionnaire. The myopia prevalence and progression (difference of SE) in baseline, 6, 12, 18 and 24 months were compared by generalised estimating equations. Results Children with persistent protective behaviour had significant lower prevalence of myopia. The protective impact was statistically significant from 6 to 24 months. In 2 years follow-up, risk ratio after adjusting the background variables and the other two behaviours in near work distance, near work time and outdoor time were 0.71, 0.89 and 0.77. In SE analysis, after adjusting the other two behaviours, near work distance >30 cm (−0.7 vs −1.04 D; p<0.001), discontinuing near work every 30 min (−0.77 vs −0.96 D, p=0.005) and more time outdoors in recess from parent self-report (−0.75 vs −0.98 D; p=0.012) revealed protective impacts on diminishing myopia progression from 6 to 24 months. Conclusion In myopic children aged around 10 years in Taipei, longer distance in near work, discontinuing near work every 30 min and more outdoor time from parent self-report are protective behaviours in myopia prevalence and progression in 6–24 months.