Miracle-dz/UniFAR-FTUs huggingface dataset:
Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice

Abstract Advancement in both bioengineering and cell biology of the liver led to the establishment of the first-generation humanized liver chimeric mouse (HLCM) model in 2001. The HLCM system was initially developed to satisfy the necessity for a convenient and physiologically representative small animal model for studies of hepatitis B virus and hepatitis C virus infection. Over the last two decades, the HLCM system has substantially evolved in quality, production capacity, and utility, thereby growing its versatility beyond the study of viral hepatitis. Hence, it has been increasingly employed for a variety of applications including, but not limited to, the investigation of drug metabolism and pharmacokinetics and stem cell biology. To date, more than a dozen distinctive HLCM systems have been established, and each model system has similarities as well as unique characteristics, which are often perplexing for end-users. Thus, this review aims to summarize the history, evolution, advantages, and pitfalls of each model system with the goal of providing comprehensive information that is necessary for researchers to implement the ideal HLCM system for their purposes. Furthermore, this review article summarizes the contribution of HLCM and its derivatives to our mechanistic understanding of various human liver diseases, its potential for novel applications, and its current limitations.
Characterization of a Flavonoid 3’/5’/7-O-Methyltransferase from Citrus reticulata and Evaluation of the In Vitro Cytotoxicity of Its Methylated Products

O-methylation of flavonoids is an important modification reaction that occurs in plants. O-methylation contributes to the structural diversity of flavonoids, which have several biological and pharmacological functions. In this study, an O-methyltransferase gene (CrOMT2) was isolated from the fruit peel of Citrus reticulata, which encoding a multifunctional O-methyltransferase and could effectively catalyze the methylation of 3’-, 5’-, and 7-OH of flavonoids with vicinal hydroxyl substitutions. Substrate preference assays indicated that this recombinant enzyme favored polymethoxylated flavones (PMF)-type substrates in vitro, thereby providing biochemical evidence for the potential role of the enzyme in plants. Additionally, the cytotoxicity of the methylated products from the enzymatic catalytic reaction was evaluated in vitro using human gastric cell lines SGC-7901 and BGC-823. The results showed that the in vitro cytotoxicity of the flavonoids with the unsaturated C2-C3 bond was increased after being methylated at position 3’. These combined results provide biochemical insight regarding CrOMT2 in vitro and indicate the in vitro cytotoxicity of the products methylated by its catalytic reaction.
Expansion of the genus Imleria in North America to include Imleria floridana, sp. nov., and Imleria pallida, comb. nov.

ABSTRACT Imleria is a small genus of Boletaceae found primarily in the Northern Hemisphere characterized by the light to dark brown hymenophore that stains blue. In Florida, specimens of Imleria were collected that resembled I. badia, a species known primarily from northeastern North America and Europe. Five nuclear loci of these Florida specimens were sequenced and phylogenetically analyzed. A nuc rDNA internal transcribed spacer ITS1-5.8S-ITS2 (ITS) phylogeny of Imleria was generated using primarily uncultured environmental sequences to confirm ectomycorrhizal associations. Based on morphological and molecular data, we describe a new species, Imleria floridana. Results from these analyses also support the new combination Imleria pallida. A lectotype of I. pallida is also established from Charles H. Peck’s original material. We discuss the distinguishing characters and species of Imleria found in North America and provide a key to the known worldwide species of Imleria.
Anemia and iron deficiency in Crohn’s disease

ABSTRACT Introduction: Anemia is a common extraintestinal complication of Crohn’s disease (CD) mainly caused by iron deficiency, that affects the quality of life in CD patients. Elucidation of the etiology and pathology of iron-deficiency anemia (IDA) and anemia of chronic diseases (ACD) has developed in recent years. Common biochemical parameters of iron status are insufficient for assessment of patients with anemia and CD. Thus, novel iron indices are required for accurate assessment in IDA patients with CD. Oral iron supplementation for IDA treatment is common and is associated with minor gastrointestinal side effects. Intravenous substitution improves safety profiles but may be not tolerable in some patients. Fortunately, additional therapies for anemia of active CD have emerged in recent years. Area covered: Here, we propose the review article on the link among anemia, iron deficiency, and Crohn’s disease. We discuss the current diagnosis and therapy of anemia and iron deficiency in CD and propose the new directions for future research. Expert commentary: Exploring pathogeneses and treatments of anemia and iron deficiency in Crohn’s disease will develop potential tools for early diagnosis and effective treatment of anemia in CD patients, and improve their life quality.
A Community-Based Intervention for Managing Hypertension in Rural South Asia.

BACKGROUND The burden of hypertension is escalating, and control rates are poor in low- and middle-income countries. Cardiovascular mortality is high in rural areas. METHODS We conducted a cluster-randomized, controlled trial in rural districts in Bangladesh, Pakistan, and Sri Lanka. A total of 30 communities were randomly assigned to either a multicomponent intervention (intervention group) or usual care (control group). The intervention involved home visits by trained government community health workers for blood-pressure monitoring and counseling, training of physicians, and care coordination in the public sector. A total of 2645 adults with hypertension were enrolled. The primary outcome was reduction in systolic blood pressure at 24 months. Follow-up at 24 months was completed for more than 90% of the participants. RESULTS At baseline, the mean systolic blood pressure was 146.7 mm Hg in the intervention group and 144.7 mm Hg in the control group. At 24 months, the mean systolic blood pressure fell by 9.0 mm Hg in the intervention group and by 3.9 mm Hg in the control group; the mean reduction was 5.2 mm Hg greater with the intervention (95% confidence interval [CI], 3.2 to 7.1; P<0.001). The mean reduction in diastolic blood pressure was 2.8 mm Hg greater in the intervention group than in the control group (95% CI, 1.7 to 3.9). Blood-pressure control (<140/90 mm Hg) was achieved in 53.2% of the participants in the intervention group, as compared with 43.7% of those in the control group (relative risk, 1.22; 95% CI, 1.10 to 1.35). All-cause mortality was 2.9% in the intervention group and 4.3% in the control group. CONCLUSIONS In rural communities in Bangladesh, Pakistan, and Sri Lanka, a multicomponent intervention that was centered on proactive home visits by trained government community health workers who were linked with existing public health care infrastructure led to a greater reduction in blood pressure than usual care among adults with hypertension. (Funded by the Joint Global Health Trials scheme; COBRA-BPS ClinicalTrials.gov number, NCT02657746.).
Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials.

AIMS Glucose-lowering, glucagon-like peptide-1 (GLP-1) receptor agonists reduce incidence of major cardiovascular (CV) events in patients with Type 2 diabetes mellitus (DM). However, randomized clinical trials reported inconsistent effects on myocardial infarction (MI) and stroke, and limited data in DM patients without established CV disease (CVD). Very recently, new relevant evidence was available from additional CV outcome trials (CVOTs) that also included large subgroups of patients with DM without established CVD. Thus, the aim of this meta-analysis was to investigate the effects of GLP-1 receptor agonists on major CV events and safety in DM patients with and without established CVD. METHODS AND RESULTS In this trial-level meta-analysis, we analysed data from randomized placebo-controlled CVOTs assessing efficacy and safety of GLP-1 receptor agonists in adult patients with Type 2 DM. We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases for eligible trials. Of 360 articles identified and screened for eligibility, seven CVOTs were included, with an overall of 56 004 patients included. The difference in efficacy with respect to the major adverse cardiovascular events (MACE) primary endpoint (including CV mortality, non-fatal MI, and non-fatal stroke) between patients with established CVD and patients with CV risk factors only was not significant [pooled interaction effect, expressed as ratio of hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.85-1.34]. In the analysis of the whole population of DM patients, GLP-1 receptor agonists showed a significant 12% reduction in the hazard of the three-point MACE composite endpoint (HR 0.88, 95% CI 0.80-0.96) and a significant reduction in the risk of CV mortality (HR 0.88, 95% CI 0.79-0.98), all-cause mortality (HR 0.89, 95% CI 0.81-0.97), fatal and non-fatal stroke (HR 0.84, 95% CI 0.76-0.94), and heart failure (HF) hospitalization (HR 0.92, 95% CI 0.86-0.97). No significant effect was observed for fatal and non-fatal MI (HR 0.91, 95% CI 0.82-1.02), although in a sensitivity analysis, based on a less conservative statistical approach, the pooled HR become statistically significant (HR 0.91, 95% CI 0.83-1.00; P = 0.039). No excess of hypoglycaemia, pancreatitis, and pancreatic cancer was observed between GLP-1 receptor agonists and placebo. CONCLUSION Glucagon-like peptide-1 receptor agonists significantly reduce MACE, CV and total mortality stroke, and hospitalization for HF, with a trend for reduction of MI, in patients with Type 2 DM with and without established CVD.
Efficacy and safety of long-term universal salt iodization on thyroid disorders: epidemiological evidence from 31 provinces of mainland China.

BACKGROUND Mandatory universal salt iodization (USI) has been implemented in China for twenty years. Although iodine deficiency disorders are effectively controlled, the risk of excess iodine have been debated. METHODS A nationally representative cross-sectional study with 78,470 enrolled participants, aged 18 or older, from all 31 provincial regions of mainland China was performed. The participants were given a questionnaire and B-mode ultrasonography on the thyroid. Serum concentrations of thyroid hormones, thyroid antibodies and urine iodine concentration (UIC) were measured. RESULTS The median UIC of the adult population was 177.89 µg/L. The weighted prevalence of thyroid disorders in adults were as follows: 0.78% of overt hyperthyroidism, 0.44 % of subclinical hyperthyroidism, 0.53% of Graves' disease, 1.02% of overt hypothyroidism, 12.93% of subclinical hypothyroidism, 14.19% of positive thyroid antibodies (Ab), 10.19% of positive TPOAb, 9.70% of positive TgAb, 1.17% of goiter, and 20.43 % of thyroid nodules. Iodine excess was only associated with higher odds of overt hyperthyroidism and subclinical hypothyroidism, while iodine deficiency was significantly associated with higher odds of most thyroid disorders. In addition, increased iodine intake was significantly associated with elevated serum TSH levels, but was inversely associated with thyroid antibodies and thyroid nodule. CONCLUSIONS The long-term mandatory USI program with timely adjustments is successful in preventing iodine deficiency disorders and it appears to be safe. The benefits outweigh the risks in a population with a stable median iodine intake level of up to 300 µg/L.
Hybrid Network with Attention Mechanism for Detection and Location of Myocardial Infarction Based on 12-Lead Electrocardiogram Signals

The electrocardiogram (ECG) is a non-invasive, inexpensive, and effective tool for myocardial infarction (MI) diagnosis. Conventional detection algorithms require solid domain expertise and rely heavily on handcrafted features. Although previous works have studied deep learning methods for extracting features, these methods still neglect the relationships between different leads and the temporal characteristics of ECG signals. To handle the issues, a novel multi-lead attention (MLA) mechanism integrated with convolutional neural network (CNN) and bidirectional gated recurrent unit (BiGRU) framework (MLA-CNN-BiGRU) is therefore proposed to detect and locate MI via 12-lead ECG records. Specifically, the MLA mechanism automatically measures and assigns the weights to different leads according to their contribution. The two-dimensional CNN module exploits the interrelated characteristics between leads and extracts discriminative spatial features. Moreover, the BiGRU module extracts essential temporal features inside each lead. The spatial and temporal features from these two modules are fused together as global features for classification. In experiments, MI location and detection were performed under both intra-patient scheme and inter-patient scheme to test the robustness of the proposed framework. Experimental results indicate that our intelligent framework achieved satisfactory performance and demonstrated vital clinical significance.
Feasibility and efficacy of CD19-targeted CAR-T cells with concurrent ibrutinib for CLL after ibrutinib failure.

We previously reported durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) patients treated with CD19-targeted chimeric antigen receptor-engineered T (CD19 CAR-T) cell immunotherapy after ibrutinib failure. Since pre-clinical studies showed that ibrutinib could improve CAR-T cell antitumor efficacy and reduce cytokine release syndrome (CRS), we conducted a pilot study to evaluate the safety and feasibility of administering ibrutinib concurrently with CD19 CAR-T cell immunotherapy. Nineteen CLL patients were included. The median number of prior therapies was 5, and 17 patients (89%) had high-risk cytogenetics (17p deletion and/or complex karyotype). Ibrutinib was planned to begin at least 2 weeks before leukapheresis and continue at least 3 months after CAR-T cell infusion. CD19 CAR-T cell immunotherapy with concurrent ibrutinib was well tolerated; 13 patients (68%) received ibrutinib as planned without dose reduction. The 4-week overall response rate by iwCLL criteria was 83%, and 61% achieved minimal residual disease (MRD)-negative marrow response by IGH sequencing. In this subset, the 1-year OS and PFS probabilities were 86% and 59%, respectively. Compared to CLL patients treated with CAR-T cells without ibrutinib, CAR-T cells with concurrent ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines despite equivalent in vivo CAR-T cell expansion. The 1-year PFS probabilities in all evaluable patients were 38% and 50% after CD19 CAR-T therapy with and without concurrent ibrutinib, respectively (p=0.91). CD19 CAR-T cells with concurrent ibrutinib for R/R CLL were well tolerated, with low CRS severity, and led to high rates of MRD-negative response by IGH sequencing.
The Biological Potential Hidden in Inclusion Bodies

Inclusion bodies (IBs) are protein nanoclusters obtained during recombinant protein production processes, and several studies have demonstrated their potential as biomaterials for therapeutic protein delivery. Nevertheless, IBs have been, so far, exclusively sifted by their biological activity in vitro to be considered in further protein-based treatments in vivo. Matrix metalloproteinase-9 (MMP-9) protein, which has an important role facilitating the migration of immune cells, was used as model protein. The MMP-9 IBs were compared with their soluble counterpart and with MMP-9 encapsulated in polymeric-based micelles (PM) through ionic and covalent binding. The soluble MMP-9 and the MMP-9-ionic PM showed the highest activity values in vitro. IBs showed the lowest activity values in vitro, but the specific activity evolution in 50% bovine serum at room temperature proved that they were the most stable format. The data obtained with the use of an air-pouch mouse model showed that MMP-9 IBs presented the highest in vivo activity compared to the soluble MMP-9, which was associated only to a low and a transitory peak of activity. These results demonstrated that the in vivo performance is the addition of many parameters that did not always correlate with the in vitro behavior of the protein of interest, becoming especially relevant at evaluating the potential of IBs as a protein-based nanomaterial for therapeutic purposes.
Predicting the Landscape of Recombination Using Deep Learning

Abstract Accurately inferring the genome-wide landscape of recombination rates in natural populations is a central aim in genomics, as patterns of linkage influence everything from genetic mapping to understanding evolutionary history. Here, we describe recombination landscape estimation using recurrent neural networks (ReLERNN), a deep learning method for estimating a genome-wide recombination map that is accurate even with small numbers of pooled or individually sequenced genomes. Rather than use summaries of linkage disequilibrium as its input, ReLERNN takes columns from a genotype alignment, which are then modeled as a sequence across the genome using a recurrent neural network. We demonstrate that ReLERNN improves accuracy and reduces bias relative to existing methods and maintains high accuracy in the face of demographic model misspecification, missing genotype calls, and genome inaccessibility. We apply ReLERNN to natural populations of African Drosophila melanogaster and show that genome-wide recombination landscapes, although largely correlated among populations, exhibit important population-specific differences. Lastly, we connect the inferred patterns of recombination with the frequencies of major inversions segregating in natural Drosophila populations.
5-Caffeoylquinic Acid Ameliorates Cognitive Decline and Reduces Aβ Deposition by Modulating Aβ Clearance Pathways in APP/PS2 Transgenic Mice

The accumulation of amyloid β (Aβ) in the brain is a major pathological feature of Alzheimer’s disease (AD). In our previous study, we demonstrated that coffee polyphenols (CPP) prevent cognitive dysfunction and Aβ deposition in the brain of an APP/PS2 transgenic mouse AD model. The underlying mechanisms, however, remain to be elucidated. Here, we investigated the effects of the chronic administration of 5-caffeoylquinic acid (5-CQA), the most abundant component of CPP, on cognitive dysfunction in APP/PS2 mice to identify the role of CPP in Aβ elimination. Relative to the untreated controls, the mice fed a 5-CQA-supplemented diet showed significant improvements in their cognitive function assessed by Y-maze and novel object recognition tests. Histochemical analysis revealed that 5-CQA substantially reduced Aβ plaque formation and neuronal loss in the hippocampi. Moreover, 5-CQA upregulated the gene encoding low-density lipoprotein receptor-related protein 1, an Aβ efflux receptor, and normalized the perivascular localization of aquaporin 4, which facilitates Aβ clearance along the paravascular pathway. These results suggest that 5-CQA reduces Aβ deposition in the brain by modulating the Aβ clearance pathways and ameliorating cognitive decline and neuronal loss in APP/PS2 mice. Thus, 5-CQA may be effective in preventing cognitive dysfunction in AD.
Microbial Ecology from the Himalayan Cryosphere Perspective

Cold-adapted microorganisms represent a large fraction of biomass on Earth because of the dominance of low-temperature environments. Extreme cold environments are mainly dependent on microbial activities because this climate restricts higher plants and animals. Himalaya is one of the most important cold environments on Earth as it shares climatic similarities with the polar regions. It includes a wide range of ecosystems, from temperate to extreme cold, distributed along the higher altitudes. These regions are characterized as stressful environments because of the heavy exposure to harmful rays, scarcity of nutrition, and freezing conditions. The microorganisms that colonize these regions are recognized as cold-tolerant (psychrotolerants) or/and cold-loving (psychrophiles) microorganisms. These microorganisms possess several structural and functional adaptations in order to perform normal life processes under the stressful low-temperature environments. Their biological activities maintain the nutrient flux in the environment and contribute to the global biogeochemical cycles. Limited culture-dependent and culture-independent studies have revealed their diversity in community structure and functional potential. Apart from the ecological importance, these microorganisms have been recognized as source of cold-active enzymes and novel bioactive compounds of industrial and biotechnological importance. Being an important part of the cryosphere, Himalaya needs to be explored at different dimensions related to the life of the inhabiting extremophiles. The present review discusses the distinct facts associated with microbial ecology from the Himalayan cryosphere perspective.
Serum Sclerostin But Not DKK-1 Correlated with Central Arterial Stiffness in End Stage Renal Disease Patients

Sclerostin and dickkopf-1 (DKK1) played a role in the development of cardiovascular diseases and arterial stiffness in chronic kidney disease (CKD) patients but with controversial results of patients in end-stage renal disease (ESRD) including hemodialysis (HD) and peritoneal dialysis (PD). This study aimed to examine the association between the mode of dialysis or the values of sclerostin or DKK1 and carotid-femoral pulse wave velocity (cfPWV) in ESRD patients. There were 122 HD and 72 PD patients enrolled in this study. By a validated tonometry system, cfPWV was measured and then segregated patients into values of >10 m/s as the high central arterial stiffness (AS) group and values ≤ 10 m/s as the control group. Serum levels of sclerostin and DKK1 were measured using a commercial enzyme-linked immunosorbent assay kit. Possible risk factors for the development of AS were analyzed by logistic regression analysis. There were 21 (29.2%) of PD and 53 (43.4%) of HD in the high AS group. Compared to patients in the control group, those in the high AS group were older, had more comorbidities, had higher systolic blood pressure, and had higher serum levels of fasting glucose, C-reactive protein, and sclerostin. Levels of sclerostin (adjusted OR 1.012, 95% CI. 1.006–1.017, p = 0.0001) was found to be an independent predictor of high AS in ESRD patients by multivariate logistic regression analysis. Furthermore, receiver operating characteristic curve analysis showed the optimal cut-off values of sclerostin for predicting AS was 208.64 pmol/L (Area under the curve 0.673, 95% CI: 0.603–0.739, p < 0.001). This study showed that serum levels of sclerostin, but not DKK1 or mode of dialysis, to be a predictor for high central AS in ESRD patients.