Miracle-dz/UniFAR-FTUs huggingface dataset:
Hydroxycarbamide effects on DNA methylation and gene expression in myeloproliferative neoplasms

Hydroxycarbamide (HC, hydroxyurea) is a cytoreductive drug inducing cell cycle blockade. However, emerging evidence suggests that HC plays a role in the modulation of transcription through the activity of transcription factors and DNA methylation. Examining the global mechanism of action of HC in the context of myeloproliferative neoplasms (MPNs), for which HC is the first-line treatment, will provide a better understanding of its molecular effects. To explore the effects of HC genome-wide, transcriptomic analyses were performed on two clinically relevant cell types at different stages of differentiation treated with HC in a murine MPN model. This study was replicated in MPN patients by profiling genome-wide gene expression and DNA methylation using patient blood samples collected longitudinally, before and following HC exposure. The effects of HC on the transcriptome were not only associated with cell cycle interruption but also with hematopoietic functions. Moreover, a group of genes were restored to normal expression levels in murine hematopoietic stem cells (HSCs) following drug treatment, including the master regulator of hematopoiesis, RUNX1. In humans, HC significantly modifies DNA methylation levels in HSCs at several distal regulatory regions, which we show to be associated with SPI1 binding sites and at the SPI1 locus itself. We have identified novel targets of HC that include pivotal transcription factors involved in hematopoiesis, and for the first time we report abnormal methylation patterns in MPN patients at the master regulator gene SPI1 and its distal binding sites, which HC is able to restore to normal levels.
Hypoimmune induced pluripotent stem cell–derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice

Significance Precise gene editing allows engineering of immune receptors and ligands to reduce the immunogenicity of cells, and strategies for the generation of immune-evasive stem cell sources are currently being developed. This article describes the translational aspect of generating universally transplantable, disease-specific, therapeutic cell products. We provide proof of concept that immune-engineered cells can treat major cardiovascular and pulmonary diseases in fully allogeneic subjects without utilizing any immunosuppression. The translational aspect is emphasized by showing improvements in clinically relevant outcome measures, which are widely used in human trials. Depending on the feasibility of large-scale manufacturing of universal cell therapeutics, this approach could enable cost-effective cell therapy. The emerging field of regenerative cell therapy is still limited by the few cell types that can reliably be differentiated from pluripotent stem cells and by the immune hurdle of commercially scalable allogeneic cell therapeutics. Here, we show that gene-edited, immune-evasive cell grafts can survive and successfully treat diseases in immunocompetent, fully allogeneic recipients. Transplanted endothelial cells improved perfusion and increased the likelihood of limb preservation in mice with critical limb ischemia. Endothelial cell grafts transduced to express a transgene for alpha1-antitrypsin (A1AT) successfully restored physiologic A1AT serum levels in mice with genetic A1AT deficiency. This cell therapy prevented both structural and functional changes of emphysematous lung disease. A mixture of endothelial cells and cardiomyocytes was injected into infarcted mouse hearts, and both cell types orthotopically engrafted in the ischemic areas. Cell therapy led to an improvement in invasive hemodynamic heart failure parameters. Our study supports the development of hypoimmune, universal regenerative cell therapeutics for cost-effective treatments of major diseases.
AUXIN RESPONSE FACTORS 6 and 17 control the flag leaf angle in rice by regulating secondary cell wall biosynthesis of lamina joints

Abstract Flag leaf angle impacts the photosynthetic capacity of densely grown plants and is thus an important agronomic breeding trait for crop architecture and yield. The hormone auxin plays a key role in regulating this trait, yet the underlying molecular and cellular mechanisms remain unclear. Here, we report that two rice (Oryza sativa) auxin response factors (ARFs), OsARF6 and OsARF17, which are highly expressed in lamina joint tissues, control flag leaf angle in response to auxin. Loss-of-function double osarf6 osarf17 mutants displayed reduced secondary cell wall levels of lamina joint sclerenchymatous cells (Scs), resulting in an exaggerated flag leaf angle and decreased grain yield under dense planting conditions. Mechanical measurements indicated that the mutant lamina joint tissues were too weak to support the weight of the flag leaf blade, resembling the phenotype of the rice increased leaf angle1 (ila1) mutant. We demonstrate that OsARF6 and OsARF17 directly bind to the ILA1 promoter independently and synergistically to activate its expression. In addition, auxin-induced ILA1 expression was dependent on OsARF6 and OsARF17. Collectively, our study reveals a mechanism that integrates auxin signaling with the secondary cell wall composition to determine flag leaf angle, providing breeding targets in rice, and potentially other cereals, for this key trait.
The Swedish Health Promoting Healthcare network and the built environment

Abstract The Health Promoting Hospitals (HPH) networks, founded by the World Health Organisation, support the introduction of health promotion in healthcare. This development involves the creation of a health promoting built environment. However, few studies have explored the HPH in relation to the built environments, and it is unclear how HPH-networks incorporate the built environment in their work. The study therefore examined the Swedish HPH-Network in relation to the built environment. The mixed-method study included data from (i) key online material from the Swedish network, (ii) a survey with open-ended questions of representatives of the networks’ workgroups and (iii) semi-structured interviews with the built environment workgroup. The study showed that the built environment is unevenly and incoherently incorporated in the network. Moreover, there is more attention for healing and healthy rather than health-promotive strategies, indicating a knowledge gap. Descriptions of the health promoting built environment are diverse, and address design features, design strategies or indicate places for health promotion interventions. The descriptions of the built environment are combined with various HPH goals and population groups. To utilize the built environment as a resource for HPHs, the networks should consider incorporating the built environment in documents and action plans at all organizational levels.
author-version of: Alkaloids from Lepidium meyenii (Maca), structural revision of macaridine and UPLC-MS/MS feature-based molecular networking

Lepidium meyenii Walp. , known as Peruvian ginseng, is widely used in ethnomedicine. To date, L. meyenii is cultivated worldwide at high-altitude and is commonly used as a food supplement. However, its medicinal value is still controversial and its mechanism of action remains unknown, due to limited knowledge about the phytochemical constituents of this plant species. In this study, a multidisciplinary approach comprising conventional NMR-and HRMS-based structure elucidation, quantum mechanical calculation of NMR chemical shifts and UPLC-MS/MS feature-based molecular networking was applied to analyse the phytochemical profile of L. meyenii . In the current work, three previously undescribed imidazole alkaloids were identified using extensive spectroscopic techniques (HRMS, NMR), for which the names lepidiline E, F and G were adopted. In addition, two amidine alkaloids were reported, representing an undescribed class of alkaloids in L. meyenii , and 1,2,3,4-tetrahydro-β -carboline-3-carboxylic acid, a well-known β - carboline alkaloid, was also isolated from L. meyenii for the first time. Molecular networks of imidazole, amidine and β -carboline alkaloids in L. meyenii were constructed by the Global Natural Products Social Molecular Networking (GNPS) web platform, resulting in the tentative identification of three undescribed analogues. In addition, the structure of a previously reported compound named ‘macaridine’ was revised as macapyrrolin C based on density functional theory (DFT) calculations and comprehensive comparison of NMR data.
Nanoporous Materials: From Catalysis and Hydrogen Storage to Wastewater Treatment

Porous inorganic solids have found great utility as catalysts and sorption media because of their large internal surface area, i.e. the presence of voids of controllable dimensions at the atomic, molecular, and nanometer scales. With increasing environmental concerns worldwide, nanoporous materials have become more important and useful for the separation of polluting species and the recovery of useful ones. Their prospective applications include the use as templates for the production of electrically conducting nanowires and also for highly selective biosensors and biomembrane materials. Inorganic-organic or hybrid nanoporous crystalline materials have recently attracted much attention and increasing interest due to their promising use in gas processing and hydrogen storage. This review covers our recent developments in the synthesis, characterisation and property evaluation of new nanoporous inorganic and some hybrid solids with the emphasis on the silica and phosphate-based frameworks by using hydrothermal and microvawe procedures with X-ray diffraction, spectroscopic (XAS, NMR) and electron microscopy characterisation techniques. The functionalisation of nanoporous materials by physical and/or chemical treatments, studies of their fundamental properties, such as catalytic effects or adsorption and their applications, emphasising (1) catalysis, (2) hydrogen and energy storage, and (3) environmental pollution control are also reviewed.
Prognostic value of circulating tumor cells in patients with bladder cancer: A meta-analysis

Background Circulating tumor cells (CTCs) have been considered diagnostic and prognostic biomarkers for urothelial cancer. However, the prognostic role of CTCs in bladder cancer (BC) remains controversial. Here, we conducted a meta-analysis to evaluate the prognostic significance of CTCs for patients with BC. Methods All studies relevant to this topic were searched in the PubMed, Embase, and Web of Science databases. The hazard ratio (HR) and 95% confidence interval (95% CI) were set as effect measures. The outcomes were overall survival (OS), cancer-free survival (CSS), progression-free survival (PFS)/time to progression (TTP), and disease-free survival (DFS)/recurrence-free survival (RFS)/time to first recurrence (TFR). All analyses were conducted in STATA 15.1. Results Eleven eligible studies comprising 1,062 patients with BC were included in this meta-analysis. Overall analyses showed that CTC-positive patients had poorer survival (OS: HR 3.88, 95% CI 2.52–5.96, p < 0.001; CSS: HR 3.89, 95% CI 2.15–7.04, p < 0.001) and more aggressive progression (PFS/TTP: HR 5.92, 95% CI 3.75–9.35, p < 0.001; DFS/RFS/TFR: HR 4.57, 95% CI 3.34–6.25, p < 0.001) than CTC-negative patients. Subgroup analyses according to the number of patients, detection method, positivity rate, and follow-up time revealed that the presence of CTCs predicted a high risk of mortality and disease progression in most subgroups. Conclusion The meta-analysis confirmed that CTCs are a promising prognostic biomarker of poor survival and aggressive tumor progression for patients with BC. Prospero registration number CRD42021224865.
Driving motor cortex oscillations modulates bradykinesia in Parkinson's disease

In Parkinson's disease (PD) patients, beta (β) and gamma (γ) oscillations are altered in the basal ganglia, and this abnormality contributes to the pathophysiology of bradykinesia. However, it is unclear whether β and γ rhythms at the primary motor cortex (M1) level influence bradykinesia. Transcranial alternating current stimulation (tACS) can modulate cortical rhythms by entraining endogenous oscillations. We tested whether β- and γ-tACS on M1 modulate bradykinesia in PD patients by analyzing the kinematic features of repetitive finger tapping, including movement amplitude, velocity, and sequence effect, recorded during β-, γ-, and sham tACS. We also verified whether possible tACS-induced bradykinesia changes depended on modifications in specific M1 circuits, as assessed by short-interval intracortical inhibition (SICI) and short-latency afferent inhibition (SAI). Patients were studied OFF and ON dopaminergic therapy. Results were compared to those obtained in a group of healthy subjects (HS). In patients, movement velocity significantly worsened during β-tACS and movement amplitude improved during γ-tACS, while the sequence effect did not change. In addition, SAI decreased (reduced inhibition) during β-tACS and SICI decreased during both γ- and β-tACS in PD. The effects of tACS were comparable between OFF and ON sessions. In patients OFF therapy, the degree of SICI modulation during β- and γ-tACS correlated with movement velocity and amplitude changes. Moreover, there was a positive correlation between the effect of γ-tACS on movement amplitude and motor symptoms severity. Our results show that cortical β and γ oscillations are relevant in the pathophysiology of bradykinesia in PD and that changes in inhibitory GABA-A-ergic interneuronal activity may reflect compensatory M1 mechanisms to counteract bradykinesia. In conclusion, abnormal oscillations at the M1 level of the basal ganglia-thalamo-cortical network play a relevant role in the pathophysiology of bradykinesia in PD.
A Sequential Niche Multimodal Conformation Sampling Algorithm for Protein Structure Prediction

Motivation Massive local minima on the protein energy surface often causes traditional conformation sampling algorithms to be easily trapped in local basin regions, because they are difficult to stride over high-energy barriers. Also, the lowest energy conformation may not correspond to the native structure due to the inaccuracy of energy models. This study investigates whether these two problems can be alleviated by a sequential niche technique without loss of accuracy. Results A sequential niche multimodal conformation sampling algorithm for protein structure prediction (SNfold) is proposed in this study. In SNfold, a derating function is designed based on the knowledge learned from the previous sampling and used to construct a series of sampling-guided energy functions. These functions then help the sampling algorithm stride over high-energy barriers and avoid the re-sampling of the explored regions. In inaccurate protein energy models, the high- energy conformation that may correspond to the native structure can be sampled with successively updated sampling-guided energy functions. The proposed SNfold is tested on 300 benchmark proteins and 24 CASP13 FM targets. Results show that SNfold is comparable with Rosetta restrained by distance (Rosetta-dist) and C-QUARK. SNfold correctly folds (TM-score ≥ 0.5) 231 out of 300 proteins. In particular, compared with Rosetta-dist protocol, SNfold achieves higher average TM- score and improves the sampling efficiency by more than 100 times. On the 24 CASP13 FM targets, SNfold is also comparable with four state-of-the-art methods in the CASP13 server group. As a plugin conformation sampling algorithm, SNfold can be extended to other protein structure prediction methods. Availability The source code and executable versions are freely available at https://github.com/iobio-zjut/SNfold. Contact zgj@zjut.edu. cn
Analysis of individual differences in pelvic and spine alignment in seated posture and impact on the seatbelt kinematics using human body model

Analysis using human body models has been performed to reduce the impact of accidents; however, no analysis has shown a relationship between lumbar and pelvic/spine angle and seat belts in reducing human damage from accidents. Lumbar and pelvic/spine angles were measured in 75 individuals and the measurements were used to create three different angles for the Total Human Model for Safety model. In the present study, we focused on lumber lordosis (LL) and pelvic angle (PA). A normal distribution and histogram were used for analysis of PA (01, 10, and 50). The Total Human Model for Safety, including LL and PA, was corrected using finite element software. Simulations were conducted under the conditions of the Japan New Car Assessment Programme (JNCAP) 56 kph full lap frontal impact. Using the results of the FEM, the amount of lap-belt cranial sliding-up, anterior movement of the pelvis, posterior tilt of the pelvis, head injury criterion (HIC), second cervical vertebrae (C2) compressive load, C2 moment, chest deflectiou (upper, middle, and lower), left and right femur load, and shoulder belt force were measured. The lap-belt cranial sliding-up was 1.91 and 2.37 for PA10 and PA01, respectively, compared to PA50; the anterior movement of the pelvis was 1.08 and 1.12 for PA10 and PA01, respectively; and the posterior tilt of the pelvis was 1.1 and 1.18 for PA10 and PA01, respectively. HIC was 1.13 for PA10 and 1.58 for PA01; there was no difference in C2 compressive load by PA, but C2 moment increased to 1.59 for PA10 and 2.72 for PA01. It was found that as LL increases and the PA decreases, the seat belt becomes likely to catch the iliac bone, making it harder to cause injury. This study could help to reconsider the safe seat and seatbelt position in the future.
Transcriptomic and metabolomic profiles of Zea mays fed with urea and ammonium

Abstract The simultaneous presence of different N‐forms in the rhizosphere leads to beneficial effects on nitrogen (N) nutrition in plants. Although widely used as fertilizers, the occurrence of cross connection between urea and ammonium nutrition has been scarcely studied in plants. Maize fed with a mixture of urea and ammonium displayed a better N‐uptake efficiency than ammonium‐ or urea‐fed plants (Buoso et al., Plant Physiol Biochem, 2021a; 162: 613–623). Through multiomic approaches, we provide the molecular characterization of maize response to urea and ammonium nutrition. Several transporters and enzymes involved in N‐nutrition were upregulated by all three N‐treatments (urea, ammonium, or urea and ammonium). Already after 1 day of treatment, the availability of different N‐forms induced specific transcriptomic and metabolomic responses. The combination of urea and ammonium induced a prompt assimilation of N, characterized by high levels of some amino acids in shoots. Moreover, ZmAMT1.1a, ZmGLN1;2, ZmGLN1;5, ZmGOT1, and ZmGOT3, as well transcripts involved in glycolysis‐TCA cycle were induced in roots by urea and ammonium mixture. Depending on N‐form, even changes in the composition of phytohormones were observed in maize. This study paves the way to formulate guidelines for the optimization of N fertilization to improve N‐use efficiency in maize and therefore limit N‐losses in the environment.
New insights into the evolution of human Y chromosome palindromes through mutation and gene conversion

Abstract About one-quarter of the euchromatic portion of the male-specific region of the human Y chromosome consists of large duplicated sequences that are organized in eight palindromes (termed P1–P8), which undergo arm-to arm gene conversion, a proposed mechanism for maintaining their sequence integrity. Although the relevance of gene conversion in the evolution of palindromic sequences has been profoundly recognized, the dynamic of this mechanism is still nuanced. To shed light into the evolution of these genomic elements, we performed a high-depth (50×) targeted next-generation sequencing of the palindrome P6 in 157 subjects belonging to the most divergent evolutionary lineages of the Y chromosome. We found 118 new paralogous sequence variants, which were placed into the context of a robust Y chromosome phylogeny based on 7240 SNPs of the X-degenerate region. We mapped along the phylogeny 80 gene conversion events that shaped the diversity of P6 arms during recent human history. In contrast to previous studies, we demonstrated that arm-to-arm gene conversion, which occurs at a rate of 6.01 × 10 −6 conversions/base/year, is not biased toward the retention of the ancestral state of sequences. We also found a significantly lower mutation rate of the arms (6.18 × 10−10 mutations/base/year) compared with the spacer (9.16 × 10−10 mutations/base/year), a finding that may explain the observed higher inter-species conservation of arms, without invoking any bias of conversion. Finally, by formally testing the mutation/conversion balance in P6, we found that the arms of this palindrome reached a steady-state equilibrium between mutation and gene conversion.
Measurement of hypoxia in the lung in idiopathic pulmonary fibrosis: an F-MISO PET/CT study

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease, with an incidence of ∼1 per 10 000 per year, and a poor prognosis with limited treatments [1]. The role of hypoxia in disease progression is unclear. This study found no detectable 18F-MISO signal in fibrotic lung despite some histological expression of hypoxic markers, and concludes that in these IPF patients, the degree of hypoxia is too low to be detectable with 18F-MISO-PET/CT https://bit.ly/3wLJwja
Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes

OBJECTIVES Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D. RESEARCH DESIGN AND METHODS In a case-control study, 817 patients with T1D from three large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m2 per year decline in estimated glomerular filtration rate (eGFR), while control was defined as <1 mL/min/1.73 m2 per year decline over a minimum 4-year follow-up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform. RESULTS At individual lipids, free fatty acid (FFA)20:2 was directly and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps, and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min/1.73 m2. A multilipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved the C-statistic of the clinical model from 0.816 to 0.841 (P = 0.039). Observations were confirmed in the validation subset. CONCLUSIONS Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at the sn1 carbon of the phospholipids’ glycerol backbone as an independent predictor of rapid GFR decline in T1D.
Early response and safety of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in patients who do not meet IMbrave150 eligibility criteria

A clinical trial (IMbrave150) indicated the efficacy and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma (HCC). In this study, we evaluated this therapeutic combination in a real‐world setting, with a focus on patients who did not meet the IMbrave150 eligibility criteria.