Miracle-dz/UniFAR-FTUs huggingface dataset:
Learning stable and predictive structures in kinetic systems

Significance Many real-world systems can be described by a set of differential equations. Knowing these equations allows researchers to predict the system’s behavior under interventions, such as manipulations of initial or environmental conditions. For many complex systems, the differential equations are unknown. Deriving them by hand is infeasible for large systems, and data science is used to learn them from observational data. Existing techniques yield models that predict the observational data well, but fail to explain the effect of interventions. We propose an approach, CausalKinetiX, that explicitly takes into account stability across different experiments. This allows us to draw a more realistic picture of the system’s underlying causal structure and is a first step toward increasing reproducibility. Learning kinetic systems from data is one of the core challenges in many fields. Identifying stable models is essential for the generalization capabilities of data-driven inference. We introduce a computationally efficient framework, called CausalKinetiX, that identifies structure from discrete time, noisy observations, generated from heterogeneous experiments. The algorithm assumes the existence of an underlying, invariant kinetic model, a key criterion for reproducible research. Results on both simulated and real-world examples suggest that learning the structure of kinetic systems benefits from a causal perspective. The identified variables and models allow for a concise description of the dynamics across multiple experimental settings and can be used for prediction in unseen experiments. We observe significant improvements compared to well-established approaches focusing solely on predictive performance, especially for out-of-sample generalization.
Impact of Glucoraphanin-Mediated Activation of Nrf2 on Non-Alcoholic Fatty Liver Disease with a Focus on Mitochondrial Dysfunction

Non-alcoholic fatty liver disease (NAFLD) is a common disease in Western nations and ranges in severity from steatosis to steatohepatitis (NASH). NAFLD is a genetic-environmental-metabolic stress-related disease of unclear pathogenesis. NAFLD is triggered by caloric overconsumption and physical inactivity, which lead to insulin resistance and oxidative stress. A growing body of evidence indicates that mitochondrial dysfunction plays a critical role in the pathogenesis of NAFLD. Mitochondrial dysfunction not only promotes fat accumulation, but also leads to generation of reactive oxygen species (ROS) and lipid peroxidation, resulting in oxidative stress in hepatocytes. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important modulator of antioxidant signaling that serves as a primary cellular defense against the cytotoxic effects of oxidative stress. The pharmacological induction of Nrf2 ameliorates obesity-associated insulin resistance and NAFLD in a mouse model. Sulforaphane and its precursor glucoraphanin are derived from broccoli sprouts and are the most potent natural Nrf2 inducers—they may protect mitochondrial function, thus suppressing the development of NASH. In this review, we briefly describe the role of mitochondrial dysfunction in the pathogenesis of NASH and the effects of glucoraphanin on its development.
Responses of Melilotus officinalis Growth to the Composition of Different Topsoil Substitute Materials in the Reclamation of Open-Pit Mining Grassland Area in Inner Mongolia

The purpose of this study was to reveal that reconstructed soil composed of different types and proportions of materials has different effects on the growth of Melilotus officinalis, and to determine the most suitable formula of reconstructed soil materials to use for soil replacement. Using topsoil, coal gangue, fly ash, and rock and soil stripping materials from Shengli Mining Area of Inner Mongolia as raw materials, stratified and mixed pot experiments were carried out in a greenhouse using different proportions of each material. The differences in the aboveground biomass, leaf width, plant height, and root length of Melilotus officinalis plants in pot experiments were then compared using analysis of variance. The results showed that using different combinations of materials in different proportions affected the growth status of Melilotus officinalis, and their effects on biomass were greater than their effects on plant height, root length, and leaf width. When topsoil, coal gangue, and rock and soil stripping materials were mixed at a ratio of 3:3:4, respectively, the biomass of Melilotus officinalis increased by nearly 30% compared with that of plants potted in pure topsoil. When the content of coal gangue was controlled to be 30%, the content of fly ash was below 10%, and the content of rock and soil stripping materials was below 40%, the reconstructed soil conditions clearly promoted the growth of Melilotus officinalis. Coal gangue, rock and soil stripping materials, and fly ash can thus be used as substitutes for topsoil. Mixing soil reconstruction materials in the optimal proportion can solve the scarcity of topsoil in the grassland mining areas in the study region and, at the same time, can effectively improve the utilization of solid waste in this mining area.
Model Optimization and In Silico Analysis of Potential Dipeptidyl Peptidase IV Antagonists from GC-MS Identified Compounds in Nauclea latifolia Leaf Extracts

Dipeptidyl peptidase IV (DPP-IV) is a pharmacotherapeutic target in type 2 diabetes. Inhibitors of this enzyme constitute a new class of drugs used in the treatment and management of type 2 diabetes. In this study, phytocompounds in Nauclea latifolia (NL) leaf extracts, identified using gas chromatography–mass spectroscopy (GC-MS), were tested for potential antagonists of DPP-IV via in silico techniques. Phytocompounds present in N. latifolia aqueous (NLA) and ethanol (NLE) leaf extracts were identified using GC–MS. DPP-IV model optimization and molecular docking of the identified compounds/standard inhibitors in the binding pocket was simulated. Drug-likeness, pharmacokinetic and pharmacodynamic properties of promising docked leads were also predicted. Results showed the presence of 50 phytocompounds in NL extracts of which only 2-O-p-methylphenyl-1-thio-β-d-glucoside, 3-tosylsedoheptulose, 4-benzyloxy-6-hydroxymethyl-tetrahydropyran-2,3,5-triol and vitamin E exhibited comparable or better binding iGEMDOCK and AutoDock Vina scores than the clinically prescribed standards. These four compounds exhibited promising drug-likeness as well as absorption, distribution, metabolism, excretion and toxicity (ADMET) properties suggesting their candidature as novel leads for developing DPP-IV inhibitors.
Neonatal weight loss and gain patterns in caesarean section born infants: integrative systematic review

Abstract There is evidence that caesarean section delivery can impact on neonatal weight loss and weight gain patterns in the first 5 days of life. We conducted an integrative systematic review to examine the association of mode of delivery on early neonatal weight loss. Pubmed, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Excerpta Medica dataBASE, and Medical Literature Analysis and Retrieval System Online were searched for relevant papers published before June 2019. Reference lists from the relevant papers were then backwards and forwards searched. As neonatal weight loss was reported in different formats, a meta‐analysis could not be carried out. Most studies did not distinguish between elective and emergency caesarean sections or instrumental and nonassisted vaginal deliveries. Seven papers were included. All papers except one found that caesarean section was associated with higher weight loss in the early days of life. Two papers presented data from studies on babies followed up to 1 month. One study found that on day 25, babies born by caesarean section had significantly higher weight gain than those born vaginally, while another found that by day 28, babies born vaginally gained more weight per day (11.9 g/kg/day) than those born by caesarean section (10.9 g/kg/day; p = .02). Overall, infants born by caesarean section lost more weight than those born vaginally, but due to the small number of studies included, more are needed to look at this difference and why it may occur. This discrepancy in weight between the two groups may be corrected over time, but future studies will need larger sample sizes and longer follow‐up periods to examine this.
化疗联合异基因自然杀伤细胞巩固治疗低中危急性髓系白血病的疗效观察

目的 评价巩固化疗联合异基因NK细胞输注治疗低中危急性髓系白血病（AML）的疗效。 方法 回顾性分析2014年1月至2019年6月北京大学人民医院诊治的23例经化疗达血液学完全缓解（CR），且巩固治疗3个疗程后，应用巩固化疗联合异基因NK细胞回输治疗的低中危AML患者，对照组为1∶2配对的46例AML患者，配对因素为患者的性别、年龄、诊断、预后危险分层、诱导CR及NK细胞输注前巩固化疗的疗程数。 比较两组微小残留病（MRD）转阴率、复发率、无白血病生存（LFS）及总生存（OS）。 结果 治疗组23例低中危AML患者于巩固化疗第4~7个疗程共输注NK细胞45次，中位NK细胞输注数量7. 5（6.6~8.6）×109/L，NK细胞中位存活率95. 4%（93.9%~96.9%），中位扩增倍数141. 1（86.1~171.1），其中中位CD3−CD56+细胞数5. 0（1.4~6.4）×109/L，占回输细胞总数的76. 8%（30.8%~82.9%）；CD3+CD56+细胞数0. 55（0.24~1.74）×109/L，占回输细胞总数的8. 8%（4.9%~20.9%）。 NK细胞输注前，治疗组MRD阳性患者为9例（39.1%），对照组MRD阳性患者为19例（41.3%），两组间差异无统计学意义（χ2=0.030，P=0.862）。 治疗组输注NK细胞前后疗效评估与同期对照组对比，MRD阴性转阳性比例两组差异无统计学意义[14.3%（2/14）对22. 2%（6/27），χ2=0.037，P=0.847]。 治疗组MRD由阳性转为阴性的患者占66. 7%（6/9），明显高于对照组的10. 5%（2/19）（χ2=6.811，P=0.009）。 其中治疗组有1例MRD阴性患者发生了形态学复发，对照组有2例MRD阳性患者形态学复发。 截至末次随访，中位随访35（10~59）个月，治疗组与对照组MRD阴性患者比例差异无统计学意义[43.5%（10/23）对43.5%（20/46），χ2=1.045，P=0.307]。 在形态学复发方面，虽然两组差异无统计学意义，但是治疗组形态学复发患者比例明显低于对照组[30.4%（7/23）对50. 2%（24/46），χ2=2.929，P=0.087]。 治疗组预计3年LFS率为（65.1±11.1）%，明显高于对照组的（50.0±7.4）%（P=0.047）。 治疗组、对照组的预计3年OS率分别为（78.1±10.2）%、（65.8±8.0）%（P=0.212）。 结论 巩固化疗联合异基因NK细胞输注可能有助于低中危AML患者达到更深层次的缓解，减少远期复发。
Toxicity assessment of nano‐TiO2 in Apis mellifera L., 1758: histological and immunohistochemical assays

The aim of this study was to evaluate the toxicity of titanium dioxide nanoparticles (TiO2NPs) by short‐term toxicity tests in Apis mellifera, considered an excellent bioindicator organism mainly due to its sensitivity. Bees have been exposed to several concentrations of TiO2NPs (1 × 10−3, 1 × 10−4, 1 × 10−5, 1 × 10−6 mg/10 ml) for 10 days. Morphostructural and histological assays were done on gut and honey sac. The research of exposure biomarkers like metallothioneins 1 (MT1) and Heat Shock Protein 70 (HSP70) was performed to verify if a detoxification mechanism has been activated in the exposed animals. No histological alteration on the epithelium of the gut and honey sac were observed in exposed samples. A significant positivity for anti‐MT1 antibody was observed only in the honey sac cells. A weak positivity for HSP70 was observed in both structures analyzed. In several studies have shown the non‐toxicity of TiO2NPs on other model organisms, in our study, titanium dioxide nanoparticles was proven to be highly toxic at the highest concentration tested (100% of lethality to 1 × 10−3 mg/10 ml) and moderately toxic at lower concentrations. Honey bees proved to be excellent models for study of NPs toxicity and for monitoring environment.
White adipose tissue mitochondrial metabolism in health and in obesity

White adipose tissue is one of the largest organs of the body. It plays a key role in whole‐body energy status and metabolism; it not only stores excess energy but also secretes various hormones and metabolites to regulate body energy balance. Healthy adipose tissue capable of expanding is needed for metabolic well‐being and to prevent accumulation of triglycerides to other organs. Mitochondria govern several important functions in the adipose tissue. We review the derangements of mitochondrial function in white adipose tissue in the obese state. Downregulation of mitochondrial function or biogenesis in the white adipose tissue is a central driver for obesity‐associated metabolic diseases. Mitochondrial functions compromised in obesity include oxidative functions and renewal and enlargement of the adipose tissue through recruitment and differentiation of adipocyte progenitor cells. These changes adversely affect whole‐body metabolic health. Dysfunction of the white adipose tissue mitochondria in obesity has long‐term consequences for the metabolism of adipose tissue and the whole body. Understanding the pathways behind mitochondrial dysfunction may help reveal targets for pharmacological or nutritional interventions that enhance mitochondrial biogenesis or function in adipose tissue.
Phospholipid Component Defines Pharmacokinetic and Pharmacodynamic Properties of Synthetic High-Density Lipoproteins

Synthetic high-density lipoprotein (sHDL) nanoparticles composed of apolipoprotein A-I mimetic peptide and phospholipids have been shown to reduce atherosclerosis in animal models. Cholesterol is mobilized from atheroma macrophages by sHDL into the blood compartment and delivered to the liver for elimination. Historically, sHDL drug discovery efforts were focused on optimizing peptide sequences for interaction with cholesterol cellular transporters rather than understanding how both sHDL components, peptide and lipid, influence its pharmacokinetic and pharmacodynamic profiles. We designed two sets of sHDL having either identical phospholipid but variable peptide sequences with different plasma stability or identical peptide and phospholipids with variable fatty acid chain length and saturation. We found that sHDL prepared with proteolytically stable 22A-P peptide had 2-fold longer circulation half-time relative to the less stable 22A peptide. Yet, longer half-life did not translate into any improvement in cholesterol mobilization. In contrast, sHDL with variable phospholipid compositions showed significant differences in phospholipid PK, with distearoyl phosphatidylcholine-based sHDL demonstrating the longest half-life of 6.0 hours relative to 1.0 hour for palmitoyl-oleoyl phosphatidylcholine-based sHDL. This increase in half-life corresponded to an approx. 6.5-fold increase in the area under the curve for the mobilized cholesterol. Therefore, the phospholipid component in sHDL plays a major role in cholesterol mobilization in vivo and should not be overlooked in the design of future sHDL. SIGNIFICANCE STATEMENT The phospholipid composition in sHDL plays a critical role in determining half-life and cholesterol mobilization in vivo.
Do differences in developmental mode shape the potential for local adaptation?

Future climate change is leading to the redistribution of life on Earth as species struggle to cope with rising temperatures. Local adaptation allows species to become locally optimised and persist despite environmental selection, but the extent to which this occurs in nature may be limited by dispersal and gene flow. Congeneric marine gastropod species (Littorina littorea and L. saxatilis) with markedly different developmental modes were collected from across a latitudinal thermal gradient to explore the prevalence of local adaptation to temperature. The acute response of metabolic rate (using oxygen consumption as a proxy) to up-ramping and down-ramping temperature regimes between 6-36ºC was quantified for five populations of each species. The highly dispersive L. littorea exhibited minimal evidence of local adaptation to the thermal gradient, with no change in thermal optimum (Topt) or thermal breadth (Tbr) and a decline in maximal performance (μmax) with increasing latitude. In contrast, the direct developing L. saxatilis displayed evidence of local optimisation, although these varied idiosyncratically with latitude, suggesting a suite of selective pressures may be involved in shaping thermal physiology in this relatively sedentary species. Our results show that the biogeography of thermal traits can differ significantly between related species, and show that inter-population differences in thermal performance do not necessarily follow simple patterns which may be predicted based on latitudinal changes in environmental temperatures. Further research is clearly required to better understand the mechanisms that can lead to the emergence of local adaptation in marine systems and allow improved predictions of species redistribution in response to climate change.
Chromosome-Scale Genome Assembly of Two Australian Nannochloropsis oceanica Isolates Exhibiting Superior Lipid Characteristics

Nannochloropsis oceanica strains BR2 and KB1 are microalgal isolates from brackish water in the Brisbane River and a coastal rock pool at the Sunshine Coast in Australia which display superior productivity at high temperatures. We used long-read sequencing to sequence their genomes and to facilitate elucidation of loci associated with these traits. ABSTRACT Nannochloropsis oceanica strains BR2 and KB1 are microalgal isolates from brackish water in the Brisbane River and a coastal rock pool at the Sunshine Coast in Australia which display superior productivity at high temperatures. We used long-read sequencing to sequence their genomes and to facilitate elucidation of loci associated with these traits.
mPRα mediates P4/Org OD02‐0 to improve the sensitivity of lung adenocarcinoma to EGFR‐TKIs via the EGFR‐SRC‐ERK1/2 pathway

The discovery of epidermal growth factor receptor (EGFR) mutations has made EGFR tyrosine kinase inhibitors (EGFR‐TKIs) a milestone in the treatment for advanced non–small cell lung cancer (NSCLC). However, patients lacking EGFR mutations are not sensitive to EGFR‐TKI treatment and the emergence of secondary resistance poses new challenges for the targeted therapy of lung cancer. In this study, we identified that the expression of membrane progesterone receptor α (mPRα) was associated with EGFR mutations in lung adenocarcinoma patients and subsequently affected the efficacy of EGFR‐TKIs. Progesterone (P4) or its derivative Org OD02‐0 (Org), which is mediated by mPRα, increases the function of EGFR‐TKIs to suppress the proliferation, migration, and invasion of lung adenocarcinoma cells in vitro and in vivo. In addition, the mPRα pathway triggers delayed resistance to EGFR‐TKIs. Mechanistic investigations demonstrated that the mPRα pathway can crosstalk with the EGFR pathway by activating nongenomic effects to inhibit the EGFR‐SRC‐ERK1/2 pathway, thereby promoting antitumorigenic effects. In conclusion, our data describe an essential role for mPRα in improving sensitivity to EGFR‐TKIs, thus rationalizing its potential as a therapeutic target for lung adenocarcinomas.
Medical Eligibility for Contraception in Women at Increased Risk.

BACKGROUND Most women of child-bearing age want a safe method of contraception. Numerous methods are available, with different modes of application. In situations involving particular risks, the selection of the right method poses a special challenge. METHODS Contraceptive methods for use in various situations with increased risk are presented in the light of a selective review of the literature, including the relevant current guidelines. RESULTS The current recommendations of the World Health Organization (WHO) can be used to determine whether any particular contraceptive method is applicable. In particular, the use of combined hormonal contraceptives may be contraindicated in the presence of certain risk factors, especially when there is an elevated risk of thromboembolism. Situations of increased risk include a genetic predisposition to thrombophilia, diabetes mellitus, age over 35, and nicotine abuse. Careful attention to the choice of an appropriate contraceptive agent is also necessary for women with hypertension, hepatic tumors, headache (including migraine), and epilepsy. For such patients, good alternatives include the use of a gestagen (=progesterone) single-agent preparation, an intrauterine device, or a pessary. CONCLUSION Meticulous history-taking and clinical examination are important components of contraceptive counseling that enable the identification of all potential risk factors. In situations of increased risk, decisions must be taken individually. Depending on the nature of the patient's underlying illness, interdisciplinary collaboration may be advisable. Even in situations of increased risk, an appropriated risk-benefit analysis should make it possible to find a suitable contraceptive method for any woman who needs one.
Revealing the Importance of Aging, Environment, Size and Stabilization Mechanisms on the Stability of Metal Nanoparticles: A Case Study for Silver Nanoparticles in a Minimally Defined and Complex Undefined Bacterial Growth Medium

Although the production and stabilization of metal nanoparticles (MNPs) is well understood, the behavior of these MNPs (possible aggregation or disaggregation) when they are intentionally or unintentionally exposed to different environments is a factor that continues to be underrated or overlooked. A case study is performed to analyze the stability of silver nanoparticles (AgNPs)—one of the most frequently used MNPs with excellent antibacterial properties—within two bacterial growth media: a minimally defined medium (IDL) and an undefined complex medium (LB). Moreover, the effect of aging, size and stabilization mechanisms is considered. Results clearly indicate a strong aggregation when AgNPs are dispersed in IDL. Regarding LB, the 100 nm electrosterically stabilized AgNPs remain stable while all others aggregate. Moreover, a serious aging effect is observed for the 10 nm electrostatically stabilized AgNPs when added to LB: after aggregation a restabilization effect occurs over time. Generally, this study demonstrates that the aging, medium composition (environment), size and stabilization mechanism—rarely acknowledged as important factors in nanotoxicity studies—have a profound impact on the AgNPs stabilization and should gain more attention in scientific research.
Energetic dependencies dictate folding mechanism in a complex protein

Significance Large proteins composed of multiple domains are abundant in all proteomes, but their folding and structural dynamics remain poorly understood. Using single-molecule force spectroscopy, we have defined how stabilizing interfaces among the domains of elongation factor G (EF-G) shape its folding pathway. Contrary to the expectation that multidomain proteins fold sequentially as they emerge from the ribosome, we find that folding cannot be completed until the full protein has been synthesized. This posttranslational folding mechanism results in a propensity for misfolding. It is dictated by an energetic coupling among domains that enables conformational flexibility crucial for EF-G function. EF-G thus provides an example of how distinct biological ends—robust folding and functionally important flexibility—come into conflict during protein biogenesis. Large proteins with multiple domains are thought to fold cotranslationally to minimize interdomain misfolding. Once folded, domains interact with each other through the formation of extensive interfaces that are important for protein stability and function. However, multidomain protein folding and the energetics of domain interactions remain poorly understood. In elongation factor G (EF-G), a highly conserved protein composed of 5 domains, the 2 N-terminal domains form a stably structured unit cotranslationally. Using single-molecule optical tweezers, we have defined the steps leading to fully folded EF-G. We find that the central domain III of EF-G is highly dynamic and does not fold upon emerging from the ribosome. Surprisingly, a large interface with the N-terminal domains does not contribute to the stability of domain III. Instead, it requires interactions with its folded C-terminal neighbors to be stably structured. Because of the directionality of protein synthesis, this energetic dependency of domain III on its C-terminal neighbors disrupts cotranslational folding and imposes a posttranslational mechanism on the folding of the C-terminal part of EF-G. As a consequence, unfolded domains accumulate during synthesis, leading to the extensive population of misfolded species that interfere with productive folding. Domain III flexibility enables large-scale conformational transitions that are part of the EF-G functional cycle during ribosome translocation. Our results suggest that energetic tuning of domain stabilities, which is likely crucial for EF-G function, complicates the folding of this large multidomain protein.