Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparison of the pharmacokinetics, safety, and immunogenicity of MSB11022, a biosimilar of adalimumab, with Humira® in healthy subjects

Aims The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of the proposed adalimumab biosimilar MSB11022 (Merck) with Humira® (AbbVie), sourced from both the US (US reference product [US‐RP]) and Europe (European reference medicinal product [EU‐RMP]). Methods In this phase 1 double‐blind, parallel group trial (EMR200588‐001), 213 healthy volunteers were randomized 1 : 1 : 1 to receive a single dose (40 mg) of MSB11022, US‐RP or EU‐RMP in order to achieve 80% power assuming a 5% difference among groups and a 10% dropout rate. Following a preplanned blinded sample size re‐assessment after more than 50% of the originally planned subjects had been observed, the sample size was increased to 237 (79 per arm) to ensure 213 completers. Primary PK endpoints analyzed by non‐compartmental methods, were area under the curve (AUC) from time 0 extrapolated to infinity (AUC(0,∞)), maximum observed concentration (C max), and AUC from time 0 to the last quantifiable concentration (AUC(0,t last)). PK equivalence was declared if the 90% CI for the test : reference ratio lay within the 80–125% equivalence margin. Bioequivalence was demonstrated if all three PK parameters met the PK equivalence criteria. Safety and tolerability were also evaluated. Results Mean serum concentration–time profiles for the three treatments were similar. MSB11022 demonstrated PK equivalence to US‐RP and EU‐RMP for all primary endpoints. The geometric means of AUC(0,∞), C max and AUC(0,t last) following a single dose of MSB11022 were 2276.05 μg ml–1 h, 3.44 μg ml–1 and 1983.90 μg ml–1 h, respectively. Adverse events (AEs) were similar across all groups, with treatment‐emergent AEs (TEAEs) reported by 62.8%, 56.3% and 62.0% of subjects within the MSB11022, US‐RP and EU‐RMP groups, respectively. Most of the TEAEs were considered mild and unrelated to study drug. No deaths or severe AEs related to the study drug were reported. Conclusions Bioequivalence between MSB11022, US‐RP and EU‐RMP was demonstrated. Safety, tolerability and immunogenicity profiles were similar between subjects receiving MSB11022 and US‐RP or EU‐RMP. These data support the further clinical evaluation of MSB11022 as a proposed biosimilar of adalimumab.
Targeting Hypoxia‐Inducible Factor‐1&agr;/Pyruvate Dehydrogenase Kinase 1 Axis by Dichloroacetate Suppresses Bleomycin‐induced Pulmonary Fibrosis

&NA; Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences, such as hypoxia, contribute to their sustained activation and differentiation is poorly understood. As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia‐induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the preclinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis. Bleomycin‐induced pulmonary fibrotic progression was evaluated in two independent, fibroblast‐specific, promoter‐driven, hypoxia‐inducible factor (Hif) 1A knockout mouse models and in glycolytic inhibitor, dichloroacetate‐treated mice. Genetic and pharmacological approaches were used to explicate the role of metabolic reprogramming in myofibroblast differentiation. Hypoxia significantly enhanced transforming growth factor‐&bgr;‐induced myofibroblast differentiation through HIF‐1&agr;, whereas overexpression of the critical HIF‐1&agr;‐mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF‐1&agr;. Inhibition of the HIF‐1&agr;/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin‐induced pulmonary fibrosis. Our findings suggest that HIF‐1&agr;/PDK1‐mediated glycolytic reprogramming is a critical metabolic alteration that acts to promote myofibroblast differentiation and fibrotic progression, and demonstrate that targeting glycolytic metabolism may prove to be a potential therapeutic strategy for the treatment of pulmonary fibrosis.
Genetic variation in PPARGC1A may affect the role of diet-associated inflammation in colorectal carcinogenesis

The role of inflammation in colorectal carcinogenesis may differ according to individuals’ genetic variations. Therefore, we investigated whether genetic susceptibility alters the association between inflammatory potential of diet and the risk of colorectal cancer within the Korean population. We genotyped four polymorphisms in four genes (IL1B, TNF, PPARG, and PPARGC1A) and calculated the dietary inflammatory index (DII) in a case-control study with 701 colorectal cancer patients and 1,402 controls. Among the investigated polymorphisms, heterozygous carriers of rs3774921 in PPARGC1A showed a higher risk of colorectal cancer (OR [95% CI] = 1.26 [1.02–1.55] for TC vs. TT). When the data were stratified by rs3774921 genetic variant, the association of a pro-inflammatory diet with colorectal cancer risk was more prominent among homozygous variant allele carriers (OR [95% CI] = 5.15 [2.35–11.29] for high vs. low DII) (P for interaction = 0.009). When stratified by anatomic site, this association was much stronger for rectal cancer patients (OR [95% CI] = 8.06 [2.67–24.16] for high vs. low DII) (P for interaction = 0.006). Additionally, this interaction was stronger among those older than 50 years and not exercising regularly. Conversely, no association or interaction was found for the other investigated polymorphisms. In conclusion, the results of this study suggest that a pro-inflammatory diet may have a differential effect on colorectal cancer risk based on PPARGC1A genetic variation. This interaction may differ by anatomic location and other risk factors.
Sequence analysis of the mismatch repair gene hMSH6 in the germline of patients with familial and sporadic colorectal cancer

To evaluate the involvement of hMSH6 in colorectal cancer, the complete coding sequence and flanking intron regions of the gene were analyzed by DNA sequencing in 10 patients fulfilling Bethesda Guidelines for colorectal tumors and 10 patients with sporadic colorectal carcinoma. In addition, 10 mono‐ and 10 dinucleotide repeat markers were analyzed for microsatellite instability. A protein‐truncating T insertion at codon 218 was identified in the index person of a hereditary non‐polyposis colorectal cancer (HNPCC)‐like kindred and was accompanied by a somatic T deletion in the tumor. The tumor of this patient was positive for mono‐ but negative for dinucleotide repeat instability and lacked allelic losses at loci frequently affected in colorectal carcinomas. A novel amino acid change, F340S, was found in a patient with sporadic colon and breast cancer and leukemia but was not detected in 246 chromosomes from healthy anonymous blood donors. In addition, we describe 2 silent and 15 intronic sequence variants not previously reported. Although the frequency is low, we present further evidence for hMSH6 germline mutations that predispose patients to HNPCC‐like phenotypes and suggest that mono‐ and dinucleotide repeat instability testing may be useful for distinguishing between individuals harboring an hMSH2 or hMLH1 mutation and a mutation of the hMSH6 gene. Int. J. Cancer 85:606–613, 2000. © 2000 Wiley‐Liss, Inc.
Incentivizing Attendance to Prolonged Exposure for PTSD With Opioid Use Disorder Patients: A Randomized Controlled Trial

Objective: To determine whether contingent monetary incentives increase opioid use disorder patients’ attendance to Prolonged Exposure (PE) therapy and whether attendance is associated with improvement in posttraumatic stress disorder (PTSD) and substance use disorder (SUD) outcomes. Method: Patients (N = 58) with PTSD were offered PE or PE with incentives (PE + I; max $480) to attend PE sessions. Participants were assessed at baseline and weeks 6, 12, and 24 postrandomization. Results: Participants were mostly women (79%) and Caucasian (71%); mean age 37.43 years (SD = 11.33). PE + I participants attended a median of 9 (of 12) sessions compared to 1 session for PE participants (p < .001), which included more exposure sessions (PE + I mdn = 6; PE mdn = 0; p < .001). A Time × treatment condition interaction indicated that PE + I participants exhibited a greater decrease in PTSD severity over time than PE participants (OR = 3.1; 95% CI = 0.4–5.7; p = .024). PE + I participants remained in substance use treatment longer than PE participants (mdn days = 262 vs. 192; p = .039). There were no group differences in drug use. Conclusions: Monetary incentives increased SUD patients’ attendance to an otherwise poorly attended treatment for PTSD. Better attendance in the incentivized group was associated with greater PTSD improvement, better SUD treatment retention, and no increased drug use. Incentives are well supported for improving adherence to substance use treatment goals and promising as a means to improve therapy attendance, which may improve the effectiveness of existing psychotherapies in difficult-to-treat populations.
Multi-Agent Time-Based Decision-Making for the Search and Action Problem

Many robotic applications, such as search-and-rescue, require multiple agents to search for and perform actions on targets. However, such missions present several challenges, including cooperative exploration, task selection and allocation, time limitations, and computational complexity. To address this, we propose a decentralized multi-agent decision-making framework for the search and action problem with time constraints. The main idea is to treat time as an allocated budget in a setting where each agent action incurs a time cost and yields a certain reward. Our approach leverages probabilistic reasoning to make near-optimal decisions leading to maximized reward. We evaluate our method in the search, pick, and place scenario of the Mohamed Bin Zayed International Robotics Challenge (MBZIRC), by using a probability density map and reward prediction function to assess actions. Extensive simulations show that our algorithm outperforms benchmark strategies, and we demonstrate system integration in a Gazebo-based environment, validating the framework's readiness for field application.
Investigation of the effects of peppermint (Mentha piperita) on the biochemical and anthropometric profile of university students

The hypolipidemic effects of several medicinal plants have already been demonstrated, but many plants commonly used to treat diseases still need to be studied. Peppermint (Mentha piperita) is widely consumed by the population for different purposes, but not for the treatment of dyslipidemias. The objective of this study was to examine the effects of this plant on human biochemical and anthropometric profiles and blood pressure, based on the administration of peppermint juice twice daily for 30 days. Blood samples were collected before and after the treatment in order to determine the glycemic and lipid profiles, and the Body Mass Index (BMI) analysis was performed. Results indicated that 41.5% of the subjects showed a reduction in glycemia, 66.9% in total cholesterol levels, 58.5% in triacylglycerides, 52.3% in LDL-c (low-density lipoproteins) indices, 70% in GOT (glutamic-oxaloacetic transaminase) levels, 74.5% in GPT (glutamic-pyruvic transaminase) levels, and that 52% presented an increase in HDL-c (high-density lipoprotein cholesterol) indices. Also, 52.5% showed a decrease in blood pressure and 48.7% in BMI. The use of peppermint by humans can be considered beneficial in the prevention and treatment of risk factors of chronic degenerative diseases.
From snapshots to movies: Understanding early tooth development in four dimensions

The developing tooth offers a model for the study of ectodermal appendage organogenesis. The signaling networks that regulate tooth development have been intensively investigated, but how cell biological responses to signaling pathways regulate dental morphogenesis remains an open question. The increasing use of ex vivo imaging techniques has enabled live tracking of cell behaviors over time in high resolution. While recent studies using these techniques have improved our understanding of tooth morphogenesis, important gaps remain that require additional investigation. In addition, some discrepancies have arisen between recent studies, and resolving these will advance our knowledge of tooth development. Developmental Dynamics 246:442–450, 2016. © 2017 Wiley Periodicals, Inc.
Population Genomics of Early Events in the Ecological Differentiation of Bacteria

Some Sort of Species Certain populations of bacteria are known to show ecological differentiation, but how this happens has remained controversial. Shapiro et al. (p. 48; see the Perspective by Papke and Gogarten) examined whole-genome sequences from ecologically divergent Vibrio populations and found that genes and genome regions containing so-called “eco-SNPs” (single-nuleotide polymorphisms) have swept through populations. These regions differentiate the bacteria genetically, apparently according to the type of substratum on which they live. Subsequently, tight genotypic clusters may have emerged as a result of preferential recombination occurring within particular habitats. Although specialization into different habitats may reduce gene flow between bacterial populations, the bacteria will always remain open to taking up DNA from other populations and so they cannot be said to be species in the eukaryotic sense. Ecologically separated Vibrio populations diverge by gene-specific rather than genome-wide selective sweeps. Genetic exchange is common among bacteria, but its effect on population diversity during ecological differentiation remains controversial. A fundamental question is whether advantageous mutations lead to selection of clonal genomes or, as in sexual eukaryotes, sweep through populations on their own. Here, we show that in two recently diverged populations of ocean bacteria, ecological differentiation has occurred akin to a sexual mechanism: A few genome regions have swept through subpopulations in a habitat-specific manner, accompanied by gradual separation of gene pools as evidenced by increased habitat specificity of the most recent recombinations. These findings reconcile previous, seemingly contradictory empirical observations of the genetic structure of bacterial populations and point to a more unified process of differentiation in bacteria and sexual eukaryotes than previously thought.
Electrical machine first order short-time thermal transients model: Measurements and parameters evaluation

This paper deals with the measurements and parameters determination of a stator thermal model suitable to predict the winding thermal behavior during short-time thermal transient. A possible application of the proposed first order thermal network is the overcurrent limit prediction in electrical drives. Initially, a detailed description of the thermal model is reported with a deep discussion about its validity limits. Than the test methodology as well as the required measurements for the thermal parameters determination are presented and discussed. Two procedures for the thermal parameters determination are analyzed and compared. Finally, the accuracy of the thermal model and its parameters determination have been validate for five industrial induction motors with a rated power in the range of 4kW-55 kW. Furthermore, the proposed short time thermal test allows the quick determination of the equivalent thermal resistance of the slot insulation system. The proposed thermal model shows an accurate prediction of the winding thermal evolution in thermal transient long up to 4 minutes.
Mechanisms of nuclear pore complex assembly – two different ways of building one molecular machine

The nuclear pore complex (NPC) mediates all macromolecular transport across the nuclear envelope. In higher eukaryotes that have an open mitosis, NPCs assemble at two points in the cell cycle: during nuclear assembly in late mitosis and during nuclear growth in interphase. How the NPC, the largest nonpolymeric protein complex in eukaryotic cells, self‐assembles inside cells remained unclear. Recent studies have started to uncover the assembly process, and evidence has been accumulating that postmitotic and interphase NPC assembly use fundamentally different mechanisms; the duration, structural intermediates, and regulation by molecular players are different and different types of membrane deformation are involved. In this Review, we summarize the current understanding of these two modes of NPC assembly and discuss the structural and regulatory steps that might drive the assembly processes. We furthermore integrate understanding of NPC assembly with the mechanisms for rapid nuclear growth in embryos and, finally, speculate on the evolutionary origin of the NPC implied by the presence of two distinct assembly mechanisms.
A Fast Room Temperature NH3 Sensor Based on an Al/p-Si/Al Structure with Schottky Electrodes

In this paper, an electrical-based NH3 sensor with an Al/p-Si/Al structure is reported. The p-Si substrate is microstructured by fs-laser irradiation and then etched with 30% alkaline solution. This sensor works well at room temperature with fast response/recovery for NH3 gas at 5–100 ppm concentration. However, when the sensor is annealed in N2/H2 forming gas or short-circuited for Al/Si electrodes, its sensitivity decreases drastically and almost vanishes. Further I-V and FT-IR results show that the two back-to-back Schottky diodes on the device play a key role in its sensing performance.
Molecular machines with bio-inspired mechanisms

The widespread use of molecular-level motion in key natural processes suggests that great rewards could come from bridging the gap between the present generation of synthetic molecular machines—which by and large function as switches—and the machines of the macroscopic world, which utilize the synchronized behavior of integrated components to perform more sophisticated tasks than is possible with any individual switch. Should we try to make molecular machines of greater complexity by trying to mimic machines from the macroscopic world or instead apply unfamiliar (and no doubt have to discover or invent currently unknown) mechanisms utilized by biological machines? Here we try to answer that question by exploring some of the advances made to date using bio-inspired machine mechanisms.
Best Practices of Computer-Aided Drug Discovery: Lessons Learned from the Development of a Preclinical Candidate for Prostate Cancer with a New Mechanism of Action

Small-molecule drug design is a complex and iterative decision-making process relying on pre-existing knowledge and driven by experimental data. Low-molecular-weight chemicals represent an attractive therapeutic option, as they are readily accessible to organic synthesis and can easily be characterized.1 Their potency as well as pharmacokinetic and pharmacodynamic properties can be systematically and rationally investigated and ultimately optimized via expert science behind medicinal chemistry and methods of computer-aided drug design (CADD). In recent years, significant advances in molecular modeling techniques have afforded a variety of tools to effectively identify potential binding pockets on prospective targets, to map key interactions between ligands and their binding sites, to construct and assess energetics of the resulting complexes, to predict ADMET properties of candidate compounds, and to systematically analyze experimental and computational data to derive meaningful structure-activity relationships leading to the creation of a drug candidate. This Perspective describes a real case of a drug discovery campaign accomplished in a relatively short time with limited resources. The study integrated an arsenal of available molecular modeling techniques with an array of experimental tools to successfully develop a novel class of potent and selective androgen receptor inhibitors with a novel mode of action. It resulted in the largest academic licensing deal in Canadian history, totaling $142M. This project exemplifies the importance of team science, an integrative approach to drug discovery, and the use of best practices in CADD. We posit that the lessons learned and best practices for executing an effective CADD project can be applied, with similar success, to many drug discovery projects in both academia and industry.
ACE2‐EPC‐EXs protect ageing ECs against hypoxia/reoxygenation‐induced injury through the miR‐18a/Nox2/ROS pathway

Oxidative stress is one of the mechanisms of ageing‐associated vascular dysfunction. Angiotensin‐converting enzyme 2 (ACE2) and microRNA (miR)‐18a have shown to be down‐regulated in ageing cells. Our previous study has shown that ACE2‐primed endothelial progenitor cells (ACE2‐EPCs) have protective effects on endothelial cells (ECs), which might be due to their released exosomes (EXs). Here, we aimed to investigate whether ACE2‐EPC‐EXs could attenuate hypoxia/reoxygenation (H/R)‐induced injury in ageing ECs through their carried miR‐18a. Young and angiotensin II‐induced ageing ECs were subjected to H/R and co‐cultured with vehicle (medium), EPC‐EXs, ACE2‐EPCs‐EXs, ACE2‐EPCs‐EXs + DX600 or ACE2‐EPCs‐EXs with miR‐18a deficiency (ACE2‐EPCs‐EXsanti‐miR‐18a). Results showed (1) ageing ECs displayed increased senescence, apoptosis and ROS production, but decreased ACE2 and miR‐18a expressions and tube formation ability; (2) under H/R condition, ageing ECs showed higher rate of apoptosis, ROS overproduction and nitric oxide reduction, up‐regulation of Nox2, down‐regulation of ACE2, miR‐18a and eNOS, and compromised tube formation ability; (3) compared with EPC‐EXs, ACE2‐EPC‐EXs had better efficiencies on protecting ECs from H/R‐induced changes; (4) The protective effects were less seen in ACE2‐EPCs‐EXs + DX600 and ACE2‐EPCs‐EXsanti‐miR‐18a groups. These data suggest that ACE‐EPCs‐EXs have better protective effects on H/R injury in ageing ECs which could be through their carried miR‐18a and subsequently down‐regulating the Nox2/ROS pathway.
Zinc oxide nanoparticles induce toxic responses in human neuroblastoma SHSY5Y cells in a size-dependent manner

Due to the widespread applications of zinc oxide nanoparticles (ZnO NPs), the potential exposure of workers, consumers, and scientists to these particles has increased. This potential for exposure has attracted extensive attention in the science community. Many studies have examined the toxicological profile of ZnO NPs in the immune system, digestive system, however, information regarding the toxicity of ZnO NPs in the nervous system is scarce. In this study, we detected the cytotoxicity of two types of ZnO NPs of various sizes – ZnOa NPs and ZnOb NPs – and we characterized the shedding ability of zinc ions within culture medium and the cytoplasm. We found that reactive oxygen species played a crucial role in ZnO NP-induced cytotoxicity, likely because zinc ions were leached from ZnO NPs. Apoptosis and cytoskeleton changes were also toxic responses induced by the ZnO NPs, and ZnOb NPs induced more significant toxic responses than ZnOa NPs in SHSY5Y cells. In conclusion, ZnO NPs induced toxic responses in SHSY5Y cells in a size-dependent manner, which can probably be attributed to their ion-shedding ability.