Miracle-dz/UniFAR-FTUs huggingface dataset:
Increased expression of CXCL2 in ACPA‐positive rheumatoid arthritis and its role in osteoclastogenesis

Anti‐citrullinated protein/peptide antibodies (ACPA) play important roles in the pathogenesis of rheumatoid arthritis (RA). ACPA‐positive (ACPA+) and ACPA‐negative (ACPA−) RA were suggested to be different disease subsets, with distinct differences in genetic variation and clinical outcomes. The aims of the present study were to compare gene expression profiles in ACPA+ and ACPA− RA, and to identify novel candidate gene signatures that might serve as therapeutic targets. Comprehensive transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from ACPA+ and ACPA− RA patients and healthy controls was performed via RNA sequencing. A validation cohort was used to further investigate differentially expressed genes via polymerase chain reaction (PCR) and enzyme‐linked immunosorbent assay (ELISA). Spearman’s correlation test was used to evaluate the correlation of differentially expressed genes and the clinical and laboratory data of the patients. The role of differentially expressed genes in osteoclastogenesis was further investigated. Expression of C‐X‐C motif chemokine ligand 2 (CXCL2) was significantly increased in ACPA+ RA than in ACPA− RA, which was validated in PBMCs and serum. CXCL2 promoted the migration of CD14+ monocytes and increased osteoclastogenesis in RA patients. RAW264.7 macrophages were used to investigate specific mechanisms, and the results suggested that CXCL2 stimulated osteoclastogenesis via extracellular receptor kinase (ERK) mitogen‐activated protein kinase (MAPK) and nuclear factor kappa B pathways. In conclusion, CXCL2 was highly expressed in ACPA+ RA than in ACPA− RA. CXCL2 promoted osteoclastogenesis and was related to bone erosion in RA, which suggests that the blockade of CXCL2 might be a novel strategy for the treatment of RA.
RET Receptor Tyrosine Kinase: Role in Neurodegeneration, Obesity, and Cancer

Rearranged during transfection (RET) is the tyrosine kinase receptor that under normal circumstances interacts with ligand at the cell surface and mediates various essential roles in a variety of cellular processes such as proliferation, differentiation, survival, migration, and metabolism. RET plays a pivotal role in the development of both peripheral and central nervous systems. RET is expressed from early stages of embryogenesis and remains expressed throughout all life stages. Mutations either activating or inhibiting RET result in several aggressive diseases, namely cancer and Hirschsprung disease. However, the physiological ligand-dependent activation of RET receptor is important for the survival and maintenance of several neuronal populations, appetite, and weight gain control, thus providing an opportunity for the development of disease-modifying therapeutics against neurodegeneration and obesity. In this review, we describe the structure of RET, its signaling, and its role in both normal conditions as well as in several disorders. We highlight the differences in the signaling and outcomes of constitutive and ligand-induced RET activation. Finally, we review the data on recently developed small molecular weight RET agonists and their potential for the treatment of various diseases.
Updated definition and classification of dry eye disease: Renewed proposals using the nominal group and Delphi techniques

The aim of our research was to obtain expert consensus for updated definition and classification of dry eye disease using formal methodology. The nominal group technique (NGT) involved a steering committee of four ophthalmologists began with collection of ideas followed by group discussion. The ideas were collated, refined, and voted upon. The main characteristics considered, each with different degrees of severity in types I, II, and III, were the ability or not of the ocular surface to re-equilibrate itself, frequency of symptoms, presence of inflammation, epithelial alterations, and possible alterations in the quality of vision. This was followed by three rounds of a “mini-Delphi” involving an expert panel of 13 ophthalmologists, with the last round including all 17 ophthalmologists. Consensus in the final round of voting (⩾75% of votes) was reached on the definition of dry eye disease and on criteria for its classification in three forms. Type I is a transient and reversible form with subclinical inflammation, possible epithelial alterations, and occasional alterations in vision. Type II is a recurrent form characterized by a reduced ability to re-equilibrate the ocular surface, frequent symptoms and alterations in vision with clinically-evident inflammation, and clear evidence of epithelial alterations. Type III is a chronic form with inability to re-equilibrate the ocular surface and accompanied by clinically-evident and chronic inflammation, persistent epithelial alterations, and frequent alterations in quality of vision. The vast majority of patients with dry eye disease can be easily classified into one of these three forms. Dry eye disease definition was updated accordingly.
Family embeddedness and older adult mortality in the United States

Do different operationalizations of family structure offer different understandings of the links between family structure and older adult mortality? Using the American Health and Retirement Study (N = 29,665), we examine mortality risks by three measures of family structure: whether respondents have different family statuses (e.g. married vs. unmarried), volume of family members available (e.g. having one vs. two living immediate family members), and family embeddedness (e.g. having neither spouse nor child vs. having spouse but no child). We focus on three kin types: partner/spouse, children, and siblings. We find that differences in empirical estimates across measures of family structure are not dramatic, but that family embeddedness can show some additional heterogeneity in mortality patterns over family status variables or the volume of ties. This paper tests different ways of operationalizing family structure to study mortality outcomes and advances our understanding of how family functions as a key social determinant of health.
The Compromised Intestinal Barrier Induced by Mycotoxins

Mycotoxins are fungal metabolites that occur in human foods and animal feeds, potentially threatening human and animal health. The intestine is considered as the first barrier against these external contaminants, and it consists of interconnected physical, chemical, immunological, and microbial barriers. In this context, based on in vitro, ex vivo, and in vivo models, we summarize the literature for compromised intestinal barrier issues caused by various mycotoxins, and we reviewed events related to disrupted intestinal integrity (physical barrier), thinned mucus layer (chemical barrier), imbalanced inflammatory factors (immunological barrier), and dysfunctional bacterial homeostasis (microbial barrier). We also provide important information on deoxynivalenol, a leading mycotoxin implicated in intestinal dysfunction, and other adverse intestinal effects induced by other mycotoxins, including aflatoxins and ochratoxin A. In addition, intestinal perturbations caused by mycotoxins may also contribute to the development of mycotoxicosis, including human chronic intestinal inflammatory diseases. Therefore, we provide a clear understanding of compromised intestinal barrier induced by mycotoxins, with a view to potentially develop innovative strategies to prevent and treat mycotoxicosis. In addition, because of increased combinatorial interactions between mycotoxins, we explore the interactive effects of multiple mycotoxins in this review.
The Role of Stress Proteins in Haloarchaea and Their Adaptive Response to Environmental Shifts

Over the years, in order to survive in their natural environment, microbial communities have acquired adaptations to nonoptimal growth conditions. These shifts are usually related to stress conditions such as low/high solar radiation, extreme temperatures, oxidative stress, pH variations, changes in salinity, or a high concentration of heavy metals. In addition, climate change is resulting in these stress conditions becoming more significant due to the frequency and intensity of extreme weather events. The most relevant damaging effect of these stressors is protein denaturation. To cope with this effect, organisms have developed different mechanisms, wherein the stress genes play an important role in deciding which of them survive. Each organism has different responses that involve the activation of many genes and molecules as well as downregulation of other genes and pathways. Focused on salinity stress, the archaeal domain encompasses the most significant extremophiles living in high-salinity environments. To have the capacity to withstand this high salinity without losing protein structure and function, the microorganisms have distinct adaptations. The haloarchaeal stress response protects cells against abiotic stressors through the synthesis of stress proteins. This includes other heat shock stress proteins (Hsp), thermoprotectants, survival proteins, universal stress proteins, and multicellular structures. Gene and family stress proteins are highly conserved among members of the halophilic archaea and their study should continue in order to develop means to improve for biotechnological purposes. In this review, all the mechanisms to cope with stress response by haloarchaea are discussed from a global perspective, specifically focusing on the role played by universal stress proteins.
Will For-Profits Keep Up the Pace in the United States? The Future of the Program of All-Inclusive Care for the Elderly and Implications for Other Programs Serving Medically Vulnerable Populations

The Program of All-Inclusive Care for the Elderly (PACE) has provided, for more than 4 decades, high-quality, cost-effective medical and social care to older people in the United States under nonprofit ownership. Recent rulings by the Centers for Medicare & Medicaid Services (CMS), however, will fundamentally change the initial intent and operation of the program. CMS’s final rule (4168-F) removes the provision that PACE operators be nonprofit. This article provides the legislative background for the final ruling and critiques the study that was used to justify the removal of the nonprofit provision. Although the Balanced Budget Act of 1997 listed a number of requirements for evaluating for-profit PACE programs, the secretary of the Department of Health and Human Services did not follow them before establishing for-profit PACE sites as permanent providers. It also argues that the ruling was made without much evidence that for-profit compared to nonprofit operators can provide a similar level of quality of care, access, and cost-effectiveness and urges policymakers to increase regulatory accountability, given what we know about other shifts in profit status and health care.
Foraging Behaviour of Japanese Monkeys: a viewpoint of optimal foraging strategy

Most of the situations to which optimal foraging theory has been applied can be divided into the following four categories: (1) optimal food choice; (2) optimal food patch choice; (3) optimal time allocation to different food patches; (4) optimal patterns and speed of movements (Pyke et al., 1977). I have reviewed the ways in which the first three problems have been tackled thus far in primate feeding ecology. I have also reconsidered the foraging behaviour of the wild Japanese monkeys that inhabit Kinkazan Island, Miyagi Prefecture, in terms of net rate of energy intake which is usually employed as a measure in analyses of optimal foraging theory. I found that there was no significant tendency for the monkeys to spend more time in feeding on food items that are associated with more rapid energy intake. Furthermore, monkeys chose the higher-quality food patch (i. e., where the feeding speed was higher) and fed there, but showed no significant tendency to feed for a longer time in the higher-quality patch. I have discussed ecological factors other than the net rate of energy intake and social factors that influence these results. Finally, I have presented a summary of the general foraging strategies of Japanese monkeys that I have studied thus far.
Real-Time Cuffless Continuous Blood Pressure Estimation Using Deep Learning Model

Blood pressure monitoring is one avenue to monitor people’s health conditions. Early detection of abnormal blood pressure can help patients to get early treatment and reduce mortality associated with cardiovascular diseases. Therefore, it is very valuable to have a mechanism to perform real-time monitoring for blood pressure changes in patients. In this paper, we propose deep learning regression models using an electrocardiogram (ECG) and photoplethysmogram (PPG) for the real-time estimation of systolic blood pressure (SBP) and diastolic blood pressure (DBP) values. We use a bidirectional layer of long short-term memory (LSTM) as the first layer and add a residual connection inside each of the following layers of the LSTMs. We also perform experiments to compare the performance between the traditional machine learning methods, another existing deep learning model, and the proposed deep learning models using the dataset of Physionet’s multiparameter intelligent monitoring in intensive care II (MIMIC II) as the source of ECG and PPG signals as well as the arterial blood pressure (ABP) signal. The results show that the proposed model outperforms the existing methods and is able to achieve accurate estimation which is promising in order to be applied in clinical practice effectively.
Systematic review of the potential respiratory carcinogenicity of metallic nickel in humans

Abstract The inhalation of dust containing certain nickel compounds has been associated with an increased risk of lung and nasal cancers in occupational studies of workers who process or refine sulfidic nickel ores and are exposed to relatively high levels of mixtures of water-soluble, sulfidic, oxidic, and/or metallic forms of nickel. We conducted a systematic review of the potential carcinogenicity of metallic nickel, focusing on cancers of the respiratory tract. We evaluated the quality and risk of bias (RoB) of the relevant epidemiology, experimental animal, and in vitro mechanistic studies using the National Toxicology Program's Office of Health Assessment and Translation (OHAT) RoB Rating Tool. We then used a systematic review protocol based on the OHAT approach to critically assess whether metallic nickel should be considered a human respiratory carcinogen. Our evaluation of the epidemiology studies indicates that there is no substantive evidence of increased respiratory cancer risk in workers exposed predominantly to metallic nickel. Animal evidence indicates that metallic nickel does not increase the incidence of respiratory tumors in rodents exposed by inhalation. The in vitro studies are limited in value, as they bypass normal clearance mechanisms. Nevertheless, the mechanistic evidence indicates that metallic nickel is not mutagenic but can induce DNA strand breaks under certain conditions. Based on a standard framework for assessing causality, we conclude that the evidence does not support a causal relationship between metallic nickel exposure and respiratory cancer in humans.
Implementation of an efficient magnetic tunnel junction-based stochastic neural network with application to iris data classification

Stochastic neuromorphic computation (SNC) has the potential to enable a low power, error tolerant and scalable computing platform in comparison to its deterministic counterparts. However, the hardware implementation of complementary metal oxide semiconductor (CMOS)-based stochastic circuits involves conversion blocks that cost more than the actual processing circuits. The realization of the activation function for SNCs also requires a complicated circuit that results in a significant amount of power dissipation and area overhead. The inherent probabilistic switching behavior of nanomagnets provides an advantage to overcome these complexity issues for the realization of low power and area efficient SNC systems. This paper presents magnetic tunnel junction (MTJ)-based stochastic computing methodology for the implementation of a neural network. The stochastic switching behavior of the MTJ has been exploited to design a binary to stochastic converter to mitigate the complexity of the CMOS-based design. The paper also presents the technique for realizing stochastic sigmoid activation function using an MTJ. Such circuits are simpler than existing ones and use considerably less power. An image classification system employing the proposed circuits has been implemented to verify the effectiveness of the technique. The MTJ-based SNC system shows area and energy reduction by a factor of 13.5 and 2.5, respectively, while the prediction accuracy is 86.66%. Furthermore, this paper investigates how crucial parameters, such as stochastic bitstream length, number of hidden layers and number of nodes in a hidden layer, need to be set precisely to realize an efficient MTJ-based stochastic neural network (SNN). The proposed methodology can prove a promising alternative for highly efficient digital stochastic computing applications.
The Pathogenesis of Tuberculosis–The Koch Phenomenon Reinstated

Research on the pathogenesis of tuberculosis (TB) has been hamstrung for half a century by the paradigm that granulomas are the hallmark of active disease. Human TB, in fact, produces two types of granulomas, neither of which is involved in the development of adult type or post-primary TB. This disease begins as the early lesion; a prolonged subclinical stockpiling of secreted mycobacterial antigens in foamy alveolar macrophages and nearby highly sensitized T cells in preparation for a massive necrotizing hypersensitivity reaction, the Koch Phenomenon, that produces caseous pneumonia that is either coughed out to form cavities or retained to become the focus of post-primary granulomas and fibrocaseous disease. Post-primary TB progresses if the antigens are continuously released and regresses when they are depleted. This revised paradigm is supported by nearly 200 years of research and suggests new approaches and animal models to investigate long standing mysteries of human TB and vaccines that inhibit the early lesion to finally end its transmission.
Clinical Utility of LCT Genotyping in Children with Suspected Functional Gastrointestinal Disorder

Genetic testing is a good predictor of lactase persistence (LP) in specific populations but its clinical utility in children is less clear. We assessed the role of lactose malabsorption in functional gastrointestinal disorders (FGID) in children and the correlation between the lactase non-persistence (LNP) genotype and phenotype, based on exhaled hydrogen and gastrointestinal symptoms, during a hydrogen breath test (HBT). We also evaluate dairy consumption in this sample. We conducted a 10-year cross-sectional study in a cohort of 493 children with suspected FGID defined by Roma IV criteria. Distribution of the C/T-13910 genotype was as follows: CC, 46.0%; TT, 14.4% (LP allele frequency, 34.1%). The phenotype frequencies of lactose malabsorption and intolerance were 36.3% and 41.5%, respectively. We observed a strong correlation between genotype and both lactose malabsorption (Cramér’s V, 0.28) and intolerance (Cramér’s V, 0.54). The frequency of the LNP genotype (p = 0.002) and of malabsorption and intolerance increased with age (p = 0.001 and 0.002, respectively). In 61% of children, evaluated dairy consumption was less than recommended. No association was observed between dairy intake and diagnosis. In conclusion, we found a significant correlation between genotype and phenotype, greater in older children, suggesting that the clinical value of genetic testing increases with age.
Blade-Type Reaction Front in Micrometer-sized Germanium Particles during Lithiation.

To investigate the lithium transport mechanism in micrometer-sized germanium (Ge) particles, in situ Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM) was used to monitor the structural evolution of individual Ge particles during lithiation. Our results show that there are two types of reaction fronts during lithiation, representing the differences of reactions on the surface and in bulk. The cross-sectional SEM images and transmission electron microscopy characterizations show that the interface between amorphous LixGe and Ge has a wedge shape due to the higher Li transport rate on the surface of the particle. The blade-type reaction front is formed at the interface of the amorphous LixGe and crystalline Ge, and is attributed to the large strain at the interface.
A systematic review and meta-analysis

Background: To evaluate the clinical value of circulating tumor cell (CTC) detection in peripheral blood for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Methods:Public databases were searched, and a meta-analysis was performed to determine the specificity, sensitivity, negativelikelihood ratio (NLR) and positive-likelihood ratio (PLR), and diagnostic odds ratio (dOR) of CTC detection for the diagnosis of HCC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were analyzed for the association of CTC detection with overall survival (OS) and HCC recurrence. The Meta-DiSc 1.4 and Review Manager 5.2 software programs were used for statistical analysis. Results:Meta-analysis of 20 studies including 1191 patients showed that the specificity, sensitivity, NLR, PLR, and dOR of CTC testing for HCC diagnosis were 0.60 (95% CI=0.57–0.63), 0.95 (95%CI=0.93–0.96), 0.36 (95%CI=0.28–0.48), 11.64 (95%CI= 5.85–23.14), and 38.94 (95%CI=18.33–82.75), respectively. Meta-analysis of 18 studies including 1466 patients indicated that the OS of CTC-positive HCC patients was less than that of CTC-negative patients (HR=2.31; 95% CI=1.55–3.42; P< .01). Metaanalysis of 5 studies including 339 patients revealed that the presence of CTCs in peripheral blood significantly increased the risk of HCC recurrence (HR=3.03, 95% CI=1.89–4.86; P< .01). Conclusion:CTCs in peripheral blood may be a useful marker for HCC diagnosis. In addition, the prognosis of CTC-positive HCC patients was significantly worse than that of CTC-negative HCC patients. Therefore, further studies are warranted to confirm the clinical potential of CTC detection in peripheral blood in patients with primary HCC. Abbreviations: AFP = alpha fetoprotein, AUC = area under the curve, CI = confidence interval, CTCs = circulating tumor cells, dOR = diagnostic odds ratio, FN = false negative, FP = false positive, HCC = hepatocellular carcinoma, HR = hazard ratio, NLR = negativelikelihood ratio, NOS = Newcastle-Ottawa Scale, OS = overall survival, PLR = positive-likelihood ratio, RFS = recurrencefree survival, SROC = summary of the receiver operating characteristic, TN = true negative, TP = true positive.
Viviparous Sprouting of Melon Seed and Endogenous Abscisic Acid (ABA) Levels as Affected by Potassium Fertilization

果実内発芽し難い1系統と果実内発芽し易い2系統を供試材料とし，果実内発芽と内生アブシジン酸含量の関係を明らかにするために，カリウム濃度の異なる3種の培養液（2.4, 4. 2および6. 0 me・L−1）で栽培した．その結果，果実内発芽し易い系統では，カリウム濃度の低下により1果当たりの種子数が明らかに減少した．しかし，果実内発芽し難い系統では，カリウム濃度は種子収量に影響を与えなかった．葉柄ならびに胎座部周辺の果汁中のカリウムイオン濃度は，果実内発芽し易い系統より果実内発芽し難い系統で高かった．果実内発芽はカリウム施肥量の減少に伴い，果実内発芽し易い系統で増加したが，果実内発芽し難い系統では，いずれのカリウム濃度でも果実内発芽は認められなかった．胎座部周辺の果汁中のABA含量は，カリウム施肥量の減少に伴い減少した．ABA濃度が異なる水溶液を用い，種子の発芽試験を行ったところ，果実内発芽し難い系統ではABA濃度の増加に伴い種子の発芽が著しく抑制された．以上の結果から，カリウム施肥量の減少により胎座部周辺の果汁中のABA含量が減少し，その結果として果実内発芽が増加すること，また，果実内発芽し難い系統は，低いABA濃度閾値で種子の発芽抑制があらわれるものと推察された．