Miracle-dz/UniFAR-FTUs huggingface dataset:
Bioactivity Determination of a Therapeutic Recombinant Human Keratinocyte Growth Factor by a Validated Cell-based Bioassay

The therapeutic recombinant human keratinocyte growth factor 1 (rhKGF-1) was approved by the FDA for oral mucositis resulting from hematopoietic stem cell transplantation for hematological malignancies in 2004. However, no recommended bioassay for rhKGF-1 bioactivity has been recorded in the U.S. Pharmacopoeia. In this study, we developed an rhKGF-1-dependent bioassay for determining rhKGF-1 bioactivity based on HEK293 and HaCat cell lines that stably expressed the luciferase reporter driven by the serum response element (SRE) and human fibroblast growth factor receptor (FGFR2) IIIb. A good responsiveness to rhKGF-1 and rhKGF-2 shared by target HEK293/HaCat cell lines was demonstrated. Our stringent validation was completely focused on specificity, linearity, accuracy, precision, and robustness according to the International Council for Harmonization (ICH) Q2 (R1) guidelines, AAPS/FDA Bioanalytical Workshop and the Chinese Pharmacopoeia. We confirmed the reliability of the method in determining rhKGF bioactivity. The validated method is highly timesaving, sensitive, and simple, and is especially valuable for providing information for quality control during the manufacture, research, and development of therapeutic rhKGF.
Temperature- and rigidity-mediated rapid transport of lipid nanovesicles in hydrogels

Significance Lipid vesicles such as liposomes are widely present in biological systems and drug delivery applications. Numerous studies have focused on their roles in intercellular communication, signaling, and trafficking. Little is known, however, about the correlation between temperature and transport rate of these vesicles in biological media. Here, we report a temperature- and rigidity-mediated rapid transport mechanism by which liposomes attain optimal diffusivity near a phase transition temperature. Remarkably, liposomes with phase transition temperature around the body temperature are observed to overcome multiple biological barriers and show substantial improvement in drug delivery efficacy. Lipid nanovesicles are widely present as transport vehicles in living organisms and can serve as efficient drug delivery vectors. It is known that the size and surface charge of nanovesicles can affect their diffusion behaviors in biological hydrogels such as mucus. However, how temperature effects, including those of both ambient temperature and phase transition temperature (Tm), influence vehicle transport across various biological barriers outside and inside the cell remains unclear. Here, we utilize a series of liposomes with different Tm as typical models of nanovesicles to examine their diffusion behavior in vitro in biological hydrogels. We observe that the liposomes gain optimal diffusivity when their Tm is around the ambient temperature, which signals a drastic change in the nanovesicle rigidity, and that liposomes with Tm around body temperature (i.e., ∼37 °C) exhibit enhanced cellular uptake in mucus-secreting epithelium and show significant improvement in oral insulin delivery efficacy in diabetic rats compared with those with higher or lower Tm. Molecular-dynamics (MD) simulations and superresolution microscopy reveal a temperature- and rigidity-mediated rapid transport mechanism in which the liposomes frequently deform into an ellipsoidal shape near the phase transition temperature during diffusion in biological hydrogels. These findings enhance our understanding of the effect of temperature and rigidity on extracellular and intracellular functions of nanovesicles such as endosomes, exosomes, and argosomes, and suggest that matching Tm to ambient temperature could be a feasible way to design highly efficient nanovesicle-based drug delivery vectors.
Muscle mass adjustment method affects association of sarcopenia and sarcopenic obesity with metabolic syndrome

Dear Editor, We read with great interest “the Sarcopenia Guideline: Chapter 2: Epidemiology of sarcopenia” by Shimokata et al. In the article, the authors reviewed the prevalence, causes and risk factors, prognoses, and outcomes of sarcopenia in older adults aged ≥65 years. This chapter is a well-compiled text that includes all aspects of the epidemiology of sarcopenia and has been a very useful resource for understanding sarcopenia. We would like to contribute a number of different points. The authors stated that “The prevalence of both sarcopenia and sarcopenic obesity is higher in patients with metabolic syndrome. ” However, the relationship between sarcopenia and sarcopenic obesity with metabolic syndrome vary according the adjustment method of the muscle mass component of sarcopenia. Sarcopenia and sarcopenic obesity are associated with metabolic syndrome only if skeletal muscle mass is adjusted by weight. On the contrary, if skeletal muscle mass is adjusted by height, sarcopenia is protective against metabolic syndrome. Another point is, the authors stated that, “Complication by sarcopenia reduces the survival rate in cancer patients and increases the risk of death as a result of surgery. ” However, complications related to sarcopenia are not only limited to these complications. Pulmonary function is also reported to be adversely affected by sarcopenia, and common adverse respiratory complications increase. Peak expiratory flow is determined by the strength of respiratory muscles and the has prognostic value. Handgrip strength was reported to be associated with respiratory muscle strength by our group. Recently, handgrip strength was shown to be correlated with respiratory function in a large cross-sectional study including 605 community-dwelling women aged ≥65 years without chronic diseases or pulmonary disease. We suggest that inclusion of these remarks would improve the content of this comprehensive guideline.
Parallel distributed networks resolved at high resolution reveal close juxtaposition of distinct regions

Examination of large-scale distributed networks within the individual reveals details of cortical network organization that are absent in group-averaged studies. One recent discovery is that a distributed transmodal network, often referred to as the ‘default network’, is comprised of two separate but closely interdigitated networks, only one of which is coupled to posterior parahippocampal cortex. Not all studies of individuals have identified the same networks and questions remain about the degree to which the two networks are separate, particularly within regions hypothesized to be interconnected hubs. Here we replicate the observation of network separation across analytical (seed-based connectivity and parcellation) and data projection (volume and surface) methods in 2 individuals each scanned 31 times. Additionally, 3 individuals were examined with high-resolution fMRI to gain further insight into the anatomical details. The two networks were identified with separate regions localized to adjacent portions of the cortical ribbon, sometimes inside the same sulcus. Midline regions previously implicated as hubs revealed near complete spatial separation of the two networks, displaying a complex spatial topography in the posterior cingulate and precuneus. The network coupled to parahippocampal cortex also revealed a separate region directly within the hippocampus at or near the subiculum. These collective results support that the default network is composed of at least two spatially juxtaposed networks. Fine spatial details and juxta-positions of the two networks can be identified within individuals at high resolution, providing insight into the network organization of association cortex and placing further constraints on interpretation of group-averaged neuroimaging data.
Role of Human Ventromedial Prefrontal Cortex in Learning and Recall of Enhanced Extinction

Standard fear extinction relies on the ventromedial prefrontal cortex (vmPFC) to form a new memory given the omission of threat. Using fMRI in humans, we investigated whether replacing threat with novel neutral outcomes (instead of just omitting threat) facilitates extinction by engaging the vmPFC more effectively than standard extinction. Computational modeling of associability (indexing surprise strength and dynamically modulating learning rates) characterized skin conductance responses and vmPFC activity during novelty-facilitated but not standard extinction. Subjects who showed faster within-session updating of associability during novelty-facilitated extinction also expressed better extinction retention the next day, as expressed through skin conductance responses. Finally, separable patterns of connectivity between the amygdala and ventral versus dorsal mPFC characterized retrieval of novelty-facilitated versus standard extinction memories, respectively. These results indicate that replacing threat with novel outcomes stimulates vmPFC involvement on extinction trials, leading to a more durable long-term extinction memory. SIGNIFICANCE STATEMENT Psychiatric disorders characterized be excessive fear are a major public health concern. Popular clinical treatments, such as exposure therapy, are informed by principles of Pavlovian extinction. Thus, there is motivation to optimize extinction strategies in the laboratory so as to ultimately develop more effective clinical treatments. Here, we used functional neuroimaging in humans and found that replacing (rather than just omitting) expected aversive events with novel and neutral outcomes engages the ventromedial prefrontal cortex during extinction learning. Enhanced extinction also diminished activity in threat-related networks (e.g., the insula, thalamus) during immediate extinction and a 24 h extinction retention test. This is new evidence for how behavioral protocols designed to enhance extinction affects neurocircuitry underlying the learning and retention of extinction memories.
A New Method for Continuous Relative Blood Volume and Plasma Sodium Concentration Estimation During Hemodialysis

Objective: Non-invasive sensing and reliable estimation of physiological parameters are important features of hemodialysis machines, especially for therapy customization (biofeedback). In this paper, we present a new method for joint estimation of two important hemodialysis-related physiological parameters—relative blood volume and plasma sodium concentration. Methods: Our method makes use of a non-invasive sensor setup and a mathematical estimator. The estimator, based on the Kalman filter, allows merging data from multiple sensors, newly designed as well as onboard, with modeling knowledge about the hemodialysis process. The system was validated on in vitro hemodialysis sessions using bovine blood. Results: The estimation error we obtained (0.97 ± 0.73% on relative blood volume and 0.47 ± 0.19 mM on plasmatic sodium) proved to be comparable with that of the reference data for both parameters—the system is sufficiently accurate to be relevant in a clinical context. Conclusion: Our system has the potential to provide accurate and important information on the state of a patient undergoing hemodialysis, while only low-cost modifications to the existing onboard sensors are required. Significance: Through improved knowledge of blood parameters during hemodialysis, our method will allow better patient monitoring and therapy customization in hemodialysis.
Exploring the interaction between FGF Genes and T‐box genes among chinese nonsyndromic cleft lip with or without cleft palate case‐parent trios

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect. Genetic variants causing syndromic orofacial clefts can also contribute to the etiology of NSCL/P. The purpose of the present study was to explore gene–gene (G × G) interaction using common single nucleotide polymorphic (SNP) markers in fibroblast growth factor (FGF) family and its receptors and T‐box genes, which were associated with syndromic orofacial clefts. Our study was conducted in 806 Chinese NSCL/P case‐parent trios drawn from an international consortium. A total of 252 SNPs in FGF8, FGF10, FGFR1, FGFR2, and TBX5 passed the quality control criteria and were included in the analysis. The interactions between SNPs in different genes were assessed using Cordell's method, which fitted a conditional logistic regression model. The analysis was performed using the R‐package trio (Version 3.8.0). Bonferroni correction was used to adjust for multiple comparisons, and the overall significance threshold was set as P = 1.98 × 10−4 (0.05/252). Conditional logistic regression revealed the most significant interaction between rs2330542 in FGF10 and rs1946295 in TBX5, which remained significant (P = 9.63 × 10−6) after Bonferroni correction. The relative risk of allele C in rs2330542 (FGF10) was 1.02 (95%CI 0.81–1.28), while the relative risk was 1.42 (95%CI 1.03–1.97) when the exposure was a combination of allele C in rs2330542 and allele A in rs1946295 (TBX5). Our findings confirmed the importance of considering G × G interaction when exploring the genetic risk factors of NSCL/P. Further investigations are warranted to validate the potential interaction and reveal the biological function of FGF10/FGFR2/TBX5. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.
Bone Marrow CX3CL1/Fractalkine is a New Player of the Pro-Angiogenic Microenvironment in Multiple Myeloma Patients

C-X3-C motif chemokine ligand 1 (CX3CL1)/fractalkine is a chemokine released after cleavage by two metalloproteases, ADAM metallopeptidase domain 10 (ADAM10) and ADAM metallopeptidase domain 17 (ADAM17), involved in inflammation and angiogenesis in the cancer microenvironment. The role of the CX3CL1/ C-X3-C motif chemokine receptor 1(CX3CR1) axis in the multiple myeloma (MM) microenvironment is still unknown. Firstly, we analyzed bone marrow (BM) plasma levels of CX3CL1 in 111 patients with plasma cell disorders including 70 with active MM, 25 with smoldering myeloma (SMM), and 16 with monoclonal gammopathy of undetermined significance (MGUS). We found that BM CX3CL1 levels were significantly increased in MM patients compared to SMM and MGUS and correlated with BM microvessel density. Secondly, we explored the source of CX3CL1 in MM and BM microenvironment cells. Primary CD138+ cells did not express CXC3L1 but up-regulated its production by endothelial cells (ECs) through the involvement of tumor necrosis factor alpha (TNFα). Lastly, we demonstrated the presence of CX3CR1 on BM CD14+CD16+ monocytes of MM patients and on ECs, but not on MM cells. The role of CX3CL1 in MM-induced angiogenesis was finally demonstrated in both in vivo chick embryo chorioallantoic membrane and in vitro angiogenesis assays. Our data indicate that CX3CL1, present at a high level in the BM of MM patients, is a new player of the MM microenvironment involved in MM-induced angiogenesis.
“Need Everyone Helping to Keep Off Because Everyone Helping to Keep On” – Reducing Harms from Cannabis use in Remote Indigenous Australian Communities Involves More Than Just Users

Abstract Background: Heavy cannabis use in remote Indigenous Australian communities potentially contributes to existing health disparities. Community members’ perceptions of cannabis harms will support harm-minimization in these settings. Objective: To describe perceived cannabis harms reported by a cohort of Indigenous Australians living in small, isolated communities as an indication of their existing resources for change. Method: Inductive thematic analysis of 407 semi-structured interviews with participants in a cohort study in three remote communities in Cape York in far north Queensland (Australia) revealed major areas of concern about cannabis. Three attitudinal categories were defined according to reported cannabis impacts and urgency for change: 1- “LOW CONCERN” said cannabis was a low priority community issue; 2- “SOME CONCERN” tolerated cannabis use but identified personal or community-level concerns; and 3- “HIGH CONCERN” expressed strong aversion to cannabis and identified serious personal or community-level harms. The characteristics and the patterns of concerns were summarized across the groups. Results: “Category 1- LOW CONCERN” (n = 107), mostly current users, emphasized personal “financial impacts” and “stress. ” “Category 2 – SOME CONCERN” (n = 141) perceived community level impacts warranting systematic action, particularly on “employment”; and “Category 3 – HIGH CONCERN” (n = 159), most of the never users, emphasized concerns for families and youth. Irrespective of use history, the cohort reported financial and abstinence-related stress, overlapping alcohol issues and generally endorsed alleviating impacts on children and youth. Conclusion: Nearly ubiquitous experience with cannabis harms and impacts in this cohort suggests resources for harm reduction including family and cultural obligation, stress relief, financial management, and engagement are available across all community members, not just users.
Enrichment of indigenous arsenate reducing anaerobic bacteria from arsenic rich aquifer sediment of Brahmaputra river basin and their potential role in as mobilization

Abstract Anaerobic enrichment of As5+ reducing bacteria in the presence and/or absence of organic carbon (OC) and As5+ from As contaminated soil of Brahmaputra river basin (BRB) (Jorhat, Assam) was performed. Denaturing gradient gel electrophoresis of the 16SrRNA gene sequences amplified from the enriched microbial community indicated occurrence of maximum diversity under conditions receiving no OC (MSM) followed by moderate OC (LB). However, higher OC or As showed antagonistic effect on bacterial enrichment whereas together (BB + As) they showed a synergistic effect. Phylogenetic analysis of the prominent bands revealed an overall abundance of Lachnoanaerobaculum (39%), Clostridium (39%), Bacillus, Peptostreptococcaceae, Anaerostipes (13%), and Desulfotomaculum (8.7%). Moderate OC (LB) led to maximum As mobilization i.e. 27.42 µg/L, whereas presence of added As together with high OC (BB + As) enhanced the mobilization process. Mineralogical analyses of the sediments after incubation showed prominent weathering and loss of crystallinity in MSM and LB. Appearance of a new peak corresponding to arsenolamprite (As) in LB and LB + As indicated opening up of secondary phases of the minerals harboring As due to microbial leaching under moderate OC. This is the first study reporting Lachnoanaerobaculumas a potent As5+ dissimilating bacterium isolated from As contaminated subsurface sediment of BRB.
Dysregulation, functional implications, and prognostic ability of the circadian clock across cancers

It has been proposed that the circadian rhythm generally plays important roles in tumor suppression, but there is also evidence that disruption of the canonical circadian pathway has anticancer effects. In this study, we systematically analyzed the aberrances of circadian clock genes across cancers based on data from The Cancer Genome Atlas (TCGA). These data showed that the frequencies of mutations and copy number alterations in core clock genes (PER1/2/3, CLOCK, CRY1/2, and ARNTL) were low, but that the expression levels of core clock genes were downregulated by the higher levels of DNA methylation in most tumors. The circadian clock index (CCI) was established through a principal component analysis, and this measure well represents the overall expression of the core clock genes. In fact, the CCI was significantly lower in hepatocellular carcinoma with HBV infection than in other cancers. Furthermore, pathways such as the MAPK, JAK‐STAT, and immune‐related signaling pathways were enriched in tumors with high CCI values. Interestingly, the CCI was generally positively related to the immunophenoscores and immunophenotypes of tumors. Additionally, the expression levels of core clock genes and the CCI were also generally positively related to survival across cancers. Taken together, the results of this study provide a comprehensive analysis of circadian clock aberrances in cancer, and the results should aid further investigations of the molecular mechanisms of cancer and the development of therapeutic strategies.
Moderate Exercise Improves Experimental Cancer Cachexia by Modulating the Redox Homeostasis

Cachexia is a debilitating syndrome that complicates the management of cancer patients. Muscle wasting, one of the main features of cachexia, is associated with hyper-activation of protein degradative pathways and altered mitochondrial function that could both result from impaired redox homeostasis. This study aimed to investigate the contribution of oxidative stress to cancer-induced cachexia in the presence or in the absence of moderate exercise training. Mice bearing the colon C26 carcinoma, either sedentary or exercised, were used. The former showed muscle wasting and redox imbalance, with the activation of an antioxidant response and with upregulation of markers of proteasome-dependent protein degradation and autophagy. Moderate exercise was able to relieve muscle wasting and prevented the loss of muscle strength; such a pattern was associated with reduced levels of Reactive Oxygen Species (ROS), carbonylated proteins and markers of autophagy and with improved antioxidant capacity. The muscle of sedentary tumor hosts also showed increased levels of molecular markers of mitophagy and reduced mitochondrial mass. Conversely, exercise in the C26 hosts led to increased mitochondrial mass. In conclusion, moderate exercise could be an effective non-pharmacological approach to prevent muscle wasting in cancer patients, decreasing muscle protein catabolism and oxidative stress and preserving mitochondria.
Contact-Based Methods for Measuring Respiratory Rate

There is an ever-growing demand for measuring respiratory variables during a variety of applications, including monitoring in clinical and occupational settings, and during sporting activities and exercise. Special attention is devoted to the monitoring of respiratory rate because it is a vital sign, which responds to a variety of stressors. There are different methods for measuring respiratory rate, which can be classed as contact-based or contactless. The present paper provides an overview of the currently available contact-based methods for measuring respiratory rate. For these methods, the sensing element (or part of the instrument containing it) is attached to the subject’s body. Methods based upon the recording of respiratory airflow, sounds, air temperature, air humidity, air components, chest wall movements, and modulation of the cardiac activity are presented. Working principles, metrological characteristics, and applications in the respiratory monitoring field are presented to explore potential development and applicability for each method.
Analysis of key candidate genes and pathways of endometriosis pathophysiology by a genomics-bioinformatics approach

Abstract Endometriosis is a common disease in women, but the signaling pathways and driven genes involved remain unclear. This study integrated four datasets to elucidate potential key candidate genes and pathways in endometriosis. Four expression profile datasets including 29 endometriosis lesions and 37 normal tissues were integrated and analyzed. Differentially expressed genes (DEGs) were sorted, and the gene ontology, pathway enrichment, and protein–protein interaction network of candidate genes were then analyzed. A total of 94 shared DEGs were identified from the four datasets. The DEGs were clustered based on functions and signaling pathways through the analysis of significant enrichment. Among the DEG protein-protein interaction network complex, 87 nodes/DEGs were identified. Furthermore, 18 central node genes were identified, and most of the corresponding genes were involved in the angiotensin system, smooth muscle contraction, cell junction organization, and lipoxin pathways. Through integrated bioinformatic analysis, we identified candidate genes and pathways in endometriosis, which could improve our understanding of endometriosis.