Miracle-dz/UniFAR-FTUs huggingface dataset:
Flunarizine inhibits osteoclastogenesis by regulating calcium signaling and promotes osteogenesis

Many bone diseases such as osteoporosis and periodontitis are caused by hyperactivation of osteoclasts. Calcium (Ca2+) signals are crucial for osteoclast differentiation and function. Thus, the blockade of Ca2+ signaling may be a strategy for regulating osteoclast activity and has clinical implications. Flunarizine (FN) is a Ca2+ channel antagonist that has been used for reducing migraines. However, the role of FN in osteoclast differentiation and function remains unknown. Here, we investigated whether FN regulates osteoclastogenesis and elucidated the molecular mechanism. FN inhibited osteoclast differentiation along with decreased expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), and attenuated osteoclast maturation and bone resorption. FN inhibition of osteoclast differentiation was restored by ectopic expression of constitutively active NFATc1. FN reduced calcium oscillations and its inhibition of osteoclast differentiation and resorption function was reversed by ionomycin, an ionophore that binds Ca2+. FN also inhibited Ca2+/calmodulin‐dependent protein kinase IV (CaMKIV) and calcineurin leading to a decrease in the cAMP‐responsive element‐binding protein‐dependent cFos and peroxisome proliferator‐activated receptor‐γ coactivator 1β expression, and NFATc1 nuclear translocation. These results indicate that FN inhibits osteoclastogenesis via regulating CaMKIV and calcineurin as a Ca2+ channel blocker. In addition, FN‐induced apoptosis in osteoclasts and promoted osteogenesis. Furthermore, FN protected lipopolysaccharide‐ and ovariectomy‐induced bone destruction in mouse models, suggesting that it has therapeutic potential for treating inflammatory bone diseases and postmenopausal osteoporosis.
An analytical method of total bromine in crops by high performance liquid chromatography

高速液体クロマトグラフィー (HPLC) の溶離液に紫外吸収をもつフタル酸水素カリウム溶液を用い, カラムから溶出した紫外吸収をもたない臭素イオンを吸光度の減少として検出する方法により作物中の全臭素の分析法を検討した. 試料にエタノールアミン+エタノール+水酸化ナトリウム混液を加え, 水浴中で乾固したのち, 熱板上で炭化する. さらに電気炉中で灰化後, 臭素イオンを水で抽出し, 水酸化バリウム溶液を加えて妨害イオンを除去後, 陽イオン交換カラムで精製しHPLCで測定する. HPLCのカラムはMCI GEL SCA 02, 溶離液は5×10-4Mフタル酸水素カリウム溶液, 検出波長は245nmである. 臭素イオンの最小検出量は34ngであり, 検量線はピーク高さと注入量 (34～673ng) の間で良好な直線を示し, また, 繰り返し測定の再現性も良好であった. 検出限界は0. 7～3ppm, 回収率 (添加濃度: 14～67ppm) は73～91%であった. 本法によれば臭素イオンは通常のHPLC装置で分析でき, また, 選択的で操作が簡便であり, 臭化メチルで処理した作物中の全臭素の分析に適用可能である.
Biologics in professional and Olympic sport: a scoping review.

AIMS The aim of this study was to prepare a scoping review to investigate the use of biologic therapies in the treatment of musculoskeletal injuries in professional and Olympic athletes. METHODS Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews and Arksey and O'Malley frameworks were followed. A three-step search strategy identified relevant published primary and secondary studies, as well as grey literature. The identified studies were screened with criteria for inclusion comprising clinical studies evaluating the use of biologic therapies in professional and Olympic athletes, systematic reviews, consensus statements, and conference proceedings. Data were extracted using a standardized tool to form a descriptive analysis and a thematic summary. RESULTS A total of 202 studies were initially identified, and 35 met criteria for the scoping review; 33 (94.3%) were published within the last eight years, and 18 (51.4%) originated from the USA. Platelet rich plasma was the most studied biologic therapy, being evaluated in 33 (94.3%) studies. Ulnar collateral ligament and hamstring injuries were the conditions most studied (nine (25.7%) studies and seven (20.0%) studies, respectively). Athletes most frequently participated in baseball, soccer, and American football. Only two (5.7%) studies were level 1 evidence, with interpretation and comparison between studies limited by the variations in the injury profile, biologic preparations, and rehabilitation protocols. CONCLUSION There is diverse use of biologic therapies in the management of musculoskeletal injuries in professional and Olympic athletes. There is currently insufficient high-level evidence to support the widespread use of biologic therapies in athletes. Further research priorities include the development of condition/pathology-specific preparations of biologic therapies, and of outcome measures and imaging modalities sufficiently sensitive to detect differences in outcomes, should they exist. Cite this article: Bone Joint J 2021;103-B(7):1189-1196.
Ethical aspects of facilitating the recruitment of people with dementia for clinical trials: A call for further debate

Under‐representation of people with dementia in clinical research remains a significant obstacle to develop evidence‐based practice guidelines and recommendation for dementia care and slows down the development of disease‐modifying pharmacological interventions. This is partly due to the ethical challenges and complexities of recruiting people with dementia for clinical trials. The traditional approach adopted by research ethics committees and regulatory bodies has been to protect people with dementia as a vulnerable population from harms of participating in research. There are concerns that this approach is unduly rigid, precludes the conduct of necessary research, and has exclusionary, paternalistic and discriminatory ramifications. As such, there are increasing calls to shift to a new hybrid facilitative/protective approach. This paper identifies 4 strategies to operationalise the facilitative/protective approach in the context of dementia research. These are: (i) embedding dementia research in clinical care; (ii) increasing the recruitment of people at preclinical stages of dementia; (iii) streamlined proxy consent procedures; and (iv) advance research consent. I note that all 4 strategies hold the promise of facilitating the recruitment of people with dementia in clinical research. Nonetheless, they give rise to a diverse range of new ethical concerns and issues. This necessitates further scholarly work to explore possible ways to address the ethical concerns and issues arisen by the uptake of protective/facilitative approach. In particular, further research is necessary to clarify, to what extent, the said strategies ameliorate or increase the vulnerability of people with dementia.
The 30-day survival and recovery after hip fracture by timing of mobilization and dementia : a UK database study.

AIMS The aim of this study to compare 30-day survival and recovery of mobility between patients mobilized early (on the day of, or day after surgery for a hip fracture) and patients mobilized late (two days or more after surgery), and to determine whether the presence of dementia influences the association between the timing of mobilization, 30-day survival, and recovery. METHODS Analysis of the National Hip Fracture Database and hospital records for 126,897 patients aged ≥ 60 years who underwent surgery for a hip fracture in England and Wales between 2014 and 2016. Using logistic regression, we adjusted for covariates with a propensity score to estimate the association between the timing of mobilization, survival, and recovery of walking ability. RESULTS A total of 99,667 patients (79%) mobilized early. Among those mobilized early compared to those mobilized late, the weighted odds ratio of survival was 1.92 (95% confidence interval (CI) 1.80 to 2.05), of recovering outdoor ambulation was 1.25 (95% CI 1.03 to 1.51), and of recovering indoor ambulation was 1.53 (95% CI 1.32 to 1.78) by 30 days. The weighted probabilities of survival at 30 days post-admission were 95.9% (95% CI 95.7% to 96.0%) for those who mobilized early and 92.4% (95% CI 92.0% to 92.8%) for those who mobilized late. The weighted probabilities of regaining the ability to walk outdoors were 9.7% (95% CI 9.2% to 10.2%) and indoors 81.2% (95% CI 80.0% to 82.4%), for those who mobilized early, and 7.9% (95% CI 6.6% to 9.2%) and 73.8% (95% CI 71.3% to 76.2%), respectively, for those who mobilized late. Patients with dementia were less likely to mobilize early despite observed associations with survival and ambulation recovery for those with and without dementia. CONCLUSION Early mobilization is associated with survival and recovery for patients (with and without dementia) after hip fracture. Early mobilization should be incorporated as a measured indicator of quality. Reasons for failure to mobilize early should also be recorded to inform quality improvement initiatives. Cite this article: Bone Joint J 2021;103-B(7):1317-1324.
Improving deuterium metabolic imaging (DMI) signal‐to‐noise ratio by spectroscopic multi‐echo bSSFP: A pancreatic cancer investigation

Deuterium metabolic imaging (DMI) maps the uptake of deuterated precursors and their conversion into lactate and other markers of tumor metabolism. Even after leveraging 2H’s short T1s, DMI’s signal‐to‐noise ratio (SNR) is limited. We hypothesize that a multi‐echo balanced steady‐state free precession (ME‐bSSFP) approach would increase SNR compared to chemical shift imaging (CSI), while achieving spectral isolation of the metabolic precursors and products.
Corrigendum to: Phenology, Development, and Parasitism of Allium Leafminer (Diptera: Agromyzidae), a Recent Invasive Species in the United States

Allium leafminer, Phytomyza gymnostoma (Diptera: Agromyzidae), is an invasive species first recorded in the Western Hemisphere in 2015 and has expanded its range into northeastern and MidAtlantic states. Its host range encompasses Allium species grown for food and ornamentals, weedy species, species used for pollinator provisioning, and species of conservation concern. Using field and laboratory studies, we advanced methods for rearing, developed a phenology model for spring emergence, describe pupal development, and report on parasitism. Spring emergence was best detected by scouting wild alliums as opposed to emergence cages, and modeled using 350 degree-days above a lower threshold of 1.0°C. Spring adult flight occurred for about 5 wk. Larval development required 22 and 20 d at 17.5 and 25°C, respectively. Pupal development progressed along a color gradient, and an initial presence of fat cell clusters and an air bubble, followed by an exarate pupa. Pupal developed at 3–5% per day at 3°C and reached 25% per day at 21.5°C, but development was not successful at 30°C. Although parasitism rates were low, we documented two Chalcidoidea parasitoids, Halticoptera circulus (Walker) (Hymenoptera: Pteromalidae) and Chrysocharis oscinidis Ashmead (Hymenoptera: Pteromalidae). Together, these data provide baseline information to advance IPM for this invasive species both in crops and noncrop areas.
Chemoradiotherapy Followed by Active Surveillance Versus Standard Esophagectomy for Esophageal Cancer

Supplemental Digital Content is available in the text Objective: To compare overall survival of patients with a cCR undergoing active surveillance versus standard esophagectomy. Summary of Background Data: One-third of patients with esophageal cancer have a pathologically complete response in the resection specimen after neoadjuvant chemoradiotherapy. Active surveillance may be of benefit in patients with cCR, determined with diagnostics during response evaluations after chemoradiotherapy. Methods: A systematic review and meta-analysis was performed comparing overall survival between patients with cCR after chemoradiotherapy undergoing active surveillance versus standard esophagectomy. Authors were contacted to supply individual patient data. Overall and progression-free survival were compared using random effects meta-analysis of randomized or propensity score matched data. Locoregional recurrence rate was assessed. The study-protocol was registered (PROSPERO: CRD42020167070). Results: Seven studies were identified comprising 788 patients, of which after randomization or propensity score matching yielded 196 active surveillance and 257 standard esophagectomy patients. All authors provided individual patient data. The risk of all-cause mortality for active surveillance was 1.08 [95% confidence interval (CI): 0.62–1.87, P = 0.75] after intention-to-treat analysis and 0.93 (95% CI: 0.56–1.54, P = 0.75) after per-protocol analysis. The risk of progression or all-cause mortality for active surveillance was 1.14 (95% CI: 0.83–1.58, P = 0.36). Five-year locoregional recurrence rate during active surveillance was 40% (95% CI: 26%–59%). 95% of active surveillance patients undergoing postponed esophagectomy for locoregional recurrence had radical resection. Conclusions: Overall survival was comparable in patients with cCR after chemoradiotherapy undergoing active surveillance or standard esophagectomy. Diagnostic follow-up is mandatory in active surveillance and postponed esophagectomy should be offered to operable patients in case of locoregional recurrence.
Sodium Danshensu inhibits the progression of lung cancer by regulating PI3K/Akt signaling pathway

Sodium Danshensu, extracted from the root of the Salvia miltiorrhiza, has pleiotropic effects including anti‐oxidation, anti‐inflammation and anti‐tumor. However, whether Sodium Danshensu has an anti‐cancer effect in lung cancer remains to be elucidated. The present study aimed to illustrate the effects of Sodium Danshensu on lung cancer cells and the potential molecular mechanisms. BEAS‐2B, A549, and NCI‐H1299 cells were stimulated with 25, 50, and 100 μM Sodium Danshensu for 24, 48, and 72 h, and then cell viability, apoptosis, migration and invasion were determined using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT), flow cytometry and Transwell assays, respectively. Moreover, the levels of Proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 9 (MMP9), B‐cell lymphoma‐2 (Bcl‐2) associated X (Bax), Bcl‐2, phosphorylated (p)‐phosphoinositide 3‐kinase (PI3K), and p‐Protein kinase B (AKT) in lung cancer cells were evaluated using quantitative real‐time polymerase chain reaction (qRT‐PCR) and/or Western blot assays. We observed that Sodium Danshensu suppressed cells viability, migration, and invasion, as well as promoted cells apoptosis in A549 and NCI‐H1299 cells in a dose‐dependent manner, while Sodium Danshensu had no cytotoxic effect on the proliferation activity of BEAS‐2B cells. Moreover, the expression of PCNA, MMP9, Bcl‐2 were decreased, but Bax was up‐regulated in Sodium Danshensu‐treated A549 and NCI‐H1299 cells. Our findings also revealed that Sodium Danshensu inhibited PI3K/AKT pathway in A549 and NCI‐H1299 cells. In conclusion, our study provided the first evidence that Sodium Danshensu suppressed the malignant biological behaviors of lung cancer cells, indicating that Sodium Danshensu might be a latent candidate for lung cancer therapy.
Eponyms have a place in the anatomy classroom

It was a pleasure to read the article "NOMENs Land: The Place of Eponyms in the Anatomy Classroom" published in Anatomical Sciences Education by McNulty et al. (2021). As a senior medical student, I especially took interest in their thoughts of how eponyms impact student learning. I write this to share my experience of learning eponyms in the anatomy classroom as a learner, in response to their conclusion of furthering this discussion.
The coevolution of flower longevity and self‐fertilization in hermaphroditic plants

Self‐fertilization, prevalent in plants, is typically divided into three modes – prior, competing, and delayed selfing – based on the timing in which it occurs. Flower longevity affects both the opportunity for pollination and the resources allocated for fertility, and thus may influence the selection on different modes of self‐fertilization. Additionally, selfing causes fertilization to depend less on pollinators, which may also influence the evolution of flower longevity. Using game‐theoretical models, I investigate how inbreeding depression and the pollination environment influences the coevolution of the three modes of self‐fertilization with flower longevity. Invasion of prior selfing allows the subsequent evolution of shorter flower longevity, and thus is favored over competing selfing. Prior selfing can also invade even under high inbreeding depression when the pollen deposition rate is low, but is inhibited by a higher level of delayed selfing. In general, the evolution of selfing decreases flower longevity, and reveals asymmetric effects of pollen deposition and removal on flower longevity. This study suggests considering realization of selfing and outcrossing as concrete processes by incorporating flower reproductive strategies (e.g., flower longevity) and pollination ecology (e.g., accrual rate) may offer better understanding of the evolution of mating systems and flower reproductive traits.
Reconstruction of the Fas-Based Death-Inducing Signaling Complex (DISC) Using a Protein–Protein Docking Meta-Approach

The death-inducing signaling complex (DISC) is a fundamental multiprotein complex, which triggers the extrinsic apoptosis pathway through stimulation by death ligands. DISC consists of different death domain (DD) and death effector domain (DED) containing proteins such as the death receptor Fas (CD95) in complex with FADD, procaspase-8, and cFLIP. Despite many experimental and theoretical studies in this area, there is no global agreement neither on the DISC architecture nor on the mechanism of action of the involved species. In the current work, we have tried to reconstruct the DISC structure by identifying key protein interactions using a new protein–protein docking meta-approach. We combined the benefits of five of the most employed protein–protein docking engines, HADDOCK, ClusPro, HDOCK, GRAMM-X, and ZDOCK, in order to improve the accuracy of the predicted docking complexes. Free energy of binding and hot spot interacting residues were calculated and determined for each protein–protein interaction using molecular mechanics generalized Born surface area and alanine scanning techniques, respectively. In addition, a series of in-cellulo protein-fragment complementation assays were conducted to validate the protein–protein docking procedure. The results show that the DISC formation initiates by dimerization of adjacent FasDD trimers followed by recruitment of FADD through homotypic DD interactions with the oligomerized death receptor. Furthermore, the in-silico outcomes indicate that cFLIP cannot bind directly to FADD; instead, cFLIP recruitment to the DISC is a hierarchical and cooperative process where FADD initially recruits procaspase-8, which in turn recruits and heterodimerizes with cFLIP. Finally, a possible structure of the entire DISC is proposed based on the docking results.
Regulation of reversible conformational change, size switching, and immunomodulation of RNA nanocubes

In biological systems, conformational changes and allosteric modulation play pivotal roles in regulating biological functions, such as the dynamic change of protein molecules, in response to binding or interacting with other factors such as pH, voltage, salt, light, or ligand. RNA can be manipulated and tuned with a level of simplicity that is characteristic of DNA or polymers, while displaying versatility in structure, diversity in function, and adaptability in a configuration similar to proteins. In the past, the work on the investigation of conformational change mainly focused on protein. The induced-fit and conformational capture in RNA have also been explored, such as in the study of riboswitches. Herein, we report the engineering of three-dimensional RNA nanocubes and demonstrated the operation and regulation for its configuration. We demonstrate the operation of reconfigurable RNA nanocubes whose shapes change precisely and reversibly in response to a specific trigger strand. The shape, size, and conformation can be regulated precisely and reversibly in response to the specific triggering signals. The shape and conformational conversion were observed by cryo-EM and gel electrophoresis, respectively. Harnessing the size, shape, conformation, and self-assembly capabilities of the RNA nanocube can provide a new potential use of this technology as nanocarriers for the treatment of various diseases.
Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts

Abstract Mucopolysaccharidosis type I (MPS-I) is a rare lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase, which removes iduronic acid in both chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) and thereby contributes to the catabolism of glycosaminoglycans (GAGs). To ameliorate this genetic defect, the patients are currently treated by enzyme replacement and bone marrow transplantation, which have a number of drawbacks. This study was designed to develop an alternative treatment by inhibition of iduronic acid formation. By screening the Prestwick drug library, we identified ebselen as a potent inhibitor of enzymes that produce iduronic acid in CS/DS and HS. Ebselen efficiently inhibited iduronic acid formation during CS/DS synthesis in cultured fibroblasts. Treatment of MPS-I fibroblasts with ebselen not only reduced accumulation of CS/DS but also promoted GAG degradation. In early Xenopus embryos, this drug phenocopied the effect of downregulation of DS-epimerase 1, the main enzyme responsible for iduronic production in CS/DS, suggesting that ebselen inhibits iduronic acid production in vivo. However, ebselen failed to ameliorate the CS/DS and GAG burden in MPS-I mice. Nevertheless, the results propose a potential of iduronic acid substrate reduction therapy for MPS-I patients.
The Dynamics of Spreading of Oils on Hydrophilic and Hydrophobic Surfaces Revisited Using Computational Fluid Dynamics

The dynamics of drop spreading on horizontal smooth surfaces of different wettabilities is revisited using computational fluid dynamics (CFD). For this purpose, a recently developed CFD model, based on the volume of fluid technique (VOF), with piecewise linear interface calculations method (PLIC) for interface reconstruction, is generalized and applied to simulate the time evolution of spreading drops on solid surfaces (drop base radius and dynamic contact angle). The CFD simulations are quantitatively compared with previously published experimental results from other research groups. The influence of different factors, such as oils nature (silicone, mineral, peanut and coconut), viscosity (0.02-1 Pa·s), drop volume (0.3-38 μL) and type of surfaces (hydrophilic glass, stainless steel and hydrophobic glass) on the temporal evolution of the drop base radius and contact angle is investigated. For hydrophilic surfaces, the predictions of the CFD model agree remarkably well with the measurements. For hydrophobic surfaces, a small deviation between calculated and experimental results occurs because the model does not consider the partial slippage which can take place on hydrophobic materials. Despite neglecting this aspect, the simulations are found to capture the key features of drop spreading on hydrophobic surface. The fact that we obtain a good agreement between the proposed theory and the experimental results for a large range of oils and surfaces over five decades of time is a strong argument in favor of the model. The accuracy of the model demonstrates also that the influence of the surface wettabity (partial wetting and complete wetting) can be successfully simulated. The numerical results reproduce perfectly the spreading regimes which occur during the time course of the drop. The succession of two different regimes takes place in the following order: a hydrodynamic regime followed by a gravity regime.