Miracle-dz/UniFAR-FTUs huggingface dataset:
Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity

Purpose: Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti–PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective β-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. Patients and Methods: A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months. Results: Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders. Conclusions: Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.
Cardiovascular Protection of Hydroxychloroquine in Patients with Sjögren’s Syndrome

Sjögren’s syndrome (SS) is a chronic systemic inflammation disease with clinical presentation of dry eye, dry mouth, and polyarthralgia. Active inflammation is associated with an increased risk of associated arterial stiffness or subclinical atherosclerosis-related cardiovascular events. We used the longitudinal health insurance database of Taiwan, which includes one million participants, to evaluate the relationship between the clinical medication of hydroxychloroquine (HCQ) and the development of coronary artery disease (CAD). In total, 1674 patients with SS receiving HCQ medication were included after exclusion for previous CAD. Altogether, 1142 SS patients were included for evaluation after follow-up for more than one year. After adjusting for age, gender, medications, and chronic comorbidities, a significantly decreased hazard ratio (HR) for developing CAD was found among SS patients with higher medication possession ratio (MPR) of HCQ (HR = 0.49, 95% confidence interval, CI: 0.26–0.94) when compared with low MPR of HCQ. A low HR for CAD was observed in SS patients with a high cumulative dose of at least 100,267 mg of HCQ (HR = 0.25, 95% CI: 0.09–0.66). Long-term HCQ therapy may decrease the HR of CAD in SS patients. The significant cardiovascular protective effect of HCQ therapy was observed in our study.
Non-destructive measurement of plant growth and nitrogen status of pearl millet with low-altitude aerial photography

AbstractComputer based image analysis has led to a widespread use of satellite images and aerial photographs in agriculture. However, the application of remote sensing techniques for non-destructive determinations of plant dry matter and nutrient status in field trials has been limited due to the low resolution of satellite images and the high cost of aerial photographs. A simple method based on 24 × 36 mm low-altitude (50 to 500 m) true colour and infra-red aerial photographs taken from a balloon (low-wind conditions) or a kite (high-wind conditions) was used to determine the total dry matter of coppices of the shrub Guiera senegalensis J. F. Gmel. and widely-spaced pearl millet (Pennisetum glaucum L.) planting hills. Results from field trials showed a close relationship (r2 = 0.84 for G. senegalensis and r2 = 0.74 for millet) between the harvested total dry matter of single plants and the plant canopy area determined from the digital analysis of aerial photographs.For pearl millet, differences in the di.
Occupational exposure to graphene and silica nanoparticles. Part I: workplace measurements and samplings

Abstract Few-Layers Graphene (FLG) are able to improve the performance of materials, due to their chemical-physical properties. Engineered amorphous silica nanoparticles (SiO2NPs) are among the most widespread nanomaterials (NMs) in the world. Such nanomaterials are two case studies of the research project ‘NanoKey’ that integrated the exposure assessment through personal measurements and sampling in the workplace, as described in the present work (part I), with the biomonitoring of exposed workers (reported in part II). Measurement campaigns were conducted according to OECD and WHO harmonized approach in two production sites. The set of instruments included real-time devices for high-resolution measurements at the nanoscale and time-integrated samplers for the off-line gravimetric analysis and chemical and morphological (SEM-EDS) characterization of exposure in order to identify the contribution of production compared to the background. Values of particle number concentration (PNC) and lung deposited surface area (LDSA) within the FLG production resulted higher than the background far field (FF), even if they are always similar to the near field (NF) ones: the average diameter (Davg) during the production was higher than the NF background but always lower than the FF values. SEM-EDS analysis highlighted the presence of structures comparable to those produced. During the SiO2NPs production, the PBZ values showed PNC and LDSA levels higher than the background, with a decrease in the Davg probably due to NPs emission. SEM-EDS confirms the presence of rare silica nanoparticles. Since the exposure to airborne NMs cannot be excluded in both production sites, a prevention-through-design approach to mitigate the potential risk for workers has been recommended.
Mammalian Homologue NME3 of DYNAMO1 Regulates Peroxisome Division

Peroxisomes proliferate by sequential processes comprising elongation, constriction, and scission of peroxisomal membrane. It is known that the constriction step is mediated by a GTPase named dynamin-like protein 1 (DLP1) upon efficient loading of GTP. However, mechanism of fuelling GTP to DLP1 remains unknown in mammals. We earlier show that nucleoside diphosphate (NDP) kinase-like protein, termed dynamin-based ring motive-force organizer 1 (DYNAMO1), generates GTP for DLP1 in a red alga, Cyanidioschyzon merolae. In the present study, we identified that nucleoside diphosphate kinase 3 (NME3), a mammalian homologue of DYNAMO1, localizes to peroxisomes. Elongated peroxisomes were observed in cells with suppressed expression of NME3 and fibroblasts from a patient lacking NME3 due to the homozygous mutation at the initiation codon of NME3. Peroxisomes proliferated by elevation of NME3 upon silencing the expression of ATPase family AAA domain containing 1, ATAD1. In the wild-type cells expressing catalytically-inactive NME3, peroxisomes were elongated. These results suggest that NME3 plays an important role in peroxisome division in a manner dependent on its NDP kinase activity. Moreover, the impairment of peroxisome division reduces the level of ether-linked glycerophospholipids, ethanolamine plasmalogens, implying the physiological importance of regulation of peroxisome morphology.
The prevalence of MERS‐CoV among military personnel and their families: A single‐center study

Middle East respiratory syndrome coronavirus (MERS‐CoV) is a Betacoronavirus that results in a severe fatal respiratory disease; however, it is also associated with mild inapparent infections. The western part of the Kingdom of Saudi Arabia (KSA) contains the holy places where millions of Muslims gathered from all over the world, all year round, with a high probability of mass disease transmission. The aim of this study was to estimate the prevalence of MERS‐CoV among military personnel and their families during the period 2014–2019, in the western part of the KSA. A total of 35,203 sputum samples collected from patients with respiratory distress were screened for the presence of MERS‐CoV using real‐time reverse‐transcription polymerase chain reaction in the examined patients. MERS‐CoV infections were detected at a very low percentage in the examined patients. Only 42 of the examined subjects (0.12%) were found positive for MERS‐CoV. Most infected cases (32/42) cases were detected in 2014, and the rest of the cases were reported in 2015–2019. The cases with fatal consequences (n = 20) were only detected in 2014. It was concluded that there is a very low prevalence of MERS‐CoV infections among the military personnel and their families.
The rise of prosociality in fiction preceded democratic revolutions in Early Modern Europe

Significance We analyzed a large sample of English and French theatre plays and tracked the dynamics of words related to cooperation and dominance before and after early modern revolutions. We show that prior to both the English Civil War and French Revolution, there was a sharp rise in the frequency of words associated with prosociality, trustworthiness, and sympathy vs. words related to authoritarianism, strength and anger. Interestingly, in postrevolutionary reactionary periods, characters became stronger and less trustworthy. Finally, we also show that variations in GDP per capita partially account for these psychological changes. These findings reveal the interplay between economic environment, psychological preferences, and political events and shed lights on the rise and fall of support for democracy. The English and French Revolutions represent a turning point in history, marking the beginning of the modern rise of democracy. Recent advances in cultural evolution have put forward the idea that the early modern revolutions may be the product of a long-term psychological shift, from hierarchical and dominance-based interactions to democratic and trust-based relationships. In this study, we tested this hypothesis by analyzing theater plays during the early modern period in England and France. We found an increase in cooperation-related words over time relative to dominance-related words in both countries. Furthermore, we found that the accelerated rise of cooperation-related words preceded both the English Civil War (1642) and the French Revolution (1789). Finally, we found that rising per capita gross domestic product (GDPpc) generally led to an increase in cooperation-related words. These results highlight the likely role of long-term psychological and economic changes in explaining the rise of early modern democracies.
Security Evaluation under Different Exchange Strategies Based on Heterogeneous CPS Model in Interdependent Sensor Networks

In the real Internet of Everything scenario, many large-scale information systems can be converted into interdependent sensor networks, such as smart grids, smart medical systems, and industrial Internet systems. These complex systems usually have multiple interdependent sensor networks. Small faults or failure behaviors between networks may cause serious cascading failure effects of the entire system. Therefore, in this paper, we will focus on the security of interdependent sensor networks. Firstly, by calculating the size of the largest functional component in the entire network, the impact of random attacks on the security of interdependent sensor networks is analyzed. Secondly, it compares and analyzes the impact of cascading failures between interdependent sensor networks under different switching edge strategies. Finally, the simulation results verify the effect of the security of the system under different strategies, and give a better exchange strategy to enhance the security of the system. In addition, the research work in this article can help design how to further optimize the topology of interdependent sensor networks by reducing the impact of cascading failures.
The impact of different Saccharomyces cerevisiae strains on microbial composition and quality of Chinese rice wine fermentations

Chinese rice wine (CRW) is a popular fermented product in China, with complicated microbial composition and flavour compounds. To reveal the effects of different strains of Saccharomyces cerevisiae (N85 and XZ11) on the microbial composition in the process of brewing, metagenomic sequencing approaches were carried out to explore the dynamic changes of bacteria and fungi. Furthermore, the volatile compounds and organic acids in CRW were identified by headspace solid phase microextraction (HS‐SPME)/gas chromatography–mass spectrometry (GC‐MS) and liquid chromatography–mass spectrometry (LC‐MS) at the end of the brewing. Our results indicated that different S. cerevisiae strains could influence microbial compositions and especially affected the growth of Lactobacillus brevis and Pantoea ananatis. The changes in the microbial community structure contributed to the remarkable difference in the content of lactic acid, esters, alcohols, and aldehydes. Moreover, functional network analysis provided insights into the biological correlations between microbial species and metabolic pathways, that is, Lactobacillus genus had negative effects on metabolic activities. This study expands the idea of improving the quality of CRW by controlling the microbiome.
Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme

Objective Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). We report the largest integrated safety analysis of tofacitinib, as of March 2017, using data from phase I, II, III, IIIb/IV and long-term extension studies in adult patients with RA. Methods Data were pooled for patients with RA who received ≥1 tofacitinib dose. Incidence rates (IRs; patients with events/100 patient-years [PY]; 95% CIs) of first-time occurrences were obtained for adverse events (AEs) of interest. Results 7061 patients received tofacitinib (total exposure: 22 875 PY; median [range] exposure: 3.1 [0 to 9.6] years). IRs (95% CI) for serious AEs, serious infections, herpes zoster (all), opportunistic infections (excluding tuberculosis [TB]) and TB were 9.0 (8.6 to 9.4), 2.5 (2.3 to 2.7), 3.6 (3.4 to 3.9), 0.4 (0.3 to 0.5) and 0.2 (0.1 to 0.2), respectively. IRs (95% CI) for malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC and lymphomas were 0.8 (0.7 to 0.9), 0.6 (0.5 to 0.7) and 0.1 (0.0 to 0.1), respectively. IRs (95% CI) for gastrointestinal perforations, deep vein thrombosis, pulmonary embolism, venous thromboembolism, arterial thromboembolism and major adverse cardiovascular events were 0.1 (0.1 to 0.2), 0.2 (0.1 to 0.2), 0.1 (0.1 to 0.2), 0.3 (0.2 to 0.3), 0.4 (0.3 to 0.5) and 0.4 (0.3 to 0.5), respectively. IR (95% CI) for mortality was 0.3 (0.2 to 0.3). IRs generally remained consistent across 6-month intervals to >78 months. Conclusion This represents the largest clinical dataset for a JAK inhibitor in RA to date. IRs remained consistent with previous reports from the tofacitinib RA clinical development programme, and stable over time. Trial registration numbers NCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01164579; NCT00976599; NCT01059864; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661. For summary of phase I, phase II, phase III, phase IIIb/IV and LTE studies included in the integrated safety analysis, see online supplemental table 1.
Adjunctive Treatment With Avacopan, an Oral C5a Receptor Inhibitor, in Patients With Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

This study aimed to evaluate the safety of avacopan, an orally administered C5a receptor inhibitor, for the treatment of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis in addition to standard‐of‐care (SOC) treatment with glucocorticoids with cyclophosphamide or rituximab.
Wolbachia host shifts: routes, mechanisms, constraints and evolutionary consequences

Wolbachia is one of the most abundant endosymbionts on earth, with a wide distribution especially in arthropods. Effective maternal transmission and the induction of various phenotypes in their hosts are two key features of this bacterium. Here, we review our current understanding of another central aspect of Wolbachia's success: their ability to switch from one host species to another. We build on the proposal that Wolbachia host shifts occur in four main steps: (i) physical transfer to a new species; (ii) proliferation within that host; (iii) successful maternal transmission; and (iv) spread within the host species. Host shift can fail at each of these steps, and the likelihood of ultimate success is influenced by many factors. Some stem from traits of Wolbachia (different strains have different abilities for host switching), others on host features such as genetic resemblance (e.g. host shifting is likely to be easier between closely related species), ecological connections (the donor and recipient host need to interact), or the resident microbiota. Host shifts have enabled Wolbachia to reach its enormous current incidence and global distribution among arthropods in an epidemiological process shaped by loss and acquisition events across host species. The ability of Wolbachia to transfer between species also forms the basis of ongoing endeavours to control pests and disease vectors, following artificial introduction into uninfected hosts such as mosquitoes. Throughout, we emphasise the many knowledge gaps in our understanding of Wolbachia host shifts, and question the effectiveness of current methodology to detect these events. We conclude by discussing an apparent paradox: how can Wolbachia maintain its ability to undergo host shifts given that its biology seems dominated by vertical transmission?
Predicting dive start performance from kinematic variables at water entry in (sub-)elite swimmers

The dive start is an important component of competitive swimming, especially at shorter race distances. Previous research has suggested that start performance depends on kinematic variables pertaining to the swimmer at water entry, notably the distance from the block, the horizontal velocity of the centre of mass and the angle between body and water surface. However, the combined and relative contributions of these variables to start performance remain to be determined. The aim of the present study was therefore to develop a model to predict start performance (time from take-off to reaching the 15-m line) from a set of kinematic variables that collectively define the swimmer’s entry state. To obtain an appropriate database for this purpose, fifteen well-trained, (sub-)elite swimmers performed dive starts under different instructions intended to induce substantial variation in entry state. Kinematic data were extracted from video recordings of these starts, optimised and analysed statistically. A mixed effects analysis of the relation between entry state and start performance was conducted, which revealed a significant and robust dependence of start performance on entry state (χ2(3) = 88, p < . 001), explaining 86.1% of the variance. Start time was reduced by 0.6 s (p < .001) when the horizontal displacement at water entry was 1 m further, by 0.3 s (p < .001) when the horizontal velocity of the centre of mass was 1 m/s higher, and by 0.5 s (p < .01) when the entry angle was 1 radian flatter. The robustness of the analysis was confirmed by a similar mixed effects analysis of the relation between entry state and time to the 5-m line. In conclusion, dive start performance can be predicted to a considerable extent from the swimmer’s state at water entry. The implications of those findings for studying and improving block phase kinetics are discussed.
The feasibility and effectiveness of internet-based rehabilitation for patients with knee osteoarthritis

Abstract Background: Internet-based rehabilitation can ease the progression of chronic diseases. There had been studies on internet-based rehabilitation of knee osteoarthritis (OA), but them were conducted at home and ignored the potential benefits in the community setting. This study will explore the feasibility and effectiveness of internet-based rehabilitation accompanies wearable devices in the community setting for the patients with knee OA. Methods: An assessor-blinded randomized controlled feasibility trial will be performed to study the feasibility and effectiveness of internet-based rehabilitation program for the patients with knee OA in the community setting. Forty participants with knee OA will be recruited and randomly allocated into internet-based rehabilitation group (IRG) or control group (CG). The interventions of IRG will be performed in the community setting via web-based platform and wearable devices. The outcome measures will be conducted at baseline, and post-intervention 6 weeks, 12 weeks during the study. The feasibility will be tested by the proportion of participants who will complete the internet-based rehabilitation program within 12 weeks in IRG as well as the compliance and satisfaction. Additionally, the effectiveness of internet-based rehabilitation will be assessed by the Western Ontario and McMaster Universities Osteoarthritis Index, 11-point Numerical Rating Scale and Short Form-36 quality-of-life questionnaire. Conclusion: The internet-based rehabilitation program and community-based interventions is feasible and efficacy to ameliorate the osteoarthritic pain and promote the physical function and quality of life for the patients with knee OA in the community setting. Trial registration number: The study was registered in the clinical trial registry ChiCTR2000033397.
Cricket-Enriched Oat Biscuit: Technological Analysis and Sensory Evaluation

Insect-containing products are gaining more space in the market. Bakery products are one of the most promising since the added ground insects can enhance not only the nutritional quality of the dough, but technological parameters and sensory properties of the final products. In the present research, different amounts of ground Acheta domesticus (house cricket) were used to produce oat biscuits. Colour, hardness, and total titratable acidity (TTA) values were measured as well as a consumer sensory test was completed using the check-all-that-apply (CATA) method. An estimation of nutrient composition of the samples revealed that, according to the European Union’s Regulation No. 1924/2006, the products with 10 and 15 g/100 g cricket enrichment (CP10 and CP15, respectively) can be labelled as protein sources. Results of the colour, TTA, and texture measurements showed that even small amounts of the cricket powder darkened the colour of the samples and increased their acidity, but did not influence the texture significantly. Among product-related check all that apply (CATA) attributes, fatty and cheesy flavour showed a significant positive effect on overall liking (OAL). On the other hand, burnt flavour and brown colour significantly decreased OAL. OAL values showed that consumers preferred the control product (CP0) and the product with 5 g/100 g cricket enrichment (CP5) samples over CP10 and rejected CP15.