bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative analysis of generic Cefixime in healthy subjects using UPLC-MS/MS and its bioavailability and pharmacokinetics evaluation utilization
Authors: Subiakto Yuli , Rismawan Haris , Tuba Syahrul
Published: August 2022

This study aims to compare the bioavailability of Lafsefik Dry Syrup (Lafsefik DS) containing 100 mg/5 ml cefixime with Suprax Oral Suspension (Suprax OS). The bioequivalence test was carried out with a cross-sectional study design with two stages, a randomized, crossover, two-way, double-blind, single-dose control, with pharmacokinetic parameters including AUC 0-t, Cmax, Tmax T1/2, which included 21 male and female healthy adult individuals under fasting conditions. Blood plasma levels were measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). The comparative dissolution test for the Lafsefik DS test drug product was 28.82% at pH 1.2, 62.99% at pH 4.5, and 69.90% at pH 6.8, as indicated by the F2 value. The F2 value was <50% with Suprax OS at pH 1.2 and >50% at pH 4.5 and pH 6.8. The results of the bioequivalence test showed AUC0-32= 22,857±7,639 ng ml-1 hour, AUC0-inf = 23,440±7,720 ng mL-1.hour, Cmax = 2,695± 858 ng mL-1, Tmax= 4.05 ±0.79 hours, and T½= 3.98 ± 0.38 hours. The values of the Suprax OS innovator were AUC0-32 = 21,496±5,849 ng mL-1.hour, AUC0-inf = 22,032.±5,863 ng mL-1hour, Cmax = 2,561±554 ng mL-1, Tmax = 4.19 ±0.84 hours, and T½ = 4.02 ±0.51 hours. The geometric mean ratio of test drug to innovator drug (90% CI) showed bioequivalence with values ​​of AUC0-32= 104.71% (98.13-111.23), Cmax= 102.61% (95.79-109.61), CV intrasubject of AUC0-32= 11.70%, and Cmax = 11.31%. The Lafsefik DS test drug product shows a similarity of an F2 value >50% and is bioequivalent to the comparison drug product.
Estimating the risk of incident SARS-CoV-2 infection among healthcare workers in quarantine hospitals: the Egyptian example
Authors: Jijón Sofía , Shafie Ahmad Al , Hassan Essam ,   EMAE-MESuRS working group on nosocomial SARS-CoV-2 modeling, Temime Laura , Jean Kévin , El-Kassas Mohamed
Published: August 2022

In response to the COVID-19 epidemic, Egypt established a unique care model based on quarantine hospitals where only externally-referred confirmed COVID-19 patients were admitted, and healthcare workers resided continuously over 1- to 2-week working shifts. While the COVID-19 risk for HCWs has been widely reported in standard healthcare settings, it has not been evaluated yet in quarantine hospitals. Here, we relied on longitudinal data, including results of routine RT-PCR tests, collected within three quarantine hospitals located in Cairo and Fayoum, Egypt. Using a mathematical model accounting for the time-since-exposure variation in false-negative rates of RT-PCR tests, we computed the incidence rate of SARS-CoV-2 infection among HCWs. Our results thus unveil the proportion of infections remaining undiagnosed despite routine testing. We estimated that the risk for an HCW to be infected during a working shift lied within the range of risk levels previously documented in standard healthcare settings for two quarantine hospitals, whereas it was > 3-fold higher for the third hospital. This large variation suggests that HCWs from quarantine hospitals may face a high occupational risk of infection, but that, with sufficient infection control measures, this risk can be brought down to levels similar to those observed in standard healthcare settings.
Febrile illness in high-risk children: a prospective, international observational study
Authors: Velden Fabian J.S. van der , de Vries Gabriella , Martin Alexander , Lim Emma , von Both Ulrich , Kolberg Laura , Carrol Enitan D. , Khanijau Aakash , Herberg Jethro A. , De Tisham , Galassini Rachel , Kuijpers Taco W. , Martinón-Torres Federico , Rivero-Calle Irene , Vermont Clementien L. , Hagedoorn Nienke N. , Pokorn Marko , Pollard Andrew J. , Schlapbach Luregn J. , Tsolia Maria , Elefhteriou Irini , Yeung Shunmay , Zavadska Dace , Fink Colin , Voice Marie , Zenz Werner , Kohlmaier Benno , Agyeman Philipp K.A. , Usuf Effua , Secka Fatou , de Groot Ronald , Levin Michael , Flier Michiel van der , Emonts Marieke , Consortium PERFORM
Published: August 2022

PurposeTo assess and describe the aetiology and management of febrile illness in children with primary or acquired immunodeficiency at high-risk of serious bacterial infection, as seen in emergency departments in tertiary hospitals.MethodsProspective data on demographics, presenting features, investigations, microbiology, management, and outcome of patients within the ‘Biomarker Validation in HR patients’ database in PERFORM, were analysed. Immunocompromised children (<18 years old) presented to fifteen European hospitals in nine countries, and one Gambian hospital, with fever or suspected infection and clinical indication for blood investigations. Febrile episodes were assigned clinical phenotypes using the validated PERFORM algorithm. Logistic regression was used to assess effect size of predictive features of proven/presumed bacterial or viral infection.Results599 episodes in 482 children were analysed. Only 78 episodes (13.0%) were definite bacterial, 55 definite viral (9.2%), and 190 were unknown bacterial or viral infections (31.7%). Predictive features of proven/presumed bacterial infection were ill appearance (OR 3.1 (95%CI 2.1-4.6)) and HIV (OR 10.4 (95%CI 2.0-54.4)). Ill appearance reduced the odds of having a proven/presumed viral infection (OR 0.5 (95%CI 0.3-0.9)). 82.1% had new empirical antibiotics started on admission (N=492); 94.3% of proven/presumed bacterial, 66.1% of proven/presumed viral, and 93.2% of unknown bacterial or viral infections. Mortality was 1.9% and 87.1% made full recovery. ConclusionsAetiology of febrile illness in immunocompromised children is diverse. In one-third of cases no cause for the fever will be identified. Justification for standard intravenous antibiotic treatment for every febrile immunocompromised child is debatable, yet effective. Better clinical decision-making tools and new biomarkers are needed for this population.
Explainable Automated Recognition of Emotional States from Canine Facial Expressions: The Case of Positive Anticipation and Frustration
Authors: Boneh-Shitrit Tali , Feighelstein Marcelo , Bremhorst Annika , Amir Shir , Distelfeld Tomer , Dassa Yaniv , Yaroshetsky Sharon , Riemer Stefanie , Shimshoni Ilan , Mills Daniel S. , Zamansky Anna
Published: August 2022

Internal affective states are closely linked to facial expressions in both human and many non-human animals. For some animal species, objective tools for facial expression analysis such as AnimalFACS are available and are only just beginning to be increasingly used. However, their use requires special expertise, training, and certification, while there is still some remaining risk for human bias, and its application is time-consuming. Automation of facial analysis offers a promising alternative and is already being addressed by a large body of research in the human domain.
In animal research, automation has so far been addressed for a few species in the context of pain, while emotional state recognition remains underexplored, especially in canine species due to the complexity of their facial morphology and expressions. The contribution of the present study is twofold. First, this is the first study to address automated recognition of emotional states in dogs using a dataset obtained in a controlled experimental setting, including videos from (n=29) Labrador Retrievers assumed to be in two experimentally induced emotional states: negative (frustration) and positive (anticipation). Two different approaches are compared in relation to our aim: (1) A DogFACS-based approach with a two-step pipeline consisting of (i) an Action Unit (AU) detector and (ii) a positive/negative state Decision Tree classifier; (2) An approach using deep learning techniques with no intermediate representation. The approaches reach accuracy of above 71% and 89%, respectively, with the deep learning approach performing better.
Secondly, this study is the first to address the explainability of AI models in the context of understanding the expression of emotion in animals. The DogFACS-based approach provides decision trees, that is a mathematical representation which reflects previous findings by human experts in relation to certain DogFACS variables being correlates of specific emotional states. The deep learning approach offers a different, visual form of explainability in the form of heatmaps reflecting regions of focus of the network's attention, which in some cases show focus clearly related to the nature of particular AUs. These heatmaps may hold the key to novel insights on the sensitivity of the network to nuanced pixel patterns reflecting information invisible to the human eye.
CXCR4 enhances the inhibitory effects of bone mesenchymal stem cells on lung cell apoptosis in a rat model of smoking-induced COPD
Authors: GAO JIANSHENG , LIANG YULI , CHEN JIABAO , SHEN HUIHUI , LIU HUA
Published: August 2022

Objective
Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death worldwide, and treatments are unsatisfactory, resulting in a major economic burden. Cellular therapy is commonly used for lung disease. We investigated treatment with CXCR4-overexpressing BMSCs during COPD model establishment.
Methods
We extracted and purified BMSCs from SD rats. Apoptosis induced by COPD was established by cigarette smoke exposure. BMSCs were transplanted in vivo twice a month during model establishment, and alveolar rupture in the lung was assessed. Lung cell apoptosis was assessed by TUNEL analysis, and the concentrations of apoptotic proteins in the lungs were detected by Western blotting.
Results
We successfully isolated BMSCs and established CXCR4-overexpressing BMSCs. Continuous cigarette smoke exposure caused alveolar septal rupture: in the model group, the 1-month alveolar MLI was significantly lower than that at the third month (p < 0.05). In the third month, the alveolar MLIs of the control and CXCR4-BMSC groups were lower than those of the model group (control group p < 0.01, CXCR4-BMSC group p < 0.05), and as shown by TUNEL staining, the apoptosis rates of the control and CXCR4-BMSC groups were significantly lower than those of the model groups (p < 0.01). The levels of the apoptotic proteins cleaved caspase-8, cleaved caspase-3 and cleaved PARP-1 were higher in the model group than in the control group (p < 0.05) and significantly lower in the CXCR4-BMSC group than in the model group (p < 0.05).
Conclusion
Transplantation of CXCR4-overexpressing BMSCs during COPD model generation significantly inhibited apoptosis via the extrinsic apoptosis pathway.
Community - Minimal Invasive Tissue Sampling (cMITS) using modified ambulance for ascertaining cause of death: A novel approach piloted in remote inaccessible rural area in India
Authors: Satav Ashish , Wairagkar Niteen , Khirwadkar Shubhada , Dani Vibhawari , Rasaily Reeta , Agrawal Usha , Thakar Yagnesh , Raje Dhananjay , Siraj Fouzia , Garge Pradyot , Palaskar Sameer , Kumbhare Shraddha , Simões Eric A. F.
Published: August 2022

BACKGROUND: Melghat in India is a hilly, forested, difficult to access, impoverished rural area with high mortality. Home deaths contribute to 67% of deaths, which are difficult to track and cause of death is mostly unknown. METHODS: A feasibility study was carried out in 93 rural villages and 5 hospitals to assess feasibility of tracking real-time community mortality and to ascertain cause of death in 0-60 months and 16-60 years age group using Minimal Invasive Tissue Sampling (MITS) in purpose-modified ambulance. We used the network of village health workers (VHW)s, to establish real-time community mortality tracking. Upon receipt of reports of home death, we performed MITS within 4 hours of death in the vicinity of the village. RESULTS: We conducted 16 MITS. Nine, in MITS ambulance in community and seven at MAHAN hospital. The acceptance rate of MITS was 59.26%. Standard operating procedure (SOP) of conducting community MITS in an ambulance, is established. Major challenges were, Covid19 lockdown, reluctance of tribal parents for consent for MITS due to illiteracy, superstitions and fear of organ removal. Ambulance was an easy to reach transport means in remote area, provided a well-designed and discrete facility to perform MITS in community, winning the confidence of bereaved family. This has reduced time interval between time of death and performing MITS. CONCLUSIONS: MITS in purpose-modified Ambulance can be used worldwide for community MITS especially in areas which are remote and lack healthcare access. This solution needs to be assessed in different cultural settings to document culture specific issues.
Diagnostic value of a nanopore sequencing assay of bronchoalveolar lavage fluid in smear- negative pulmonary tuberculosis
Authors: Liu Zhifeng , Yang Yang , Wang Qingfeng , Wang Lei , Nie Wenjuan , Chu Naihui
Published: August 2022

Purpose: To determine the diagnostic accuracy of a nanopore sequencing assay for testing of bronchoalveolar lavage ﬂuid (BALF) samples or sputum samples from suspected PTB patients and compare the results to results obtained for MGIT and Xpert assays. Methods: Cases with suspected PTB (n = 55) were diagnosed from January 2019 to December 2021 based on results of nanopore sequencing, MGIT culture, and Xpert MTB/RIF testing of BALF and sputum samples collected during hospitalization. Diagnostic accuracies of assays were compared. Results: Ultimately, data from 29 PTB patients and 26 non-PTB cases were analyzed. PTB diagnostic sensitivities of MGIT, Xpert MTB/RIF, and nanopore sequencing assays were 48.28%, 41.38%, and 75.86%, respectively, thus demonstrating that nanopore sequencing provided greater sensitivity than was provided by MGIT culture and Xpert assays (P<0.05). PTB diagnostic specificities of the respective assays were 65.38%, 100%, and 80.77%, which corresponded with kappa coefficient (κ) values of 0.14, 0.40, and 0.56, respectively. These results indicate that nanopore sequencing provided superior overall performance as compared to Xpert and MGIT culture assays and provided significantly greater PTB diagnostic accuracy than Xpert and sensitivity comparable to that of the MGIT culture assay. Conclusion: Our ﬁndings suggest that improved detection of PTB in suspected cases was achieved using nanopore sequencing-based testing of BALF or sputum samples than was achieved using Xpert and MGIT culture-based assays, and nanopore sequencing results alone cannot be used to rule out PTB.
Dopamine signals integrate innate and learnt valences to regulate memory dynamics
Authors: Schnitzer Mark , Huang Cheng , Luo Junjie , Woo Seung Je , Roitman Lucas , Li Jizhou , Pieribone Vincent , Kannan Madhuvanthi , Vasan Ganesh
Published: August 2022

To survive in dynamic environments, animals make behavioral decisions based on innate and learnt information about the valences of sensory cues. In the brains of multiple species, innate and learnt sensory valence signals are initially encoded by distinct neural populations1–7 but then reconverge in downstream brain structures that guide behavioral choices6–9. This reconvergence hinges on the prior acquisition of learnt valence information, which in turn might depend upon innate valence signals. However, it remains unknown whether and how innate sensory valence cues shape the acquisition of learnt valence information. Here we show that in the fruit fly brain, interactions between innate and learnt sensory valence signals within interconnected short- and long-term memory units of the mushroom body jointly regulate memory formation and expression via modulation of dopamine teaching signals. By using time-lapse, in vivo optical voltage imaging to record neural spiking with millisecond-resolution in flies undergoing olfactory associative conditioning, we found that PPL1 dopamine neurons (PPL1-DANs) heterogeneously and bi-directionally encode punishment, reward, and innate and learnt odor-valence cues. Learning modulates these representations in a way that combines innate and learnt valence information and allows the PPL1-DANs to regulate memory storage in their downstream targets, mushroom body output neurons (MBONs). PPL1-γ1pedc and PPL1-γ2α’1 neurons control short-term memory formation. After repeated conditioning, feedback signals carrying short-term memory data from MBON-γ1pedc>α/β to PPL1-α’2α2 and PPL1-α3 allow these dopamine cells to encode previously learnt valences and promote long-lasting memory formation. A computational model constrained by the mushroom body connectome and our spiking data explains how dopamine signals integrate innate and learnt valence data to regulate memory storage, extinction, and the interactions between short- and long-term memory traces. The model yields non-intuitive predictions about the effects of different training protocols, which our experiments confirm. Overall, the mushroom body achieves flexible learning through dopamine-mediated integration of innate and learnt valences in parallel sets of DAN/MBON learning units with feedback interconnections. This hybrid physiologic-anatomic mechanism may be a general means by which ecological information regulates learning and memory in other species and brain structures relying on dopaminergic signaling, including the vertebrate basal ganglia10.
Utility of novel echocardiographic measurements to improve prenatal diagnosis of coarctation of the aorta
Authors: Fujisaki Takuya , Ishii Yoichiro , Takahashi Kunihiko , Mori Masayoshi , Matsuo Kumiyo , Asada Dai , Aoki Hisaaki , Tsumura Sanae , Iwai Shigemitsu , Kayatani Futoshi
Published: August 2022

Objective
Prenatal recognition of coarctation of the aorta (CoA) may improve neonatal survival and reduce morbidity. However, prenatal diagnosis of CoA remains challenging, with relatively high false–positive and false–negative rates. This study aimed to identify a novel formula based on fetal echocardiographic measures to predict prenatal identification of CoA.
Methods
A retrospective comparison on the echocardiographic evaluation of 30 patients with suspected CoA between May 2016 and April 2021 was performed. Fetal echocardiograms were measured for the following: Z-score of right and left ventricular diameters, tricuspid and mitral valve diameters, pulmonary artery and ascending aorta diameters, pulmonary valve and aortic valve diameters, ductus arteriosus and aortic isthmus diameters and their respective ratios, and distal aortic arch (DA) index, which is the distance between the second and third branches of the aortic arch / distal aortic arch diameter. The patients were divided into a postnatal surgical intervention group (n = 13) and a non-intervention group (n = 17).
Results
The measurements that showed significant differences were aortic isthmus diameter Z-score (p < 0.001), ductus arteriosus diameter/aortic isthmus diameter (p < 0.001) and DA index (p < 0.001). In the receiver operating characteristic curves analysis, the DA index was the largest with an area under the curve of 0.941 and a cutoff value of 1.28, with a sensitivity of 85% and a specificity of 94%. Among the three parameters that showed significant differences, the DA index had the lowest false-positive rate (5.9%).
Conclusions
The DA index ≧ 1.28 allows for the extraction of fetal CoA cases requiring surgical intervention.
Chemoproteomic identification of a dipeptidyl peptidase 4 (DPP4) homolog in Bacteroides thetaiotaomicron important for envelope integrity and fitness
Authors: Keller Laura , Nguyen Taylor , Liu Lawrence , Lakemeyer Markus , Gelsinger Danielle , Chanin Rachel , Ngo Nhi , Lum Kenneth , Faucher Franco , Ipock Phillip , Niphakis Micah , Bhatt Ami , O'Donoghue Anthony , Huang Kerwyn , Bogyo Matthew
Published: August 2022

Serine hydrolases play important roles in signaling and human metabolism, yet little is known about the functions of these enzymes in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human protease dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Functional studies reveal that BT4193 is a true homolog of hDPP4 while the other is misannotated and is a proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and is inhibited by FDA-approved type 2 diabetes drugs that target hDPP4. Loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. Taken together, our findings suggest that serine hydrolases contribute to gut microbiota dynamics and may be off-targets for existing drugs that could cause unintended impact on the microbiota.
Photothermal Effects of Terahertz-band and Optical Electromagnetic Radiation on Human Tissues
Authors: Reddy Innem Venkata Anudeep Kumar , Jornet Josep , Furlani Edward
Published: August 2022

The field of wireless communication has witnessed tremendous advancements in the past few decades, leading to more pervasive and ubiquitous networks. Human bodies are continually exposed to electromagnetic radiation, but typically this does not impact the body as the radiation is non-ionizing and the waves carry low power. However, with progress in the sixth generation (6G) of wireless networks and the adoption of the spectrum above 100~GHz in the next few years, higher power radiation is needed to cover larger areas, exposing humans to stronger and more prolonged radiation. Also, water has a high absorption coefficient at these frequencies and could lead to thermal effects on the skin. Hence, there is a need to study the radiation effects on human tissues, specifically the photothermal effects. In this paper, we present a custom-built, multi-physics model to investigate electromagnetic wave propagation in human tissue and study its subsequent photothermal effects. The proposed finite-element model consists of two segments -- the first one estimates the intensity distribution along the beam path, while the second calculates the increase in temperature due to the wave distribution inside the tissue. We determine the intensity variation in the tissue using the radiative transfer equation and compare the results with Monte Carlo analysis and existing analytical models. The intensity information is then utilized to predict the rise in temperature with a bio-heat transfer module, powered by Pennes' bioheat equation. The model is parametric, and we perform a systematic photothermal analysis to recognize the crucial variables responsible for the temperature growth inside the tissue, particularly for terahertz and near-infrared optical frequencies. Our numerical model can serve as a benchmark for studying the high-frequency radiation effects on complex heterogeneous media such as human tissue.
High reliability model of mechanical response in drilling of CFRP/Al stacks
Authors: Gong Qinghong , Li Liang , Yuan Xinman , Hu Zhiqin , Chen Jie , Ma Ke
Published: August 2022

CFRP/Al laminate material is widely used in aerospace due to its advantages of light weight and high machinability. For assembling, crowded assembly holes need to be drilled for CFRP/Al laminate products. However, the damages of burr, delamination, and tearing appear frequently in drilling without precise guidance by mechanical response model. In order to reduce the machining damages, in this paper, a high-reliability mechanical response model is established for each stage in laminate materials drilling to ascertain the matching method between materials, tools, and cutting parameters. The theoretical expression of drilling thrust based on the thin plate theory is established considering the influence of cutting parameters, and further corrected with the cutting parameter correction terms to predict drilling thrust force, and further guiding the optimization of drilling parameters. According to the experimental results, the proposed model has a reliability greater than 97.3% and a prediction deviation lower than 13.2% in CFRP/Al laminate material drilling thrust force prediction. In the cutting with optimized parameters from the proposed model, the inlet orifice of the laminated material has no flanging burr, and the CFRP layer exit orifice has no defects as burr, delamination, or tearing.
PACAP signaling is not involved in GTN- and levcromakalim-induced hypersensitivity in mouse models of migraine
Authors: Guo Song , Ernstsen Charlotte , Hay-Schmidt Anders , Ashina Messoud , Olesen Jes , Christensen Sarah Louise
Published: August 2022

Background
Calcitonin gene-related peptide (CGRP) antagonizing drugs represents the most important advance in migraine therapy for decades. However, these new drugs are only effective in 50–60% of patients. Recent studies have shown that the pituitary adenylate cyclase-activating peptide (PACAP38) pathway is independent from the CGRP signaling pathway. Here, we investigate PACAP38 signaling pathways in relation to glyceryl trinitrate (GTN), levcromakalim and sumatriptan.
Methods
In vivo mouse models of PACAP38-, GTN-, and levcromakalim-induced migraine were applied using tactile sensitivity to von Frey filaments as measuring readout. Signaling pathways involved in the three models were dissected using PACAP-inhibiting antibodies (mAbs) and sumatriptan.
Results
We showed that PACAP mAbs block PACAP38 induced hypersensitivity, but not via signaling pathways involved in GTN and levcromakalim. Also, sumatriptan has no effect on PACAP38-induced hypersensitivity relevant to migraine. This is the first study testing the effect of a PACAP-inhibiting drug on GTN- and levcromakalim-induced hypersensitivity.
Conclusions
Based on the findings in our mouse model of migraine using migraine-inducing compounds and anti-migraine drugs, we suggest that PACAP acts via a distinct pathway. Using PACAP38 antagonism may be a novel therapeutic target of interest in a subgroup of migraine patients who do not respond to existing therapies.
CDCP1 expression is frequently increased in aggressive urothelial carcinoma and promotes urothelial tumor progression
Authors: Saponaro Miriam , Flottmann Sina , Eckstein Markus , Hommerding Oliver , Klümper Niklas , Corvino Dillon , Hosni Sana , Schmidt Anja , Mönig Nicolas , Schmidt Doris , Ellinger Jörg , Toma Marieta , Kristiansen Glen , Bald Tobias , Alimonti Andrea , Ritter Manuel , Hölzel Michael , Alajati Abdullah
Published: August 2022

The prognosis of patients with advanced urothelial carcinoma (UC) remains poor and improving its treatment continues to be a major medical need. CUB domain containing protein 1 (CDCP1) is a known oncogene in various types of solid cancers and its overexpression is associated with impaired prognosis. However, its role in UC remains undetermined. Here we assessed the clinical relevance of CDCP1 in two cohorts of UC at different stages of the disease. Immunohistochemistry showed that CDCP is highly expressed in advanced UC, which significantly correlates with shorter overall survivals. Importantly, the basal/squamous (Ba/Sq) UC subtype showed significantly enriched protein and mRNA levels for CDCP1. Moreover, ex-vivo organoids derived from CDCP1pcLSL/+ transgenic mouse model were used to assess the functional role of CDCP1 overexpression, while UC cell lines knockouts for CDCP1 were generated using CRISPR-Cas9-technology to model the effect of targeting CDCP1. Interestingly, CDCP1 overexpression significantly induced proliferation and activation of MAPK pathways in ex-vivo organoids. In addition, CDCP1 knockout in UC cell lines reduced their proliferation and migration, concomitant with MAPK pathway activity reduction. Our results showed highlight the relevance of CDCP1 in advanced UC and demonstrate its oncogenic role in UC, suggesting that targeting CDCP1 could be a rational therapeutic strategy for advanced UC.
Synergetic Therapeutic Efficacy of Fasudil and Bone Marrow Derived-Neuronal Stem Cell in a Parkinson's Disease Mouse Model
Authors: Yan Yu-Chen , Li Yan-Hua , Xiao Bao-Guo , Xi Jian-Ying , Yu Wen-Bo
Published: August 2022

Bone marrow-derived neural stem cells (BM-NSCs) have shed light on novel therapeutic approaches for PD with the potential to halt or even reverse disease progression. Various strategies have been developed to promote therapeutic efficacy via optimizing implanted cells and the microenvironment of transplantation in the central nervous system (CNS). This current study further proved that the combination of fasudil, a Rho-kinase inhibitor, and BM-NSCs exhibited a synergetic effect on restoring neuron loss in the MPTP-PD mice model. It simultaneously unveiled cellular mechanisms underlying synergistic neuron-protection effects of fasudil and NSCs, which included promoting the proliferation, differentiation, and maturation of exogenous and endogenous NSCs, and contributing to microglia shift into the M2 phenotype. Corresponding molecular mechanisms were observed, including the inhibition of inflammatory responses, the elevation of neurotrophic factors, and the induction of WNT/β-catenin and PI3K/Akt/mTOR signaling pathways. Our study provides evidence for the co-intervention of BM-NSCs and fasudil as a promising therapeutic method with enhanced efficacy in treating neurodegenerative diseases.
Large Eddy Simulation and Acoustic Analysis of Combustion Instability in an Annular Combustor with Low-Swirl Flames
Authors: Liu Weijie , Jiang Jingjing , Xue Ranran , Su He , Wang Xionghui
Published: August 2022

Self-excited combustion instability in an annular combustor with low-swirl flames is studied with the combination of LES and acoustic solvers. Acoustic analysis with a Helmholtz solver provides an estimate of frequencies and modal structure in the annular combustor. LES gives detailed modal dynamics at specific instability modes. Combustion instabilities in the annular combustor including longitudinal, spinning and standing modes are successfully captured in single LES. Numerical results show the instability modes are not constant, they switch among these modes randomly and rapidly. The flow oscillates back and forth in phase with the largest pressure amplitude locating near the outlet of the injectors for the longitudinal mode. The azimuthal instability oscillates at the 1A2L mode of the annular system. In the spinning mode, the pressure anti-nodes move forwards while the modal structure keeps constant. For the standing mode, the locations of pressure anti-nodes are fixed in the annular combustor and the fluctuations at the pressure anti-nodes keep out of phase. The near-zero value of mean spin ratio indicates the dominant azimuthal mode is the standing mode. The azimuthal modes captured by LES are in good agreements with that predicted by Helmholtz solver in terms of frequency and modal structure. The maximum deviation of the predicted frequency is less than 5%. This adds values before putting the low-swirl injector into the actual annular combustor.
Construction and Validation of the Oxford Neurodevelopment Assessment (OX- NDA) in 1-year-old Brazilian Children
Authors: Fernandes Michelle , Bassani Diego , Albernaz Elaine , Bertoldi Andréa , Silveira Mariangela Freitas , Matijsevich Alicia , Anselmi Luciana , Cruz Suélen , Halal Camila S , Tovo-Rodrigues Luciana , Cruz Gloria Isabel Nino , Metgud Deepa , Santos Ina S
Published: August 2022

Background: Over 250 million children under 5 years, globally, are at risk of developmental delay. Interventions during the first 2 years of life have enduring positive effects if children at risk are identified, using standardized assessments, within this window. However, identifying developmental delay during infancy is challenging and there are limited infant development assessments suitable for use in low- and middle-income (LMIC) settings. Here, we describe a new tool, the Oxford Neurodevelopment Assessment (OX-NDA), measuring cognition, language, motor, and behaviour, outcomes in 1-year-old children. We present the results of its evaluation against the Bayley Scales of Infant Development IIIrd edition (BSID-III) and its psychometric properties.Methods: Sixteen international tools measuring infant development were analysed to inform the OX-NDA’s construction. Its agreement with the BSID-III, for cognitive, motor and language domains, was evaluated using intra-class correlations (ICCs, for absolute agreement), Bland-Altman analyses (for bias and limits of agreement), and sensitivity and specificity analyses (for accuracy) in 104 Brazilian children, aged 12 months (SD 8.4 days), recruited from the 2015 Pelotas Birth Cohort Study. Behaviour was not evaluated, as the BSID-III’s adaptive behaviour scale was not included in the cohort’s protocol. Cohen’s kappas and Cronbach’s alphas were calculated to determine the OX-NDA’s reliability and internal consistency respectively. Results: Agreement was moderate for cognition and motor outcomes (ICCs 0.63 and 0.68, p<0.001) and low for language outcomes (ICC 0.30, p<0.04). Bland-Altman analysis showed little to no bias between measures across domains. The OX-NDA’s sensitivity and specificity for predicting moderate-to-severe delay on the BSID-III was 76%, 73% and 43% and 75%, 80% and 33% for cognition, motor and language outcomes, respectively. Inter-rater (k=0.80-0.96) and test-rest (k=0.85-0.94) reliability was high for all domains. Administration time was <20 minutes.Conclusion: The OX-NDA shows moderate agreement with the BSID-III for identifying infants at risk of neurodevelopmental delay. It is a rapid, low-cost assessment constructed specifically for use in LMIC populations. Further work is needed to evaluate its use in populations beyond Brazil.
Quantifying the effect of climate variability on seasonal precipitation using Bayesian clustering approach in Kebir Rhumel Basin, Algeria
Authors: Belkhiri Lazhar , Krakauer Nir
Published: August 2022

This paper presents a Bayesian clustering approach that allows quantifying the effect of climate variability on seasonal precipitation data in Kebir Rhumel Basin (KRB). We applied this approach to simultaneously identify clusters of stations with similar characteristics, the climate variability associated with each cluster and for the individual stations within each cluster. Both full pooling Bayesian clustering (FPBC) and partial pooling Bayesian clustering (PPBC) models with nonstationary generalized extreme value (GEV) distribution are applied to each season. In these models, the climate variable, namely the El Niño Southern Oscillation (ENSO), is included as a time-varying covariate with an appropriate basis function to represent the temporal variation of one or more of the parameters of the distribution. Results reveal that the partial pooling Bayesian clustering model provided the best fit for the seasonal precipitation data. The significant effect of ENSO differs from one season to another. During spring and autumn, ENSO significantly effects precipitation across large parts of KRB. Furthermore, the southern part and northern part of KRB are positively and negatively influenced by ENSO during winter and summer, respectively. Moreover, almost all stations during spring and autumn are negatively and positively influenced by ENSO, respectively. Finally, we demonstrated that the proposed model helps to reduce the uncertainty in the parameter estimation and provides more robust results.
Acceleration of Iterative Refinement for Singular Value Decomposition
Authors: Uchino Yuki , Terao Takeshi , Ozaki Katsuhisa
Published: August 2022

We propose fast numerical algorithms to improve the accuracy of singular vectors for a real matrix.Recently, Ogita and Aishima proposed an iterative refinement algorithm for singular value decomposition that is constructed with highly accurate matrix multiplications carried out six times per iteration.The algorithm runs for the problem that has no multiple and clustered singular values.In this study, we show that the same algorithm can be run with highly accurate matrix multiplications carried out five times.Also, we proposed four algorithms constructed with highly accurate matrix multiplications, two algorithms with the multiplications carried out four times, and the other two with the multiplications carried out five times. These algorithms adopt the idea of a mixed-precision iterative refinement method for linear systems.Numerical experiments demonstrate speed-up and quadratic convergence of the proposed algorithms.As a result, the fastest algorithm is 1.7 and 1.4 times faster than the Ogita-Aishima algorithm per iteration on a CPU and GPU, respectively.
Prevalence of depression and its impact on quality of life among Afghan healthcare workers: A cross-sectional survey study
Authors: Mohammadi Ab. Qadim , Neyazi Ahmad , Rangelova Vanya , Odey Goodness Ogeyi , Ogbodum Molly Unoh , Griffiths Mark D.
Published: August 2022

Background
According to the World Health Organization, approximately 280 million individuals worldwide suffer from depression. One occupational group that is more prone to mental health issues is healthcare workers (HCWs). However, very little is known about the mental health of HCWs in Afghanistan. Therefore, the present study estimated the prevalence of depression, quality of life (QOL) and related factors among Afghan HCWs.
Methods
A cross-sectional survey was administered in June 2022 to 299 healthcare workers in the Herat province of Afghanistan. The survey examined depression, its risk factors and predictors among HCWs.
Results
Depression was found among 73.6% of all the 299 participants. Low monthly income, working in a private hospital, and being a cigarette smoker were among the main variables associated with depression among Afghan HCWs. Multiple regression analysis indicated that field of work (OR = 095, p = .039), monthly income (OR=-.061, p < .001), job type (OR=-.194, p < .001), cigarette smoking (OR = .107, p = .014), a bad event during the past month (OR=-.122, p = .004), physical domain of quality of life (OR=-.004, p = .009), and psychological domain of quality of life (OR=-.006, p < .001) were significantly associated with depression.
Conclusion
The prevalence of depression is high among healthcare workers in the Herat province of Afghanistan. One of the variables found to have a major impact on the prevalence of depression was their monthly income. Considering its impact on quality of life and the overall quality of healthcare services, the government should implement regular screening for depression, psychological counselling services, and psychiatric treatment for vulnerable healthcare workers.
Molecular Mechanism of Cold Stress Tolerance in Barley (Hordeum vulgare L.) via Meta-analysis of Transcriptome Data
Authors: Alamholo Mostafa , Tarinejad Alireza
Published: August 2022

The authors have requested that this preprint be removed from Research Square.
Major ions and Nutrients loading by atmospheric wet deposition in Mbeya Urban, Tanzania
Authors: Stephano Azaria , Mnyawi Silvester Raymond , Justine Phenson Nsima , Lufingo Mesia
Published: August 2022

This study aimed to investigate the contributions of the atmospheric wet depositions to the major ions and nutrient loading in the surface water of Mbeya urban. A total of 22 rainwater samples were collected from six different sampling stations (MUST, Mbalizi, Kabwe, Rufaa, Uyole, and Kalobe) using the rain collector buckets installed 2 meters above the ground from December (18.12.2021) to February (06.02.2022). All the rainwater samples were analyzed for the major ions (Na+, K+, Ca2+, Mg2+, HCO3−, Cl−, CO32−, and SO42−) and nutrients (NH4+, PO43−, and NO3−), pH, and temperature. The pH of the rainwater was found to range from 6.8 to 9.3, indicating that in the region there are emissions of alkaline dust into the atmosphere. The temperature was found to range from 17°C to 22°C, with a mean temperature of 19.77°C. The dominance of the major cations and anions was found in the order of Mg2+> Ca2+>Na+ > K+ and HCO3−> Cl−> SO42−> CO32−ions respectively, and the nutrient dominance sequence followed the order of NH4+>SO42−>NO3−>PO43−. Some parameters showed decreasing trends from one rain event to another, and some showed non–uniformity of the trend among the rain events. The non–uniformity of the trend of the parameters was associated with the point source pollution in the specific sampling stations and the non–uniformity of the rain in the region. Despite the non–uniformity of the trend of the parameters, the results have shown the contributions of the atmospheric wet depositions to the major ions and nutrient loading on the surface. In this regard, to get a clear and representative picture of the pollution status of the Mbeya urban area, major ions and nutrients loaded onto the surface of both wet and dry atmospheric depositions need to be analyzed.
Functional interactions between neurofibromatosis tumor suppressors drive Schwann cell tumor de-differentiation and treatment resistance
Authors: Raleigh David , Vasudevan Harish , Payne Emily , Delley Cyrille , Sale Matthew , Liu Siyuan , Lastella Sydney , Lucas Calixto-Hope , Eaton Charlotte , Casey-Clyde Tim , Magill Stephen , Chen William , Reddy Alyssa , Braunstein Steve , Perry Arie , Jacques Line , Pekmezci Melike , Abate Adam , McCormick Frank
Published: August 2022

Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise sporadically or in patients with neurofibromatosis type-1 (NF-1) or type-2 (NF-2). NF-1 is caused by loss of NF1, a negative regulator of Ras signaling. NF-2 is caused by loss of NF2, a pleiotropic tumor suppressor that inhibits PAK signaling. Functional interactions between the NF1 and NF2 tumor suppressors and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here, we integrate DNA methylation profiling, whole exome sequencing, bulk and single-cell RNA sequencing, biochemistry, and pharmacology across human samples, patient-derived cell lines, and mouse xenografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance in Schwann cell tumors. Our data show molecular groups of Schwann cell tumors are distinguished by de-differentiation trajectories that drive resistance to MEK inhibition, the only approved molecular therapy for patients with NF-1. Functional genomic screening for mediators of MEK inhibitor responses in NF1-deficient tumor cells reveals NF2 loss and PAK activation underlie Schwann cell tumor de-differentiation and MEK inhibitor resistance. In support of these findings, we identify a group of de-differentiated Schwann cell tumors with concurrent loss of NF1 and NF2, and find combination molecular therapy inhibiting MEK and PAK is an effective treatment for de-differentiated Schwann cell tumor xenografts. In sum, we elucidate a paradigm of de-differentiation driving malignant transformation and treatment resistance, uncovering a functional link between the NF1 and NF2 tumor suppressors that sheds light on a novel therapeutic vulnerability.
Influence of Photobiomodulation Therapy on Regenerative Potential of Necrotic Mature Permanent Teeth in Dogs
Authors: Khattab Salma Fathy Ahmed , Gomaa Yasser Fathy , Khattab Nagwa Mohamed Ali
Published: August 2022

Background: The conventional treatment methods of necrotic mature permanent teeth that remove immune mechanisms, increase the susceptibility of root fracture and possibility of reinfection, therefore, regenerative endodontic therapy is an alternative treatment modality specially when adding the possible biostimulatory effects of Photobiomodulation (PBM) on cells functions, so the purpose of this study was to evaluate the influence of photobiomodulation therapy on regenerative potential of necrotic mature permanent teeth in dogs. Methods: 54 mature permanent roots of premolar teeth in dogs aged 12 months old were selected and divided into three equal groups (18 roots / each): Group I; regeneration procedures using blood clot as scaffold (positive control group) and Group II, was treated with the same regenerative protocol as group I, then subjected to photobiomodulation therapy (study group) and Group III (negative control group), no intervention. Each group was further divided into three subgroups (6 per subgroup) according to evaluation periods 3, 10, 15 weeks. In each group blood vessels area percentage and fibroblasts count were evaluated according to evaluation periods. Results: Data analysis revealed significant differences for blood vessels area percentage between studied groups at the different intervals (P< 0.001). Also, significant differences were detected in fibroblasts count between groups at 3 and at 15 weeks intervals (P< 0.005). Photobiomodulation therapy was significantly influenced tissue regeneration compared to conventional regeneration using blood clot scaffold only. Conclusion: The results of this study support the revascularization of necrotic mature permanent teeth as an alternative treatment modality. Photobiomodulation could improve the constructure of regenerated tissue.
Global patterns of diversity and metabolism of microbial communities in deep-sea hydrothermal vent deposits
Authors: Zhou Zhichao , John Emily St. , Anantharaman Karthik , Reysenbach Anna-Louise
Published: August 2022

Background
When deep-sea hydrothermal fluids mix with cold oxygenated fluids, minerals precipitate out of solution and form hydrothermal deposits. These actively venting deep-sea hydrothermal vent deposits support a rich diversity of thermophilic microorganisms which are involved in a range of carbon, sulfur, nitrogen, and hydrogen metabolisms. Global patterns of thermophilic microbial diversity in deep-sea hydrothermal ecosystems have illustrated the strong connectivity between geological processes and microbial colonization, but little is known about the genomic diversity and physiological potential of these novel taxa. Here we explore this genomic diversity in 42 metagenomes from four deep-sea hydrothermal vent fields and a deep-sea volcano collected from 2004 to 2018, and document their potential implications in biogeochemical cycles.
Results
Our dataset represents 3,635 metagenome-assembled genomes encompassing 511 novel genera, with 395 Bacteria and 116 Archaea, providing many targets for cultivation of novel archaeal and bacterial families. Notably, 52% (206) of the novel bacterial genera and 72% (84) of the novel archaeal genera were found at the deep-sea Brothers volcano, many of which were endemic to the volcano. We report some of the first examples of medium to high-quality MAGs from phyla and families never previously identified, or poorly sampled, from deep-sea hydrothermal environments. We greatly expand the novel diversity of Thermoproteia, Patescibacteria (Candidate Phyla Radiation, CPR), and Chloroflexota found at deep-sea hydrothermal vents and identify a small sampling of two potentially novel phyla, designated JALSQH01 and JALWCF01. Metabolic pathway analysis of metagenomes provides insights into the prevalent carbon, nitrogen, sulfur and hydrogen metabolic processes across all sites, and illustrates sulfur and nitrogen metabolic ‘handoffs’ in community interactions. We confirm that Campylobacteria and Gammaproteobacteria occupy similar ecological guilds but their prevalence in a particular site is driven by shifts in the geochemical environment.
Conclusion
Our study of globally-distributed hydrothermal vent deposits provides a significant expansion of microbial genomic diversity associated with hydrothermal vent deposits and highlights the metabolic adaptation of taxonomic guilds. Collectively, our results illustrate the importance of comparative biodiversity studies in establishing patterns of shared phylogenetic diversity and physiological ecology, while providing many targets for enrichment and cultivation of novel and endemic taxa.