bluuebunny/crossref_metadata_2025 huggingface dataset:
Real Time Mask Detection, Social Distance and Crowd Analysis using Convolutional Neural Networks and YOLO Architecture Designs
Authors: Gurkan Caglar , Kozalioglu Sude , Palandoken Merih
Published: October 2021

Bu çalışmanın amacı koronavirüsün yayılım hızını düşürmede önemli bir etkisi olan maske takma, sosyal mesafe ve kalabılık analizinin yapılmasıdır. Bu analiz için çalışmada derin öğrenme tabanlı yöntemler olan Evrişimli Sinir Ağları (ESA) ve YOLO mimari tasarımları kullanılmıştır. Maske tespitinin yapılması için yeni bir veri seti oluşturulmuştur. Oluşturulan veri seti ‘maskeli’ ve ‘maskesiz’ sınıflandırma işleminin yapılması için AlexNet, DenseNet, MobileNet, ResNet, ShuffleNet, SqueezeNet, VGG, Xception ve ZFNet gibi ESA mimari tasarımları ile kullanılmıştır. En iyi sınıflandırma performansını %96.86 doğruluk oranı ve %91.81 F1-skoru değeri ile DenseNet-121 mimari tasarımı elde etmiştir. Sosyal mesafe ve kalabalık analizi için çalışmada YOLOv3 algoritması ve COCO veri seti kullanılmıştır. Daha sonra maske sınıflandırması görevinde elde edilen ağırlık dosyası, Haar Cascade yüz sınıflandırıcı algoritması ile birlikte kullanılarak, sosyal mesafe ve kalabalık analizini sağlayan algoritmaya dahil edilmiştir. Sonuç olarak ise hem maske tespitini sağlayan hem de sosyal mesafe ve kişi sayısını hesaplayan tümleşik bir yazılım oluşturulmuştur.
Extracellular Vesicles Secreted by TDO2-Augmented Fibroblasts Regulate Pro-inflammatory Response in Macrophages
Authors: Peck Kiel A. , Ciullo Alessandra , Li Liang , Li Chang , Morris Ashley , Marbán Eduardo , Ibrahim Ahmed Gamal
Published: October 2021

Extracellular vesicles (EVs) are secreted lipid bilayer vesicles that mediate cell to cell communication and are effectors of cell therapy. Previous work has shown that canonical Wnt signaling is necessary for cell and EV therapeutic potency. Tryptophan 2,3-dioxygenase (TDO2) is a target gene of canonical Wnt signaling. Augmenting TDO2 in therapeutically inert fibroblasts endows their EVs with immunomodulatory capacity including attenuating inflammatory signaling in macrophages. Transcriptomic analysis showed that macrophages treated with EVs from fibroblasts overexpressing TDO2 had blunted inflammatory response compared to control fibroblast EVs. In vivo, EVs from TDO2-overexpressing fibroblasts preserved cardiac function. Taken together, these results describe the role of a major canonical Wnt-target gene (TDO2) in driving the therapeutic potency of cells and their EVs.
An E2F5-TFDP1-BRG1 Complex Mediates Transcriptional Activation of MYCN in Hepatocytes
Authors: Fan Zhiwen , Kong Ming , Miao Xiulian , Guo Yan , Ren Haozhen , Wang Jinglin , Wang Shuai , Tang Ning , Shang Longcheng , Zhu Zhengyi , Liu Hanyi , Zhu Wei , Shi Xiaolei
Published: October 2021

Liver regeneration is characterized by cell cycle reentrance of hepatocytes. N-Myc, encoded by MYCN, is a member of the Myc family of transcription factors. Elevation of MYCN expression has been noted in the course of liver regeneration whereas the underlying mechanism remains unclear. Here we describe that up-regulation of MYCN expression, as measured by quantitative PCR, Western blotting, and immunohistochemical staining, paralleled liver regeneration in animal and cell models. MYCN expression was up-regulated as a result of transcriptional activation. Ingenuity pathway analysis (IPA) revealed several up-stream transcriptional regulators for MYCN and RNA interference validated E2F5 and TFDP1 as essential for hepatocyte growth factor (HGF)-induced MYCN trans-activation. Further examination showed that deficiency of BRG1, a chromatin remodeling protein, attenuated MYCN induction during liver regeneration. BRG1 interacted with and was recruited by E2F5/TFDP1 to the MYCN promoter. Mechanistically, BRG1 might play a role regulating histone H3 acetylation and H3K4 trimethylation and facilitating/stabilizing the binding of RNA polymerase II surrounding the MYCN promoter. Over-expression of ectopic MYCN in BRG1-null hepatocytes overcame deficiency of proliferation. Importantly, a positive correlation between MYCN expression and BRG1/E2F5/TFDP1 expression was observed in human liver specimens. In conclusion, our data identify a novel epigenetic pathway where an E2F5-TFDP1-BRG1 complex regulates MYCN transcription to promote liver regeneration.
Rapid Detection of SARS-CoV-2 Using Duplex Reverse Transcription-Multienzyme Isothermal Rapid Amplification in a Point-of-Care Testing
Authors: Chen Hui , Sun Chang , Wang Yang , Gao Xiaojiao , You Jinwei , Yu Wanwan , Sun Ning , Yang Yang , Li Xiaojun
Published: October 2021

In December 2019, a severe acute respiratory syndrome caused by SARS-CoV-2 spread rapidly worldwide. Portable nucleic acid tests of SARS-CoV-2 are critically important for diagnostics. In this study, we used an isothermal amplification method—Multienzyme Isothermal Rapid Amplification (MIRA)—for rapid detection of SARS-CoV-2. We designed the primers and probes in ORF1ab and N gene of SARS-CoV-2. The amplicons could be monitored by lateral flow dipsticks (LFDs). The reaction temperature, time, concentrations of primers and probes, and working volume were optimized. Four commercial swab collection buffers were used to test the amplification efficacy of our assay without RNA extraction. Our assay was able to amplify duplex targets of SARS-CoV-2 in one single reaction using one-step RT-MIRA. The assay worked well in a low volume of 10 μl at 38°C for 20 min. Using three collection buffers without guanidinium, our assay was able to amplify efficaciously without RNA extraction. The 95% limit of detection (LoD) of the RT-MIRA assay was 49.5 (95% CI, 46.8–52.7) copies/ml for ORF1ab gene and 48.8 (95% CI, 46.5–52.6) copies/ml for N gene. There is no cross-reaction with other human respiratory pathogens, such as SARS-CoV, MERS-CoV, influenza A virus, influenza B virus, human adenovirus, respiratory syncytial virus, human parainfluenza virus, and coronavirus 229E in our assay. The precision evaluation revealed that the C50−20% to C50+20% range bounds the C5–C95 interval. This assay also showed high anti-interference ability. The extraction-free RT-MIRA and qPCR detection results of 243 nucleic acid specimens from suspected patients or national references showed a 100.0% (95% confidence interval, 94.2%–100.0%) positive predictive value and a 100.0% (95% confidence interval, 92.7%–100.0%) negative predictive value. Compared with qPCR, the kappa value of the two assays was 1.00 (P < 0.0001). In conclusion, we provide a portable and visualized method for detection of SARS-CoV-2 without RNA extraction, allowing its application in SARS-CoV-2 on-site detection.
Inflammation-Based Scores as a Common Tool for Prognostic Assessment in Heart Failure or Cancer
Authors: Arfsten Henrike , Cho Anna , Prausmüller Suriya , Spinka Georg , Novak Johannes , Goliasch Georg , Bartko Philipp E. , Raderer Markus , Gisslinger Heinz , Kornek Gabriela , Köstler Wolfgang , Strunk Guido , Preusser Matthias , Hengstenberg Christian , Hülsmann Martin , Pavo Noemi
Published: October 2021

Background: Inflammation-based scores are widely tested in cancer and have been evaluated in cardiovascular diseases including heart failure.

Objectives: We investigated the impact of established inflammation-based scores on disease severity and survival in patients with stable heart failure with reduced ejection fraction (HFrEF) paralleling results to an intra-institutional cohort of treatment naïve cancer patients.

Methods: HFrEF and cancer patients were prospectively enrolled. The neutrophil-to-lymphocyte-ratio (NLR), the monocyte-to-lymphocyte-ratio (MLR), the platelet-to-lymphocyte-ratio (PLR), and the prognostic nutritional index (PNI) at index day were calculated. Association of scores with disease severity and impact on overall survival was determined. Interaction analysis was performed for the different populations.

Results: Between 2011 and 2017, a total of 818 patients (443 HFrEF and 375 cancer patients) were enrolled. In HFrEF, there was a strong association between all scores and disease severity reflected by NT-proBNP and NYHA class (p ≤ 0.001 for all). In oncologic patients, association with tumor stage was significant for the PNI only (p = 0.035). In both disease entities, all scores were associated with all-cause mortality (p ≤ 0.014 for all scores). Kaplan–Meier analysis confirmed the discriminatory power of all scores in the HFrEF and the oncologic study population, respectively (log-rank p ≤ 0.026 for all scores). A significant interaction with disease (HFrEF vs. cancer) was observed for PNI (pinteraction = 0.013) or PLR (pinteraction = 0.005), respectively, with higher increase in risk per inflammatory score increment for HFrEF.

Conclusion: In crude models, the inflammatory scores NLR, MLR, PLR, and PNI are associated with severity of disease in HFrEF and with survival in HFrEF similarly to cancer patients. For PNI and PLR, the association with increase in risk per increment was even stronger in HFrEF than in malignant disease.
Investigation of Specific Proteins Related to Different Types of Coronary Atherosclerosis
Authors: Meng Heyu , Ruan Jianjun , Chen Yanqiu , Yan Zhaohan , Shi Kaiyao , Li Xiangdong , Yang Ping , Meng Fanbo
Published: October 2021

Objective: Coronary heart disease (CHD) is a complex disease caused by multifaceted interaction between genetic and environmental factors, which makes identification of the most likely disease candidate proteins and their associated risk markers a big challenge. Atherosclerosis is presented by a broad spectrum of heart diseases, including stable coronary artery disease (SCAD) and acute myocardial infarction (AMI), which is the progressive stage of SCAD. As such, the correct and prompt diagnosis of atherosclerosis turns into imperative for precise and prompt disease diagnosis, treatment and prognosis.

Methods: The current work aims to look for specific protein markers for differential diagnosis of coronary atherosclerosis. Thirty male patients between 45 and 55 years diagnosed with atherosclerosis were analyzed by tandem mass tag (TMT) mass spectrometry. The study excluded those who were additionally diagnosed with hypertension and type 1 and 2 diabetes. The Mufuzz analysis was applied to select target proteins for precise and prompt diagnosis of atherosclerosis, most of which were most related to high lipid metabolism. The parallel reaction monitoring (PRM) was used to verify the selected target proteins. Finally, The receiver operating characteristic curve (ROC) was calculated by a random forest experiment.

Results: One thousand one hundred and forty seven proteins were identified in the TMT mass spectrometry, 907 of which were quantifiable. In the PRM study, six proteins related to lipid metabolism pathway were selected for verification and they were ALB, SHBG, APOC2, APOC3, APOC4, SAA4.

Conclusion: Through the detected specific changes in these six proteins, our results provide accuracy in atherosclerosis patients' diagnosis, especially in cases with varying types of the disease.
Characteristics of Shale Pores and Surfaces and Their Potential Effects on the Fluid Flow From Shale Formation to Fractures
Authors: Li Xu , Cai Jingong , Gao Bo , Long Shengxiang , Feng Dongjun , Peng Zeyang , Guo Benqiang
Published: October 2021

Fluid flow is critical for the efficient exploitation of shale resources and can be split into two stages: the flow in the artificial fractures and, more importantly, the flow from shale formations to the artificial fractures. In this study, X-ray diffraction, N2 adsorption, mercury intrusion, and ethylene glycol monoethyl ether adsorption were conducted on the shales collected from Es3middle, Es3lower, and Es4upper sub-members in the Dongying Sag to reveal the potential effects of the characteristics and properties of pores and surfaces on the fluid flow in shale formations. The results are indicated as follows: 1) The shales from Es3middle and Es3lower contain more I/S and detrital minerals but less illite and carbonate minerals than those of Es4upper. 2) The shales from Es3middle and Es3lower are mainly composed of smaller pores present in larger surface areas and lead to the steeper slope between the BrunauerEmmettTeller specific surface area (BET-SSA) and pore volumes. 3) Clay minerals mainly contribute to pore development, and carbonate minerals inhibit pore development. All kinds of surface areas (especially the inner surface area) are sourced by clay minerals, while I/S and illite present opposite effects. 4) Pore size and surface properties affect significantly the fluid flow in shale formations. The shales from Es4upper are the favorable interval for shale oil accumulation and flow, especially for the shales with depth ranges of 3360∼3410 m, which possess high carbonates, illite and total organic carbon content, low clay mineral content, large pore volume, high large pore content, and small surface areas. Additionally, fluid composition needs to be paid more concern in the future.
Reproduction Method of Rockfall Geologic Hazards Based on Oblique Photography and Three-Dimensional Discontinuous Deformation Analysis
Authors: Fu Xiaodong , Ding Haifeng , Sheng Qian , Chen Jian , Chen He , Li Guo , Fang Liuyang , Du Wenjie
Published: October 2021

Rockfall geologic hazards are widely distributed. Due to their concealed nature, rockfalls are difficult to investigate using traditional contact survey methods, and the hazards they pose affect major projects and people’s safety. Reproducing methods, including scene survey and movement process analysis, are primary tasks used to prevent these hazards; however, few reconstruction methods can directly apply the parameters of the rockfall geologic hazards obtained by the scene survey to evaluate the movement process. To address this problem, a method of reproduction based on oblique photography and three-dimensional discontinuous deformation analysis (3D-DDA) is proposed; the method consists of three key techniques (oblique photography, 3D rock block system modeling, and 3D rock block system analysis). First, geometric characteristic parameters of the terrain, rockfall, and discontinuities are extracted based on oblique photography using an unmanned aerial vehicle (UAV). Second, the block system model of rockfall is reconstructed by using 3D computational geometry theory and taking these geometric characteristic parameters as an input. Finally, the whole evolution process of rockfall geologic hazard, including initiation, movement, and accumulation, is simulated by the 3D-DDA method. To verify the practicability of this reproduction method, a typical rockfall geologic hazard, located in the K8 + 050 section of the Gaohai expressway, Yunnan, China, is studied. In addition, the characteristics of 19 dangerous rock masses in the survey area are clarified, and the geometric features of the discontinuities in the rock masses are extracted based on oblique photography using an UAV. The block system model of a potential rockfall is reconstructed, the movement trajectory is simulated by the 3D-DDA method, and the evolution process of velocity and kinetic energy of the rockfall verifies that the spatial layout of the current three-level passive protective nets system is reasonable. The case study indicates that the proposed method provides a geological and mechanical model for the risk assessment of rockfall geologic hazards.
Roadkills in Northern Peninsular Malaysia
Authors: Hui Tabitha C. Y. , Slade Eleanor M. , Chong Ju Lian
Published: October 2021

As Malaysia’s economy continues to grow, an ever-expanding road network is being built to support the new developments. Whilst roads increase accessibility to resources and connect human communities, they also bring with them a host of environmental problems such as destruction and fragmentation of habitat, poaching, pollution, and roadkills. Of these, roadkills are the most direct and visible impact of building roads, yet few dedicated studies have been conducted on the extent of roadkills and how to minimize them in Malaysia. In this study, we examined the species richness and abundance of vertebrate roadkills along eight one-km stretches (two in each habitat) of highways in Terengganu and Pahang across four habitat types: rainforest, oil palm plantation, subsistence agricultural land, and village. Each stretch of highway was surveyed by walking it six times between May to October 2017 for the Terengganu segments and May to October 2018 for the Pahang segments. A total of 305 roadkilled animals were recorded, consisting of at least 24 species. Three of these are protected by Malaysian law. The most common roadkilled animals were frogs (102 individuals) followed by birds (70 individuals), mammals (67 individuals) and reptiles (66 individuals). The highest number of roadkills were recorded in roads going through villages (112 individuals), followed by oil palm plantations (81 individuals), forests (65 individuals) and subsistence agricultural land (47 individuals). For every roadkill we also recorded the location’s specific habitat and landscape characteristics such as distance to the nearest fruit tree, tree, shrub, water body, human structure, and overhead cable. Most roadkills were found close to vegetation cover and water bodies. However, we found that roadkills decreased to near zero between 30 and 80 m from the nearest shrub or tree. Roadkills decreased over larger distances from the nearest water body, but in oil palm and village habitats, reducing water bodies within 20–50 m from a road would almost half the number of roadkills. We suggest that making changes to the structure and composition of roadside vegetation and other landscape features, such as thinning vegetation to discourage wildlife from gathering near roads, could significantly reduce the number of roadkills.
Impact of Hospital Wastewater on the Occurrence and Diversity of Beta-Lactamase Genes During Wastewater Treatment with an Emphasis on Carbapenemase Genes: A Metagenomic Approach
Authors: Hubeny Jakub , Ciesielski Sławomir , Harnisz Monika , Korzeniewska Ewa , Dulski Tomasz , Jałowiecki Łukasz , Płaza Grażyna
Published: October 2021

The diversity of beta-lactam antibiotic resistance genes, with particular emphasis on carbapenemase genes, during the treatment process at two wastewater treatment plants (WWTPs) with different levels of hospital wastewater inflow was investigated using high-throughput sequencing. An additional aspect of the study was to determine the taxonomic diversity of microorganisms in the studied samples. The obtained results suggest that bacteria of the Fusobacteriaceae family, not associated to date with this phenomenon, may be involved in the spread of antibiotic resistance in the environment. In samples from both wastewater treatment plants, the dominant beta-lactamase genes included blaOXA, blaGES, blaBEL, blaCfxA, and blaTEM. It is worth noting that the blaKPC and blaNDM genes were only found in untreated municipal wastewater with a higher hospital wastewater content. Moreover, an increase in the abundance of the blaIMP gene after the biological treatment stage in the studied treatment plants was found. In wastewater characterized by a higher proportion of hospital wastewater, 94 correlations were observed, while in wastewater with its lower proportion, 41 correlations were noted. Considering the above, the current research indicates that the inflow of hospital wastewater contributes to the spread of antibiotic resistance in the aquatic environment.
SeekFusion - A Clinically Validated Fusion Transcript Detection Pipeline for PCR-Based Next-Generation Sequencing of RNA
Authors: Balan Jagadheshwar , Jenkinson Garrett , Nair Asha , Saha Neiladri , Koganti Tejaswi , Voss Jesse , Zysk Christopher , Barr Fritcher Emily G. , Ross Christian A. , Giannini Caterina , Raghunathan Aditya , Kipp Benjamin R. , Jenkins Robert , Ida Cris , Halling Kevin C. , Blackburn Patrick R. , Dasari Surendra , Oliver Gavin R. , Klee Eric W.
Published: October 2021

Detecting gene fusions involving driver oncogenes is pivotal in clinical diagnosis and treatment of cancer patients. Recent developments in next-generation sequencing (NGS) technologies have enabled improved assays for bioinformatics-based gene fusions detection. In clinical applications, where a small number of fusions are clinically actionable, targeted polymerase chain reaction (PCR)-based NGS chemistries, such as the QIAseq RNAscan assay, aim to improve accuracy compared to standard RNA sequencing. Existing informatics methods for gene fusion detection in NGS-based RNA sequencing assays traditionally use a transcriptome-based spliced alignment approach or a de-novo assembly approach. Transcriptome-based spliced alignment methods face challenges with short read mapping yielding low quality alignments. De-novo assembly-based methods yield longer contigs from short reads that can be more sensitive for genomic rearrangements, but face performance and scalability challenges. Consequently, there exists a need for a method to efficiently and accurately detect fusions in targeted PCR-based NGS chemistries. We describe SeekFusion, a highly accurate and computationally efficient pipeline enabling identification of gene fusions from PCR-based NGS chemistries. Utilizing biological samples processed with the QIAseq RNAscan assay and in-silico simulated data we demonstrate that SeekFusion gene fusion detection accuracy outperforms popular existing methods such as STAR-Fusion, TOPHAT-Fusion and JAFFA-hybrid. We also present results from 4,484 patient samples tested for neurological tumors and sarcoma, encompassing details on some novel fusions identified.
DAMPs and Innate Immune Training
Authors: Jentho Elisa , Weis Sebastian
Published: October 2021

The ability to remember a previous encounter with pathogens was long thought to be a key feature of the adaptive immune system enabling the host to mount a faster, more specific and more effective immune response upon the reencounter, reducing the severity of infectious diseases. Over the last 15 years, an increasing amount of evidence has accumulated showing that the innate immune system also has features of a memory. In contrast to the memory of adaptive immunity, innate immune memory is mediated by restructuration of the active chromatin landscape and imprinted by persisting adaptations of myelopoiesis. While originally described to occur in response to pathogen-associated molecular patterns, recent data indicate that host-derived damage-associated molecular patterns, i.e. alarmins, can also induce an innate immune memory. Potentially this is mediated by the same pattern recognition receptors and downstream signaling transduction pathways responsible for pathogen-associated innate immune training. Here, we summarize the available experimental data underlying innate immune memory in response to damage-associated molecular patterns. Further, we expound that trained immunity is a general component of innate immunity and outline several open questions for the rising field of pathogen-independent trained immunity.
Novel Systemic Inflammation Markers to Predict COVID-19 Prognosis
Authors: Karimi Amirali , Shobeiri Parnian , Kulasinghe Arutha , Rezaei Nima
Published: October 2021

Coronavirus disease 2019 (COVID-19) has resulted in a global pandemic, challenging both the medical and scientific community for the development of novel vaccines and a greater understanding of the effects of the SARS-CoV-2 virus. COVID-19 has been associated with a pronounced and out-of-control inflammatory response. Studies have sought to understand the effects of inflammatory response markers to prognosticate the disease. Herein, we aimed to review the evidence of 11 groups of systemic inflammatory markers for risk-stratifying patients and prognosticating outcomes related to COVID-19. Numerous studies have demonstrated the effectiveness of neutrophil to lymphocyte ratio (NLR) in prognosticating patient outcomes, including but not limited to severe disease, hospitalization, intensive care unit (ICU) admission, intubation, and death. A few markers outperformed NLR in predicting outcomes, including 1) systemic immune-inflammation index (SII), 2) prognostic nutritional index (PNI), 3) C-reactive protein (CRP) to albumin ratio (CAR) and high-sensitivity CAR (hsCAR), and 4) CRP to prealbumin ratio (CPAR) and high-sensitivity CPAR (hsCPAR). However, there are a limited number of studies comparing NLR with these markers, and such conclusions require larger validation studies. Overall, the evidence suggests that most of the studied markers are able to predict COVID-19 prognosis, however NLR seems to be the most robust marker.
An Enriched Environment Alters DNA Repair and Inflammatory Responses After Radiation Exposure
Authors: Sakama Sae , Kurusu Keisuke , Morita Mayu , Oizumi Takashi , Masugata Shinya , Oka Shohei , Yokomizo Shinya , Nishimura Mayumi , Morioka Takamitsu , Kakinuma Shizuko , Shimada Yoshiya , Nakamura Asako J.
Published: October 2021

After the Fukushima Daiichi Nuclear Power Plant accident, there is growing concern about radiation-induced carcinogenesis. In addition, living in a long-term shelter or temporary housing due to disasters might cause unpleasant stress, which adversely affects physical and mental health. It’s been experimentally demonstrated that “eustress”, which is rich and comfortable, has beneficial effects for health using mouse models. In a previous study, mice raised in the enriched environment (EE) has shown effects such as suppression of tumor growth and enhancement of drug sensitivity during cancer treatment. However, it’s not yet been evaluated whether EE affects radiation-induced carcinogenesis. Therefore, to evaluate whether EE suppresses a radiation-induced carcinogenesis after radiation exposure, in this study, we assessed the serum leptin levels, radiation-induced DNA damage response and inflammatory response using the mouse model. In brief, serum and tissues were collected and analyzed over time in irradiated mice after manipulating the raising environment during the juvenile or adult stage. To assess the radiation-induced DNA damage response, we performed immunostaining for phosphorylated H2AX which is a marker of DNA double-strand break. Focusing on the polarization of macrophages in the inflammatory reaction that has an important role in carcinogenesis, we performed analysis using tissue immunofluorescence staining and RT-qPCR. Our data confirmed that EE breeding before radiation exposure improved the responsiveness to radiation-induced DNA damage and basal immunity, further suppressing the chronic inflammatory response, and that might lead to a reduction of the risk of radiation-induced carcinogenesis.
Ultrafast Nonlinear Optical Response and Carrier Dynamics in Layered Gallium Sulfide (GaS) Single-Crystalline Thin Films
Authors: Lu Haishuang , Chen Yu , Yang Kexin , Kuang Yawei , Li Zhongguo , Liu Yushen
Published: October 2021

Gallium sulfide (GaS) is a layered metal monochalcogenide semiconductor that has recently garnered considerable attention in various fields. In this study, we investigated the nonlinear absorption characteristics of multilayer β-GaS thin films on sapphire substrate by using femtosecond open-aperture Z-scan method. The β-GaS films exhibit saturable absorption behavior at 532 nm while nonlinear absorption appears under 650 nm excitation. The nonlinear absorption coefficient of β-GaS was determined to be −1.8 × 10–8 m/W and 4.9 × 10–8 m/W at 532 and 650 nm, respectively. The carrier dynamics of β-GaS films was studied via femtosecond transient absorption (TA) measurements. The TA results demonstrated that β-GaS films have broad photo-induced absorption in the visible regime and sub-nanosecond lifetime. Our results indicate that gallium sulfide has large nonlinear optical response and long carrier lifetime, which could be applied in future photonic devices.
Transcriptomics Analysis Indicates Trifarotene Reverses Acne-Related Gene Expression Changes
Authors: Dreno Brigitte , Chavda Rajeev , Julia Valerie , Khammari Amir , Blanchet-Réthoré Sandrine , Krishnaswamy Jayendra Kumar
Published: October 2021

Background and Objectives: Trifarotene is a topical retinoid selective for retinoic acid receptor gamma that was recently approved for treatment of acne vulgaris. We performed a gene expression analysis to identify the molecular and cellular impact of trifarotene treatment on acne papules.

Methods: In this open-label prospective study, subjects with moderate inflammatory acne of the back were treated with trifarotene 0.005% or vehicle cream on dedicated areas for 27 days, and 4 biopsies were collected from each subject (1 from skin without a visible acne lesion and three at the site of an acne papule: one baseline, one after vehicle treatment, and one after trifarotene treatment). Large scale gene expression profiling of the biopsies was performed using Affymetrix technology, treatment-specific gene expression profiles were generated using statistical modeling, and pathway analysis was performed. Using single-cell RNAseq data, in silico deconvolution of transcriptomics data was performed to identify cellular signatures.

Results: We discovered a unique set of 67 genes modulated by trifarotene that are primarily involved in cellular migration, inflammation, and extracellular matrix reorganization. Changes in cellular expression were similar in both trifarotene-treated and spontaneously-resolving lesions. However, only trifarotene treatment impacted SPP1+ macrophages, a subset of highly proliferative macrophages recently identified in fibrotic tissue.

Conclusions: These results show that trifarotene has a novel action in acne treatment by affecting epidermal and immune components of acne pathogenesis.
Physiological Dysregulation, Frailty, and Impacts on Adverse Health and Functional Outcomes
Authors: Lu Yanxia , Gwee Xinyi , Chua Denise Q. L. , Tan Crystal T. Y. , Yap Keng Bee , Larbi Anis , Ng Tze Pin
Published: October 2021

Background: Multi-system physiological dysregulation (PD) may represent a biological endo-phenotype of clinical frailty. We investigated the co-occurrence of PD with physical frailty and its contributions to the known impact of frailty on adverse health outcomes.

Methods: Data of 2,725 participants from the Singapore Longitudinal Aging Studies (SLAS-2), included baseline measures of physical frailty and PD derived from Mahalanobis distance (Dm) value of 23 blood biomarkers. We analyzed their concurrent association and their impacts on 9-year mortality, MMSE cognition, GDS depression, number of medications, disability, and hospitalization at baseline and follow up (mean 4.5 years).

Results: Global PD (Log10Dm, mean = 1.24, SD = 0.24) was significantly but weakly associated with pre-frailty-and-frailty. Controlling for age, sex and education, pre-frailty-and-frailty (HR = 2.12, 95% CI = 1.51–3.00) and PD (HR = 3.88, 95% CI = 2.15–6.98) predicted mortality. Together in the same model, mortality HR associated with pre-frailty-and-frailty (HR = 1.83, 95% CI = 1.22–2.73) and PD (HR = 3.06, 95% CI = 1.60–5.85) were reduced after additionally adding global PD to the prediction model. The predictive accuracy for mortality were both approximately the same (PD: AUC = 0.62, frailty: AUC = 0.64), but AUC was significantly increased to 0.68 when combined (p < 0.001). Taken into account in the same model, frailty remained significantly associated with all health and functional outcomes, and PD was significantly associated with only MMSE, disability and medications used. In secondary analyses, there were mixed associations of system-specific PDs with frailty and different adverse outcomes.

Conclusions: Co-existing PD and physical frailty independently predict mortality and functional and health outcomes, with increased predictive accuracy when combined. PD appears to be a valid representation of a biological endo-phenotype of frailty, and the potential utility of such subclinical measures of frailty could be further studied.
Characterization of 67 Confirmed Clustered Regularly Interspaced Short Palindromic Repeats Loci in 52 Strains of Staphylococci
Authors: Wang Ying , Mao Tingting , Li Yinxia , Xiao Wenwei , Liang Xuan , Duan Guangcai , Yang Haiyan
Published: October 2021

Staphylococcus aureus (S. aureus), which is one of the most important species of Staphylococci, poses a great threat to public health. Clustered regularly interspaced short palindromic repeats (CRISPR) and their CRISPR-associated proteins (Cas) are an adaptive immune platform to combat foreign mobile genetic elements (MGEs) such as plasmids and phages. The aim of this study is to describe the distribution and structure of CRISPR-Cas system in S. aureus, and to explore the relationship between CRISPR and horizontal gene transfer (HGT). Here, we analyzed 67 confirmed CRISPR loci and 15 companion Cas proteins in 52 strains of Staphylococci with bioinformatics methods. Comparing with the orphan CRISPR loci in Staphylococci, the strains harboring complete CRISPR-Cas systems contained multiple CRISPR loci, direct repeat sequences (DR) forming stable RNA secondary structures with lower minimum free energy (MFE), and variable spacers with detectable protospacers. In S. aureus, unlike the orphan CRISPRs away from Staphylococcal cassette chromosome mec (SCCmec), the complete CRISPR-Cas systems were in J1 region of SCCmec. In addition, we found a conserved motif 5′-TTCTCGT-3′ that may protect their downstream sequences from DNA interference. In general, orphan CRISPR locus in S. aureus differed greatly from the structural characteristics of the CRISPR-Cas system. Collectively, our results provided new insight into the diversity and characterization of the CRISPR-Cas system in S. aureus.
Differential Diagnosis of Latent Tuberculosis Infection and Active Tuberculosis: A Key to a Successful Tuberculosis Control Strategy
Authors: Gong Wenping , Wu Xueqiong
Published: October 2021

As an ancient infectious disease, tuberculosis (TB) is still the leading cause of death from a single infectious agent worldwide. Latent TB infection (LTBI) has been recognized as the largest source of new TB cases and is one of the biggest obstacles to achieving the aim of the End TB Strategy. The latest data indicate that a considerable percentage of the population with LTBI and the lack of differential diagnosis between LTBI and active TB (aTB) may be potential reasons for the high TB morbidity and mortality in countries with high TB burdens. The tuberculin skin test (TST) has been used to diagnose TB for > 100 years, but it fails to distinguish patients with LTBI from those with aTB and people who have received Bacillus Calmette–Guérin vaccination. To overcome the limitations of TST, several new skin tests and interferon-gamma release assays have been developed, such as the Diaskintest, C-Tb skin test, EC-Test, and T-cell spot of the TB assay, QuantiFERON-TB Gold In-Tube, QuantiFERON-TB Gold-Plus, LIAISON QuantiFERON-TB Gold Plus test, and LIOFeron TB/LTBI. However, these methods cannot distinguish LTBI from aTB. To investigate the reasons why all these methods cannot distinguish LTBI from aTB, we have explained the concept and definition of LTBI and expounded on the immunological mechanism of LTBI in this review. In addition, we have outlined the research status, future directions, and challenges of LTBI differential diagnosis, including novel biomarkers derived from Mycobacterium tuberculosis and hosts, new models and algorithms, omics technologies, and microbiota.
Primary Bedaquiline Resistance Among Cases of Drug-Resistant Tuberculosis in Taiwan
Authors: Wu Sheng-Han , Chan Hsin-Hua , Hsiao Hseuh-Chien , Jou Ruwen
Published: October 2021

Bedaquiline (BDQ), which is recommended for the treatment of drug-resistant tuberculosis (DR-TB), was introduced in Taiwan in 2014. Due to the alarming emergence of BDQ resistance, we conducted BDQ resistance analyses to strengthen our DR-TB management program. This retrospective population-based study included initial Mycobacterium tuberculosis isolates from 898 rifampicin-resistant (RR) or multidrug-resistant (MDR) TB cases never exposed to BDQ during 2008–2019. We randomly selected 65 isolates and identified 28 isolates with BDQ MIC<0.25μg/ml and MIC≥0.25μg/ml as the control and study groups, respectively. BDQ drug susceptibility testing (DST) using the MGIT960 system and Sanger sequencing of the atpE, Rv0678, and pepQ genes was conducted. Notably, 18 isolates with BDQ MIC=0.25μg/ml, 38.9% (7/18), and 61.1% (11/18) isolates were MGIT-BDQ resistant and susceptible, respectively. Consequently, we recommended redefining MIC=0.25μg/ml as an intermediate-susceptible category to resolve discordance between different DST methods. Of the 93 isolates, 22 isolates were MGIT-BDQ-resistant and 77.3% (17/22) of MGIT-BDQ-resistant isolates harbored Rv0678 mutations. After excluding 2 MGIT-BDQ-resistant isolates with borderline resistance (GU400growth control-GU100BDQ≤1day), 100% (15/15) harbored Rv0678 gene mutations, including seven novel mutations [g-14a, Ile80Ser (N=2), Phe100Tyr, Ala102Val, Ins g 181–182 frameshift mutation (N=2), Del 11–63 frameshift mutation, and whole gene deletion (N=2)]. Since the other 22.7% (5/22) MGIT-BDQ-resistant isolates with borderline resistance (GU400growth control-GU100BDQ≤1day) had no mutation in three analyzed genes. For isolates with phenotypic MGIT-BDQ borderline resistance, checking for GU differences or conducting genotypic analyses are suggested for ruling out BDQ resistance. In addition, we observed favorable outcomes among patients with BDQ-resistant isolates who received BDQ-containing regimens regardless of Rv0678 mutations. We concluded that based on MIC≥0.25μg/ml, 3.1% (28/898) of drug-resistant TB cases without BDQ exposure showed BDQ resistance, Rv0678 was not a robust marker of BDQ resistance, and its mutations were not associated with treatment outcomes.
The Therapeutic Potential and Limitations of Ketones in Traumatic Brain Injury
Authors: Daines Savannah Anne
Published: October 2021

Traumatic brain injury (TBI) represents a significant health crisis. To date, no FDA approved pharmacotherapies are available to prevent the neurological deficits caused by TBI. As an alternative to pharmacotherapy treatment of TBI, ketones could be used as a metabolically based therapeutic strategy. Ketones can help combat post-traumatic cerebral energy deficits while also reducing inflammation, oxidative stress, and neurodegeneration. Experimental models of TBI suggest that administering ketones to TBI patients may provide significant benefits to improve recovery. However, studies evaluating the effectiveness of ketones in human TBI are limited. Unanswered questions remain about age- and sex-dependent factors, the optimal timing and duration of ketone supplementation, and the optimal levels of circulating and cerebral ketones. Further research and improvements in metabolic monitoring technology are also needed to determine if ketone supplementation can improve TBI recovery outcomes in humans.
Acute Stroke With Large Vessel Occlusion and Minor Clinical Deficits: Prognostic Factors and Therapeutic Implications
Authors: Volbers Bastian , Gröger Rebecca , Engelhorn Tobias , Marsch Armin , Macha Kosmas , Schwab Stefan , Dörfler Arnd , Lang Stefan , Kallmünzer Bernd
Published: October 2021

Background and Purpose: The optimal acute management of patients with large vessel occlusion (LVO) and minor clinical deficits on admission [National Institutes of Health Stroke Scale (NIHSS) ≤ 4] remains to be elucidated. The aim of the present study was to investigate the prognostic factors and therapeutic management of those patients.

Methods: In this retrospective cohort study, we investigated (1) all patients with acute ischemic stroke due to an LVO who underwent mechanical thrombectomy (MT) and (2) all patients with minor clinical deficits (NIHSS ≤ 4) on admission due to an LVO between January 2013 and December 2016 at the University Medical Center Erlangen. We dichotomized management of patients with minor deficits treated with MT for analysis according to immediate mechanical thrombectomy (IT) and initial medical management with rescue intervention (MM) in case of secondary deterioration. Primary endpoints were secondary deterioration, in-hospital mortality, and functional outcome on day 90 (dichotomized modified Rankin Scale 0–2: favorable, 3–6: poor).

Results: Two hundred twenty-three patients (83% with anterior circulation stroke, 13 (6%) with minor deficits) treated with MT and 88 patients with minor deficits due to LVO [13 (15%) treated with MT] were included. Secondary deterioration (n = 19) was independently associated with poor outcome in patients with minor deficits and LVO [odds ratio (OR), 0.060; 95% confidence interval (CI), 0.013–0.280], which in turn was associated with the occlusion site [especially M1 occlusion: 11 (58%) vs. 3 (4%) in patients without secondary deterioration, p < 0.0001]. IT (n = 8) was associated with a lower intrahospital mortality compared to MM (n = 5; 13 vs. 80%; OR, 0.036; 95% CI, 0.002–0.741). Seven of eight patients with IT survived until discharge, with 29% showing a favorable functional outcome on day 90.

Conclusions: Secondary deterioration is associated with poor outcome in patients with LVO and minor deficits, which in turn was associated with occlusion site. Future randomized controlled trials should assess whether selected patients, depending on occlusion site and associated characteristics, may benefit from MT.
Case Report: Multiple Sclerosis Relapses After Vaccination Against SARS-CoV2: A Series of Clinical Cases
Authors: Nistri Riccardo , Barbuti Elena , Rinaldi Virginia , Tufano Laura , Pozzilli Valeria , Ianniello Antonio , Marinelli Fabiana , De Luca Giovanna , Prosperini Luca , Tomassini Valentina , Pozzilli Carlo
Published: October 2021

Objective: To describe a temporal association between COVID-19 vaccine administration and multiple sclerosis (MS) relapses.

Methods: This case series study was collected in four MS Centres in Central Italy, using data from 16 MS patients who received COVID-19 vaccination and presented both clinically and radiologically confirmed relapses between March and June 2021. We collected patients' relevant medical history, including demographics, MS clinical course, disease-modifying treatment (DMT) received (if applicable), and data from MRI scans obtained after the COVID-19 vaccination.

Results: Three out of 16 patients received a diagnosis of MS with a first episode occurring after COVID-19 vaccination; 13 had already a diagnosis of MS and, among them, 9 were on treatment with DMTs. Ten patients received BNT162b2/Pfizer-BioNTech, 2 patients mRNA-1273/Moderna, and 4 patients ChAdOx1 nCoV-19/AstraZeneca. All MS relapses occurred from 3 days to 3 weeks after receiving the first dose of the COVID-19 vaccination or the booster. All patients had evidence of radiological activity on MRI.

Discussion: Clinical and radiological findings in these cohort of MS patients confirmed disease re/activation and suggested a temporal association between disease activity and COVID-19 vaccination. The nature of this temporal association, whether causative or incidental, remains to be established.
A Quantitative Perspective of Alpha-Synuclein Dynamics – Why Numbers Matter
Authors: Specht Christian G.
Published: October 2021

The function of synapses depends on spatially and temporally controlled molecular interactions between synaptic components that can be described in terms of copy numbers, binding affinities, and diffusion properties. To understand the functional role of a given synaptic protein, it is therefore crucial to quantitatively characterise its biophysical behaviour in its native cellular environment. Single molecule localisation microscopy (SMLM) is ideally suited to obtain quantitative information about synaptic proteins on the nanometre scale. Molecule counting of recombinant proteins tagged with genetically encoded fluorophores offers a means to determine their absolute copy numbers at synapses due to the known stoichiometry of the labelling. As a consequence of its high spatial precision, SMLM also yields accurate quantitative measurements of molecule concentrations. In addition, live imaging of fluorescently tagged proteins at synapses can reveal diffusion dynamics and local binding properties of behaving proteins under normal conditions or during pathological processes. In this perspective, it is argued that the detailed structural information provided by super-resolution imaging can be harnessed to gain new quantitative information about the organisation and dynamics of synaptic components in cellula. To illustrate this point, I discuss the concentration-dependent aggregation of α-synuclein in the axon and the concomitant changes in the dynamic equilibrium of α-synuclein at synapses in quantitative terms.
How to Estimate Food Prices and Diet Costs in Population-Based Studies?
Authors: de Mello Aline Veroneze , Sarti Flavia Mori , Fisberg Regina Mara
Published: October 2021

Health and nutrition surveys usually comprise detailed information on health characteristics and food consumption of certain population groups; however, the lack of data collection on the food prices may pose challenges for the estimation of the diet costs for the comprehensive analysis of food demand. The Household Budget Survey (HBS) represents an opportunity to obtain the data on the food prices for the nutrition surveys in the diverse countries worldwide. Although the HBS and the health and nutrition surveys may correspond to different periods, the application of the appropriate Consumer Price Index (CPI) allows to address the changes in the relative prices to perform the linkage between the data of food consumption with information on the food prices. Therefore, the aim of this study was to present the methods for the extraction and linkage of the food prices data from the Brazilian HBS (2002–2003 and 2008–2009) by using the pairing features related to the household characteristics to match the Health Survey of São Paulo [Inquérito de Saúde de São Paulo (ISA-Capital)] conducted in 2003, 2008, and 2015. Data referring to the household characteristics and food prices acquired by the household members living in São Paulo municipality were selected from the HBS datasets for integration with the ISA-Capital dataset. Specific deflators referring to the food items surveyed in São Paulo were obtained from the datasets of the Brazilian Broad Consumer Price Index (BCPI). Therefore, the pairing criteria referring to time, location, and household characteristics were adopted to allow linking foods consumed by the individuals in the ISA-Capital with the prices from the foods acquired by household members interviewed in the HBS. Matching data on the key pairing criteria (location/year/household income per capita/number of residents/family profile) resulted in the linkage of 94.4% (2003), 92.6% (2008), and 81.2% of the cases (2015). Following the data linkage, it was possible to estimate diet costs per gram and per calorie including application of cooking and conversion factors. Data were presented in the International Monetary Unit under the purchasing power parity (PPP) to allow the comparison at the international level. The mean diet costs identified in the population of São Paulo municipality were $8.45 (dp = 0.38) per capita per day in 2003, $8.72 (dp = 0.24) per capita per day in 2008, and $9.62 (dp = 0.23) per capita per day in 2015. Thus, it was possible to estimate the diet costs based on the prices of food items through pairing linkage of information from the household surveys, such as the Brazilian HBS, with the health and nutrition surveys lacking information on the expenditures or prices such as the ISA-Capital. Similar procedures may be used in the diverse countries with availability of the datasets of the household expenditures and health and nutrition surveys, allowing the researchers worldwide to associate the diet quality with food demand.