bluuebunny/crossref_metadata_2025 huggingface dataset:
Design, Synthesis, Biological Evaluation and Molecular Docking Studies of 5-fluorouracil-dithiocarbamate Conjugates
Authors: Zhan Yifeng , Wang Youyun , Wang Puzhao , Zhu Hongda , Guo Huiling , Sun Hongmei , Liu Mingxing
Published: January 2022

In this paper, a series of novel 5-fluorouracil-dithiocarbamate conjugates were designed, synthesized and evaluated in vitro . The results of cytotoxicity assays illuminated that these conjugates had anti-tumor activity against B16, Hela and U87MG, and compound P3 exhibited excellent growth inhibition against U87MG cells. Interestingly, the cytotoxicity of these conjugates was significantly increased when combined with copper ions. Meanwhile, colony-formation assays, transwell migration assays, cell apoptosis assays and cell cycle distribution assays were performed to explore the anti-tumor mechanism of conjugates. Compound P3 and P4 exhibited good biological activity in above four experiments when combined with copper ions. Especially, P3 displayed better bioactivity compared to the other three compounds. These results indicated that conjugates might be metabolized in the cells to produce dithiocarbamates, then metabolites formed complexes with copper ions, generating anti-tumor effects. Furthermore, conjugates and their metabolized dithiocarbamate derivatives were investigated by molecular docking, the results exhibited that P3 had the strongest interaction with the proteins 6CCY and 5T92, which was consistent with the obtained results of cell experiments. Compound P3 might be a potential lead-compound for the treatment of breast cancer and glioma. Further research in vivo about these compounds would be performed in our following work.
E-waste Management In Indian Microscale Informal Sectors – An Environmental Perspective Towards Policy Regulation
Authors: Dasgupta Dipsikha , Majumder Santanu , Adhikari Jishnu , Ghosh Pinaki , Purchase Diane , Garelick Hemda , Debsarkar Anupam , Chatterjee Debashis
Published: January 2022

Inappropriate e-waste processing in the informal sector is a serious issue in developing countries. Field investigations in microscale informal recycling sites have been performed to study the impact of hazardous metal(loid)s (released from e-waste dismantling) on the environment (water and soil). Eight hazardous metal(loid)s (Pb, Cd, Cu, Zn, As, Hg, Ni and Cr) were found at elevated levels in the monitored water and soil samples (Sangrampur, West Bengal) as a consequence of widespread informal e-waste handling and primitive processing. Pd, Cu and As were found in high concentrations in water samples (1.62, 1.40, 0.03 mgL-1 respectively). Significant levels of Cu, Pd and Cd were detected in collected soil samples, both topsoil (Cu up to 2328.60 ± 217.60, Pb up to 342.90 ± 32.36 and Cd 18.34 ± 3.81 mgkg-1) and subsurface soil (2491.40 ± 276.20, 1853.33 ± 144.79, 25.90 ± 9.53 mgkg-1), compared to the levels of Zn, As, Hg, Ni and Cr. The results of seasonal variation indicated that higher levels of these hazardous meta(loids) were detected in the pre-monsoon (Nov – May) season than the rest of the year, as open dumping/burning of e-waste were practiced commonly and frequently in the monitored sites. The results highlighted that the composition and the handling of e-waste were important factors affecting the metal(loid) concentrations. E-waste policy and legislation have great influence on the handling and disposal procedures. A novel improved e-waste management practice has been proposed to encourage eco-friendly and safe e-waste disposal. It is recommended that regulatory agencies and manufacturers should create a road map to convince the informal sector to develop a systematic approach towards a more standardized formal e-waste management practices at the microscale field level.
Utilization of Frequency Ratio Method for the Development of Landslide Susceptibility Maps: Karaburun Peninsula Case, Turkey
Authors: Karaman Muhittin Ozan , ÇABUK Saye Nihan , PEKKAN Emrah
Published: January 2022

Geographical information systems (GIS) facilitates both current landslide mapping processes and prediction of potential landslides that may be experienced in the future. Within the scope of the study, landslide susceptibility maps were developed in order to reduce the damages of possible landslides in Karaburun Peninsula of İzmir province. To fulfil this aim, landslide inventory map was produced from related databases in the first place followed by the development of parameter (elevation, aspect, slope, curvature, land use, vegetation cover, lithology, distance to roads, distance to rivers and distance to fault lines) maps. Frequency ratio method was utilized for developing the landslide susceptibility maps and Reciever Receiver Operating Characteristic (ROC) analysis was performed for accuracy testing. The resulting landslide susceptibility map revealed that 36% and 52% of the study area had high and medium risk categories, respectively. 10% of the region has low landslide risk. These results provide important inputs to guide sustainable strategic and physical planning processes in the region, which has been formerly declared as a special protection area, and is a popular destination for both tourism activities and energy facilities.
WITHDRAWN: Effectiveness of a Cognitive-behavioral Group Therapy for Complicated Grief in Family Members of Patients With Cancer
Authors: Lacasta-Reverte Maria Antonia , Cruzado Juan Antonio
Published: January 2022

Introduction: complicated grief can affect a large number of individuals who have lost a relative due to cancer. Objective: to assess the efficacy of a cognitive-behavioral group therapy (CBGT) for complicated grief in those who have lost a relative due to cancer in comparison with a psychoducational and emotional expression intervention (PSDEEI).Method: 249 relatives of deceased cancer patients with complicated grief were randomly assigned to treatment with CBGT or PSDEEI. Complicated Grief (ICG), depression (BDI-II), hopelessness (BHS), anxiety (BAI) symptoms and general health (GHQ28) were assessed at pre-treatment, post-treatment, and follow-up at 6 and 12 months. Results: the CBGT group improved significantly (p<0.001), with the scores in ICG, BDI-II, BAI, BSH, and GHQ28 (p<0.001) being higher than those for the PSDEEI group in each of the assessed moments, with high effect sizes: ICG (η2=0.16), BDI (η2=0.10), BAI (η2=0.06), BSH (η2=0.21) and GHQ28 (η2=0.21). At the 12-month follow-up, the number of cases of complicated grief decreased by 81.1% for the CBGT group vs. 31.7% in the PSDEEI group. Conclusions: The CBGT treatment is effective for complicated grief, for depression, anxiety, and hopelessness symptoms and for mental health, and is superior to PSDEEI treatment.
Clinacanthus Nutans Induces Antiproliferative and Apoptosis in Human Breast Cancer Cells Through Targeted Apoptosis Pathway
Authors: Arsad Hasni , Ismail Noor Zafirah , S Salwani Md , Adebayo Ismail Abiola , T Zaleha Md , Abas Rafedah , Zain Nur Nadhirah Mohamad
Published: January 2022

Clinacanthus nutans dichloromethane fraction (CN-Dcm) extract has previously been proven to suppress breast cancer (MCF7) cell proliferation. Despite this, the molecular mechanisms involved in C. nutans extract-treated MCF7 cells are unknown. Hence, the molecular mechanism of apoptosis in treated MCF7 was investigated in this current study. This study was intended to subfractionate CN-Dcm extract using column chromatography and analysed the treated MCF7 cells using the CellTiter 96® AQueous One Solution Cell Proliferation (MTS) assay, Annexin V/propidium iodide (PI) assay, western blot and reverse transcription-qualitative polymerase chain reaction (RT-qPCR). Out of nine subfraction extracts (SF1 to SF9), SF2 extract strongly inhibited MCF7 cells with the lowest IC50 value (23.51 ± 0.99 µg/mL) and substantially induced apoptosis in the MCF7 cells. SF2 extract significantly downregulated BCL-2 expression and upregulated P53, BAX, BID, BCL-2, caspase-8, caspase-9 and caspase-3 expressions in treated MCF7 cells. Therefore, SF2 extract was analysed using liquid chromatography coupled to quadrupole time–of–flight mass spectrometry (LC-QTOF-MS), which confirmed the presence of bioactive chemical compounds. Thus, it can be concluded that the compounds found in SF2 extract may potentially cause apoptosis in MCF7 cells through intrinsic and extrinsic pathways.
Molecular Docking Studies of Natural Immunomodulators Indicate Their Interactions With CD40 and CSF1 of Microglia
Authors: Maurya Shashank Kumar , Mishra Rajnikant
Published: January 2022

Natural products have proved beneficial in reducing neuroinflammation in neurological diseases. Their impacts have also been associated with the activities of microglia, responsible for brain-specific immunity. Recent studies have shown involvement of the number of microglia-specific proteins in the regulation of brain-specific immunity. However, molecular targets of natural products and their mechanisms of interactions with microglia-specific proteins are elusive. Since the genetic signature of microglia offers many potential targets for drug discovery, molecular docking followed by Molecular Dynamics (MD) simulations of Cluster of Differentiation 40 (CD40) and Colony-stimulating factor 1 receptor (CSF1R) proteins with some known neuro-immunomodulators (Curcumin, Cannabidiol, Ginsenosides, Resveratrol, and Sulforaphane) has been evaluated. Curcumin and Cannabidiol were observed likely to modulate CD40L and expression of cytokines and entry of inflammatory cells. Resveratrol and Cannabidiol may affect CSF1R and activation of microglia. Our finding suggests that Curcumin, Cannabidiol, and Resveratrol may serve specific drug ligands in regulating microglia-mediated brain immunity.
Estimation of Holocene bedload sedimentation rate in a paleo-drowned river-valley (Middle Harbour, Sydney estuary, Australia)
Authors: Lound Stephen P , Birch Gavin F , Dragovich Deirdre
Published: January 2022

Middle Harbour is a drowned-river valley located adjacent to the larger Sydney estuary, Australia. Extensive, high-resolution seismic data were correlated with borehole, land use, topographical, and geological data to calculate the mass of genetically different sediment deposits in Middle Harbour. The Harbour follows a well-defined drowned river-valley structure featuring small fluvial bedload delta deposits in the upper reaches of the embayments, a deep, central extensive mud basin overlying transgressive basal accumulations and a large flood-tide delta at the entrance. Deposits of an estimated 5,094 t of bedload, 21,143 t of suspended sediment and 5,947 t of transgressive basal material located in the estuary provided sedimentation rates of 0.68 t y-1, 1.29 t y-1, and 2.86 t y -1 respectively. These rates, determined from measured accumulations, were surprisingly low and substantially smaller than modelled rates. However, low sedimentation rates for suspended material may be due to fine sediment escaping over the top of the marine tidal delta, which effectively traps all bedload material from exiting the Harbour. Results of this study indicate that Holocene bedload sedimentation in Middle Harbour was slow and regular until a rapid increase after urbanisation commenced in the catchment. Most pre-Holocene material was eroded from Middle Harbour during the Last Glacial period with sediment currently present in the estuary having been deposited since sea-level recovery.
Electrochemical DNA biosensor for the multianalyte detection of HPV-16 and HPV-18 in oral and cervical lesions
Authors: Chaibun Thanyarat , Thanasapburachot Patcharanin , Chatchawal Patutong , Lee Su Yin , Jiaranuchart Sirimanas , Jearanaikoon Patcharee , Promptmas Chamras , Buajeeb Waranun , Lertanantawong Benchaporn
Published: January 2022

Infection with high-risk human papillomavirus (HPV) is a major risk factor for oral and cervical cancers. In this study, we developed an electrochemical DNA biosensor for detection of HPV-16 and HPV-18, which are the 2 most prevalent genotypes for development of oral and cervical cancers. The assay involves the sandwich hybridization of the HPV target to silica-redox dye reporter probe and capture probe, followed by electrochemical detection. The sensor was found to be highly specific and sensitive, with detection limit of 22 fM for HPV-16 and 20 fM for HPV-18, between the range of 1 fM to 1 µM. Evaluation with oral and cervical samples showed that the biosensor result was consistent with the nested PCR /gel electrophoresis detection. The biosensor assay could be completed within 90 minutes. Due to its simplicity, rapidity and high sensitivity, this biosensor could be used as an alternative method for HPV detection in clinical laboratories. [151 words]
Increased ENT2 Expression and Its Association With Altered Purine Metabolism in Different Stages of Colorectal Cancer Cell Lines
Authors: Naes Safaa M. , Ab-Rahim Sharaniza , Mazlan Musalmah , Hashim Nurul Azmir Amir , Rahman Amirah Abdul
Published: January 2022

Background Colorectal cancer (CRC) is one of the most prevalent malignant cancers worldwide. Although the purine metabolism pathway is known to be vital for cancer cells survival mechanism, not much is known on ENT2 role in CRC development and its association with purine metabolites. Hence this study is aimed to determine the level of hypoxanthine phosphoribosyl transferase (HPRT), hypoxanthine, uric acid (UA), and the activity of xanthine oxidase (XO) and relate the findings with the ENT2 expression level in different CRC stages. Methods and results Normal colon cell line; CCD-841CoN and a panel of human CRC cell lines; SW480, HCT15 and HCT116, representing different CRC stages; Dukes’ B, C, and D respectively, have been used to measure HPRT, hypoxanthine/xanthine, UA levels and the activity of XO by biochemical assays. The level of ENT2 gene expression was also performed by qRT-PCR. The levels of HPRT, hypoxanthine were significantly higher (P< 0.05), while XO and UA were lower (P< 0.05) in all CRC stages as compared to the normal colon cells. Furthermore, ENT2 expression was found to be increased in all CRC stages. Despite having the highest level of HPRT and hypoxanthine, ENT2 level is lower in Dukes' D when compared to Dukes' B and C. Conclusion The rate of salvage pathway is increased in CRC development as indicated by the elevated levels of HPRT and hypoxanthine in different CRC stages. Increase ENT2 expression implies its importance in assisting hypoxanthine uptake. This step is vital in order to increase DNA synthesis via hypoxanthine recycling. Thus, ENT2 may be a potential marker in therapeutic development.
Developing an Efficient Secure Query Processing Algorithm on Encrypted Databases using Data Compression
Authors: Taloba Ahmed , Fouly Mohamed Ahmed , Soliman Taysir
Published: January 2022

Distributed computing includes putting aside the data utilizing outsider storage and being able to get to this information from a place at any time. Due to the advancement of distributed computing and databases, high critical data are put in databases. However, the information is saved in outsourced services like Database as a Service (DaaS), security issues are raised from both server and client-side. Also, query processing on the database by different clients through the time-consuming methods and shared resources environment may cause inefficient data processing and retrieval. Secure and efficient data regaining can be obtained with the help of an efficient data processing algorithm among different clients. This method proposes a well-organized through an Efficient Secure Query Processing Algorithm (ESQPA) for query processing efficiently by utilizing the concepts of data compression before sending the encrypted results from the server to clients. We have addressed security issues through securing the data at the server-side by an encrypted database using CryptDB. Encryption techniques have recently been proposed to present clients with confidentiality in terms of cloud storage. This method allows the queries to be processed using encrypted data without decryption. To analyze the performance of ESQPA, it is compared with the current query processing algorithm in CryptDB. Results have proven the efficiency of storage space is less and it saves up to 63% of its space.
AgNPs functionalized with dithizone for the detection of Hg2+ based on surface–enhanced Raman scattering spectroscopy
Authors: Guo Na , Xu Guangda , Zhang Qijia , song peng , Xia Lixin
Published: January 2022

Mercuric ion (Hg2+), a poisonous metal ion that remained in water ecosystems, can severely damage the human central and peripheral nervous system and kidneys. Consequently, rapid and highly sensitive methods to determine trace Hg2+ are meaningful to discuss. We have proposed a novel approach of surface-enhanced Raman scattering (SERS) for the quantitative analysis of Hg2+ in water samples using dithizone (DTZ) as a Raman reporter. DTZ-modified silver nanoparticles (AgNPs) produced a strong SERS signal. In the presence of Hg2+, the DTZ can capture Hg2+ composing a stable structure, resulting in DTZ leaving the surface of the AgNPs, with an accompanying decrease in the signal. The proposed SERS assay showed a linear range of 10−4–10−8 M, with a limit of detection of 9.83 × 10−9 M. The sensor has low detection cost, rapid detection speed, and uncomplicated sample pretreatment. Furthermore, this method can be successfully utilized to detect Hg2+rapidly in water samples, which sheds new light on the detection of Hg2+ in the environment.
Molecular dynamics simulations of the
delta and omicron SARS-CoV-2 spike – ACE2 complexes
reveal distinct changes between both variants
Authors: Socher Eileen , Heger Lukas , Paulsen Friedrich , Zunke Friederike , Arnold Philipp
Published: January 2022

SARS-CoV-2, the virus which causes the COVID-19 pandemic, changes frequently through the ap-pearance of mutations constantly leading to new variants. However, only few variants evolve as dominating and will be considered as “Variants of Concern” (VOCs) by the world health organization (WHO). At the end of 2020 the alpha (B.1.1.7) variant appeared in the United Kingdom and domi-nated the pandemic situation until mid of 2021 when it was substituted by the delta variant (B.1.617.2) that first appeared in India as predominant variant. At the end of 2021, SARS-CoV-2 omi-cron (B.1.1.529) evolved as the dominating variant. Here, we use in silico modeling and molecular dynamics (MD) simulations of the receptor-binding domain of the viral spike protein and the host cell surface receptor ACE2 to analyze and compare the interaction pattern between the wild type, delta and omicron variants. We identified residue 493 in delta (glutamine) and omicron (arginine) with altered binding properties towards ACE2.
Short-Term Clinical Efficacy of Femoral Neck System Versus Multiple Cannulated Compression Screws in the Treatment of Garden III and IV Femoral Neck Fractures
Authors: Zhou Xuefeng , Gu Sichao , Li Li , Xu Lei , Wang Xujin , Wang Gang , Xu Xinzhong , Yang Jiazhao , Fang Shiyuan
Published: January 2022

Femoral neck system (FNS) , as a novel minimally invasive internal fixation device, has been gradually applied in the treatment of femoral neck fracture.However, there are few related clinical studies on FNS at present, especially there is no clinical report on FNS in treating GardenIII and IV femoral neck fractures. The aim of the present study was to compare the short-term clinical efficacy of FNS and multiple cannulated compression screws (MCCS) in the treatment of Garden III and IV femoral neck fractures. The data of 78 patients with femoral neck fracture who were admitted to three teaching hospitals affiliated to Anhui Medical University and received internal fixation with FNS and MCCS from June 2019 to December 2020 were collected for a retrospective study. There were 39 patients in both the FNS and MCCS groups. The basic data, perioperative data were recorded and compared between the two groups of patients. The results of the study are encouraging. The operation time was shorter in FNS group than that in MCCS group (p<0.001). The post-operative partial and complete weight-bearing time was earlier in FNS group than that in MCCS group (p<0.001). The Harris hip score in FNS group was higher than that in MCCS group (p<0.001). The incidence rate of lateral thigh irritation in FNS group and MCCS group was 0 (0/39) and 33.3% (13/39), respectively (χ2=15.600, p<0.001). The length of femoral neck shortening was significantly shorter in FNS group than that in MCCS group (t=-5.093, p<0.001). In conclusion, The application of FNS for Garden III and IV femoral neck fractures can shorten the operation time, reduce the frequency of intraoperative fluoroscopy, and facilitate the recovery of hip joint function, so it provides a novel choice for the treatment of Garden III and IV femoral neck fractures in young people.
Knowledge, Attitude, and Perception on Bequeathing of Bodies for Medical Education and Research among Health Science Students of the University of Health and Allied Sciences.
Authors: Quarshie Henrietta Enam , Maalman Raymond Saa-Eru , Ali Mahamudu Ayamba , Donkor Yaw Otchere , Ampong Kingsley , Quaye Jerry , Safianu Rufai , Ennin Isaac Ekow , Korpisah Joseph K.
Published: January 2022

Abstract
Background: Cadaveric dissection is an established effective teaching method in anatomical science education. Cadaver acquisition for dissection is however based on voluntary body bequeathment. As a result of the increasing numbers of medical schools and students intake, the challenges of inadequate bodies for education became visible in most parts of the world as the main cadaver source remains anonymous corpses in the custody of the state. Cultural and religious beliefs or commercial purposes are among several factors that influence the decision about body donations. This study investigates the knowledge, attitude and perception of body bequeathing among health science students who benefitted or are potential beneficiary of cadaveric studies and identified factors influencing the bequest of bodies in Ghana for educational purposes among students in University of Health and Allied Sciences. Method: This was a cross-sectional descriptive study. The study recruited 513 students in the bachelor programmes for medicine, physician assistantship, nursing, midwifery, pharmacy and allied sciences at various levels. Both closed-and open-ended questions contained in a designed Questionnaire were administered. Result: About Seventy-four percent (74.1%) of respondents had heard of body bequeathal. Majority (98.3%) agreed body bequeathal was important. However, only 39.6% knew the requirements and processes of body bequeathal. Most (>90%) had a negative attitude towards body bequeathal. Conclusion: The study concluded that there was a high awareness of the importance of body bequeathal for medical education and research but very low procedural knowledge on bequeathing a body among health science students. Also most were unwillingness to donate their body or even encouraging others to donate their body. It is therefore recommended that the medical schools should set up accessible body bequeathal programmes that provides opportunities for interested individuals to be readily assisted through the process of body bequeathal.

Keywords: Body Bequeathal, Medical Science Education, Cadaveric Dissection, Anatomical education
Risk Factors of Pregnancy Outcome in Patients with Pulmonary Hypertension
Authors: Zhao Kaixun , Yang Ziyang , Zhou Yin , Xie Nanshan , Lai Disheng , Zhang Caojin
Published: January 2022

OBJECTIVE: The purpose of this study is to explore the factors affecting the pregnancy outcome of patients with pulmonary hypertension, and to design a digital model predicting the pregnancy outcome of patients and judge whether patients have the conditions to continue pregnancy. METHODS: The clinical data of patients with pregnancy complicated with pulmonary hypertension hospitalized in Guangdong Provincial People's Hospital from January 1, 2014 to December 31, 2020 were retrospectively analyzed. The severity of pulmonary hypertension, the structural and functional indexes measured by echocardiography were compared, and the effects on maternal and neonatal outcomes were analyzed. RESULTS: A total of 158 patients met the inclusion and exclusion criteria. The results showed that tricuspid regurgitation velocity (P<0.001), right ventricular diameter (P<0.05), right atrial diameter (P<0.05), pulmonary artery diameter (P<0.001) and cardiac function classification (P<0.001) were risk factors for maternal outcomes; Tricuspid regurgitation velocity (P<0.001) and structural changes of right heart were risk factors for neonatal outcomes. By multivariate logistic regression analysis, tricuspid regurgitation velocity (P<0.001), cardiac function (P<0.05) and superior inferior diameter of right atrium (P<0.05) were significant risk factors for maternal outcomes, while tricuspid regurgitation velocity (P<0.001) and superior inferior diameter of right atrium (P<0.05) were significant risk factors for neonatal outcomes. Using significant risk factors, a risk score system was established to predict the pregnancy outcome. CONCLUSION: in this study, we analyzed the clinical data of patients with pregnancy complicated with pulmonary hypertension in our hospital in recent years, and found that the changes of right heart structure (the acceleration of tricuspid regurgitation velocity, and the increase of right atrium, right ventricular diameter, right ventricular outflow tract anteroposterior diameter and main pulmonary artery diameter), are influencing factors of pregnancy outcomes in patients with pulmonary hypertension. In addition, we preliminarily designed a risk score through multi factor analysis, which is helpful to predict the possible outcome of puerperium and neonatal outcomes of patients, and to provide some reference for clinicians and patients to make decisions on whether to continue pregnancy in clinical practice.
Simulation of COVID-19 Symptoms in a Genetically Engineered Mouse Model
Authors: Singh Mahavir , Pushpakumar Sathnur , Bard Nia , Zheng Yuting , Homme Rubens P. , Tyagi Suresh C.
Published: January 2022

The ongoing infectious viral disease pandemic (also known as the coronavirus disease-19; COVID-19) by a constantly emerging viral agent commonly referred as the severe acute respiratory syndrome corona virus 2 or SARS-CoV-2 has revealed unique pathological findings from infected human beings, and the postmortem observations. The list of disease symptoms, and post-mortem observations is too long to mention; however, a few notable ones are worth mentioning to put into a perspective in understanding the malignity of this pandemic starting with respiratory distress or dyspnea, chest congestion, muscle or body aches, malaise, fever, chills, etc. We opine that further improvement for delivering highly effective treatment, and preventive strategies would be benefited from validated animal disease models. In this context, we designed a study and show that a genetically engineered mouse expressing the human angiotensin converting enzyme 2; hACE2 (the receptor used by SARS-CoV-2 agent to enter host cells) represents an excellent investigative resource in simulating important clinical features of the COVID-19 infection. The hACE2 mouse model (which is susceptible to SARS-CoV-2) when administered with a recombinant SARS-CoV-2 spike (S) protein intranasally exhibited a profound cytokine storm capable of altering the physiological parameters including significant changes in in vivo cardiac function along with multi-organ damage that was further confirmed via histological findings. More importantly, visceral organs from SARS-CoV-2 spike (S) treated mice revealed thrombotic blood clots as seen during postmortem examination of the mice. Thus, the hACE2 engineered mouse appears to be a suitable model for studying intimate viral pathogenesis paving the way for further identification, and characterization of appropriate prophylactics as well as therapeutics for COVID-19 management.
Molecular characterization of acquired resistance to KRAS G12C inhibition in gastrointestinal cancers
Authors: Misale Sandra , Yaeger Rona , Mezzadra Riccardo , Sinopoli Jenna , Bian Yu , Marasco Michelangelo , Kaplun Esther , Gao Yijun , Zhao Huiyong , Paula Arnaud Da Cruz , Zhu Yingjie , Bowker Sydney , Chang Qing , Qeriqi Besnik , Weigelt Britta , Der-Torossian Hirak , Anderes Kenna , Socci Nicholas , Shia Jinru , Riely Greg , Murciano-Goroff Yonina , Li Bob , Christensen James , Reis-Filho Jorge , Solit David , de Stanchina Elisa , Lowe Scott , Rosen Neal
Published: January 2022

KRAS G12C inhibitors, such as sotorasib, have rapidly moved through clinical development and are poised to transform care of patients with KRAS G12C mutant cancers, in particular non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Clinical efficacy is achieved in NSCLC as a single agent and in CRC in combination with anti-EGFR monoclonal antibodies, however, secondary resistance impairs the effects of KRAS G12C blockade. In this work, we sought to determine the mechanisms of acquired resistance to concomitant KRAS-EGFR inhibition. In cell lines, patient-derived xenograft, and patient samples, a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signalling by drug can be detected at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency that does not increase substantially and sometimes disappears over time, with the exception of KRAS G12C amplification which rises in step with tumour marker levels and clinical progression. Here we show that a CRC cell line that acquired resistance to sotorasib-cetuximab combination through KRAS G12C amplification became addicted to these agents and undergoes oncogene-induced senescence upon drug withdrawal. Accordingly, the KRAS G12C signal in circulating DNA from relapsed patients harbouring G12C amplification rapidly recedes upon treatment holiday. These data indicate that KRAS G12C amplification is a recurrent resistance mechanism to KRAS-EGFR co-inhibition and suggest a potential therapeutic vulnerability, whereby therapies that target this senescence response at drug withdrawal may overcome resistance to KRAS G12C-EGFR inhibition.
Possible mechanisms related to internal dynamics for anomalously high rainfall during August 2020 of Indian Summer Monsoon
Authors: Ganai Malay , Sarkar Sahadat , Kanase Radhika , Krishna R. Phani Murali , Mukhopadhyay P
Published: January 2022

In the present study, an investigation is made to understand the physical mechanism behind the anomalous high rainfall during August 2020 over the Indian subcontinent using both observation and GFS T1534 weather forecast model. According to India Meteorological Department (IMD), the country receives 27% excess rainfall in the month of August 2020. The excess rainfall is mainly contributed by the 5 well marked low pressure systems which formed over Bay of Bengal and moved west-northwestwards across central India up to Western Madhya Pradesh and Rajasthan. The analysis reveals that the observed anomalous rainfall is distributed over central India region extending from coastal Orissa to central part of Chhattisgarh, Madhya Pradesh and western coast of Gujarat region. It is also found that the August-2020 heavy rainfall is mainly contributed by the synoptic (2-10 days) component of the total rainfall whereas the contribution of the large-scale intraseasonal oscillation (ISO) component (10-90 days) is quite less. Although the present operational Global Forecast System (GFS) T1534 (GFS T1534) is able to predict the anomalous high rainfall with day-1 lead time, it underestimates the magnitude of the synoptic variance. Further, the large-scale dynamical and thermodynamical parameters show anomalous behaviour in terms of strong low level (850 hPa) jet, vertical velocity and associated moisture convergence in the lower level. The GFS T1534 is able to forecast the above large-scale features reasonably well even with day-5 lead time. From energetics analysis, it is found that the mean kinetic energy (MKE) is stronger for August 2020 as compared to climatological value and the strong MKE efficiently transfers the energy to the synoptic scale, and hence the synoptic eddy kinetic energy is higher. Along with that, the ISO scale kinetic energy for August 2020 is less compared to the August climatological value. GFS T1534 model has some fidelity in capturing the energy conversion processes, but it has some difficulty in capturing the magnitude with increased lead time.
Comprehensive Analysis of Retrotransposon Insertions within the Survival Motor Neuron Genes Involved in Spinal Muscular Atrophy
Authors: Pinto Albano , Cunha Catarina , Chaves Raquel , Butchbach Matthew ER , Adega Filomena
Published: January 2022

Transposable elements (TEs) are interspersed repetitive DNA sequences with the ability to mobilize in the genome. The recent development of improved tools for evaluating TE-derived sequences in genomic studies has enabled an increasing attention to the contribution of TEs to human development and disease. Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease that is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene. SMN2 gene is a nearly perfect duplication of SMN1. Both genes (collectively known as SMN1/SMN2) are highly enriched in TEs. A comprehensive analysis of TEs insertions in the SMN1/2 loci of SMA carriers, patients and healthy/control individuals was completed to perceive TE dynamics in SMN1/2 and try to establish a link between these elements and SMA.We found an Alu insertion in the promoter region and one L1 element in the 3’UTR that likely play an important role as an alternative promoter and as an alternative terminator to the gene, respectively. Additionally, the several Alu repeats inserted in the genes’ introns influence splicing, giving rise to alternative splicing events that cause RNA circularization and the birth of new alternative exons. These Alu repeats present throughout the genes are also prone to recombination events that can lead to SMN1 exons deletions, that ultimately lead to SMA. The many good and bad implications associated with the presence of TEs inside SMN1/2 make this genomic region ideal for understanding the implications of TEs on genomic evolution as well as on human genomic disease.
STEEL enables high-resolution delineation of spatiotemporal transcriptomic data
Authors: Chen Yamao , Zhou Shengyu , Li Ming , Zhao Fangqing , Qi Ji
Published: January 2022

Advances in spatial transcriptomics enlarge the use of single cell technologies to unveil the expression landscape of the tissues with valuable spatial context. However, computational tools developed for single-cell transcriptomics have great limits in dealing with spatial transcriptomic data with high noise on detected transcript signals. Here we propose an unsupervised and manifold learning-based algorithm, STEEL, which identifies different cell types from spatial transcriptome by clustering cells/beads exhibiting both highly similar gene expression profiles and close spatial distance in the manner of graphs. Comprehensive evaluation of STEEL on various spatial transcriptomic datasets from 10X Visium platform demonstrates that it not only achieves a high resolution to characterize fine structures of mouse brain, but also enables the integration of multiple tissue slides individually analyzed into a larger one. STEEL outperforms previous methods to effectively distinguish different cell types of various tissues on Slide-seq datasets, featuring in higher bead density but lower transcript detection efficiency. Application of STEEL on spatial transcriptomes of early-stage mouse embryos (E9.5 to E12.5) successfully delineates a progressive development landscape of tissues from ectoderm, mesoderm and endoderm layers, and futher profiles dynamic changes on cell differentiation in heart and other organs. With the advancement of spatial transcriptome technologies, our method will have great applicability in high-resolution cell type identification and unbiased spatiotemporal data integration.
Triple negative apocrine breast carcinoma has better prognosis despite poor response to neoadjuvant chemotherapy
Authors: Hu Taobo , Liu Yiqiang , Hu Xuejiao Lina , Zhao Guiyang , Wang Shu , Long Mengping
Published: January 2022

Background: Apocrine carcinoma is a rare subtype of invasive ductal breast cancer that shows apocrine differentiation and largely with triple negative immunohistology. Triple negative breast cancers are known to have a more aggressive clinical course. However, unlike the most other types, it is reported that triple negative apocrine carcinoma has a better prognosis. Due to scarcity of reported studies, our knowledges for its clinical behavior, prognosis and response to therapy are very limited. Methods: In this study, we retrospectively retrieved 41 triple negative apocrine carcinoma cases from our breast cancer database with an average follow up 32.8 months.Results: It was found that triple negative apocrine carcinoma had poorer response to neoadjuvant therapy, but better prognosis compared with other non-apocrine types of triple negative breast cancer. Meanwhile, triple negative apocrine carcinoma has a low proliferative nature as indicated by its low Ki67 index. Analysis of SEER database showed that chemotherapy did not improve breast cancer specific survival in TNAC patients. Conclusions: Our results suggest that triple negative apocrine carcinoma is a special subtype of triple negative breast cancer for which de-escalation of chemotherapy should be considered.
A multi-part strategy for introgression of exotic germplasm into elite plant breeding programs using genomic selection
Authors: Breider Irene S. , Gaynor R. Chris , Gorjanc Gregor , Thorn Steve , Pandey Manish K. , Varshney Rajeev K. , Hickey John M.
Published: January 2022

Some of the most economically important traits in plant breeding show highly polygenic inheritance. Genetic variation is a key determinant of the rates of genetic improvement in selective breeding programs. Rapid progress in genetic improvement comes at the cost of a rapid loss of genetic variation. Germplasm available through expired Plant Variety Protection (exPVP) lines is a potential resource of variation previously lost in elite breeding programs. Introgression for polygenic traits is challenging, as many genes have a small effect on the trait of interest. Here we propose a way to overcome these challenges with a multi-part pre-breeding program that has feedback pathways to optimise recurrent genomic selection. The multi-part breeding program consists of three components, namely a bridging component, population improvement, and product development. Parameters influencing the multi-part program were optimised with the use of a grid search. Haploblock effect and origin were investigated. Results showed that the introgression of exPVP germplasm using an optimised multi-part breeding strategy resulted in 1.53 times higher genetic gain compared to a two-part breeding program. Higher gain was achieved through reducing the performance gap between exPVP and elite germplasm and breaking down linkage drag. Both first and subsequent introgression events showed to be successful. In conclusion, the multi-part breeding strategy has a potential to improve long-term genetic gain for polygenic traits and therefore, potential to contribute to global food security.
Determinants of Rural Women’s Nutrition Security Status in Northwest Ethiopia
Authors: Teshome Fentaw , Andaregie Adino , Astatkie Tessema
Published: January 2022

Background: Nutrition security of women is one of the most vital foundations for overall development and wellbeing of society. Since understanding the factors that influence the nutrition security of women is very important for implementing appropriate interventions, this study was conducted to determine the determinants of the nutrition security status of rural women in Northwest Ethiopia. Methods: Survey data were collected from 197 rural women randomly selected using a two-stage sampling method (Cluster sampling in the first stage and Stratified random sampling in the second stage). Data in the two outcomes (nutritionally secured whose BMI ≥ 18.5, and nutritionally insecure whose BMI < 18.5 kg/m2) were analyzed using Binary Logit regression model to determine the significance of the determinants on women’s nutrition security status. Results: The study showed that 72.6% of the women in the study area were nutritionally insecure. Results of the statistical analysis revealed that family size (negative effect), and women’s daily feed frequency, the consumption of milk, fruits and vegetables, and animal products, and women empowerment (all positive effect) were the significant determinants of the nutrition security status of rural women. The weight, the height, and the BMI of nutritionally insecure women (44 kg, 1.45 m, and 15.8 kg/m2, respectively) were significantly lower than those of nutritionally secured women (50.8 kg, 1.55 m, and 21.1 kg/m2, respectively). Conclusions: This is the first study on the determinants of rural women’s nutrition security status using social and demographic data collected at the grass root level and analyzed using an advanced econometric model. The findings of the study show the need for government and other stakeholders’ interventions to increase access to nutritious food products and to provide trainings on feeding culture and dietary diversity to women. The findings of this study can help the Government of Ethiopia to achieve its National Development Priorities in line with the Sustainable Development Goals (SDGs) of UN, particularly Goals 2, 3 and 5.
Global distribution of mcr gene variants in 214,095 metagenomic samples
Authors: Martiny Hannah-Marie , Munk Patrick , Brinch Christian , Szarvas Judit , Aarestrup Frank , Petersen Thomas
Published: January 2022

Since the initial discovery of a mobilized colistin resistance gene (mcr-1), several other variants have been reported, some of which might have circulated a while before being discovered. Metagenomic data provides an opportunity to re-analyze available older data to understand the evolutionary history of recently discovered antimicrobial resistance genes (ARGs). Here, we present a large-scale metagenomic study of 442 Tbp of sequencing reads from 214,095 samples to identify the host and geographical distribution and genomic context of nine mcr gene variants (mcr-1 to mcr-9). Our results show that the dissemination of each variant is not uniform. Instead, the source and location play a role in the spread. Despite the very diverse distribution, the genomic background of the mcr genes remains unchanged as the same mobile genetic elements and plasmid replicons occur. This work emphasizes the importance of sharing genomic data for surveillance of ARGs in our fight against antimicrobial resistance.
Ma's Bamboo-Based Medicinal Moxibustion Therapy of Low Back Pain in Lumbar Disc Herniation: Study Protocol for a Randomized Controlled Trial
Authors: Wang Xian-Zhu , Cui Jin , FU Jing , Xue Kai-Yang , Chen Ping-Nan , Xiao Cai-Hong
Published: January 2022

Background

Lumbar disc herniation (LDH) is a common and frequently-occurring disease in clinic. Low back pain and sciatica are the presenting symptoms of LDH. To some extent, it can be considered that measures with the capability to improve low back pain or sciatica have the potential to treat LDH. Ma's bamboo-based medicinal moxibustion therapy can effectively reduce the degree of low back pain and has been widely used. Studies of small sample size have seen significant improvement on pain relief.
Methods/design:

The trial is a multicenter, randomized, parallel-group, non-inferiority study. Three hundred and twelve patients will be randomly assigned to a Ma's bamboo-based medicinal moxibustion group (n=156) and an acupuncture group (n=156).Patients in each group will receive treatment every day,6 times a week, 12 times in total. Follow-up will be conducted 14 days after treatment. The primary outcome will be the visual analogue scale(VAS)at baseline, after 6 times of treatment,the end of treatment, and follow-up. the secondary outcomes will include Oswestry disability indexes (ODI) ,modified Japanese Orthopaedic Association low back pain (M-JOA) score,serum β-endorphin (β-EP) and serum substance P (SP). β-EP and SP as well as safety evaluation indexes (routine blood test, liver and kidney function, and ECG) will be measure at baseline and after the end of treatment.
Discussion

The results of the trial will compare the efficacy on low back pain in LDH between Ma's bamboo-based medicinal moxibustion group and acupuncture group and will be expected to make a systematic and objective evaluation on the clinical efficacy and safety of Ma's bamboo-based medicinal moxibustion therapy.
Trial registration:

ChiCTR, ChiCTR2000038725. Registered on 29 September 2020.
PENINGKATAN HASIL BELAJAR BAHASA INDONESIA MATERI DRAMA KEHIDUPAN MELALUI METODE BERMAIN PERAN (ROLE PLAYING)
Authors: * Widiasih
Published: January 2022

Indonesian language has a very important position, namely: As a National Language, and as a State Language. That is why in elementary schools, junior high schools, to universities, Indonesian is a subject that must be mastered. This study aims to determine the effectiveness of the role playing method on the learning outcomes of Indonesian in the remaining junior high schools in Kampak District. Researchers used classroom action research in class VIII through two stages of the cycle. The results show that there are differences in learning outcomes. Where the results are better when the teacher uses the role playing method in Indonesian language learning.
PRAKTIK PERCERAIAN ADAT LOMBOK DI MASA PANDEMI COVID-19 DITINJAU DARI SOSIOLOGI HUKUM
Authors: Ulfa Rahmatun
Published: January 2022

This study aims to examine the reality of the practice of customary divorce in Tawun hamlet, Lombok. As well as explaining the forms of customary divorce of the Tawun Hamlet community, in terms of sociological law. This research is a type of field research using a qualitative approach. Primary data and secondary data were collected by means of observation, direct interviews and documentation. To study further, the author uses the theory of the legal system from three elements, namely legal substance, legal structure, and legal culture. The results showed that the occurrence of customary divorce in Tawun Hamlet is a common thing and is not legally disputed by the court. Government officials from elements of village heads, hamlet heads and marriage registrar officers who contribute to customary divorce who participate in administering administrative services, clearly contradict the laws and regulations regarding marriage itself. In addition, people's understanding of divorce continues to be dominated by classical Islamic law and is textual, patriarchal, making the position of women not seen as important because divorce is understood only as a male right.