bluuebunny/crossref_metadata_2025_split huggingface dataset:
The SARS-CoV-2 host cell membrane fusion protein TMPRSS2 is a tumor suppressor and its downregulation promotes antitumor immunity and immunotherapy response in lung adenocarcinoma
Authors: Wang Xiaosheng , Liu Zhixian , Zhang Zhilan , Feng Qiushi 
Published: February 2022

Abstract
BackgroundTMPRSS2, a key molecule for SARS-CoV-2 invading human host cells, has an association with cancer. However, its association with lung cancer remains unexplored. ResultsIn five lung adenocarcinoma (LUAD) genomics datasets, we explored associations between TMPRSS2 expression and immune signatures, tumor progression phenotypes, and clinical prognosis in LUAD by the bioinformatics approach. We found that TMPRSS2 expression levels correlated negatively with the enrichment levels of both immune-stimulatory and immune-inhibitory signatures, while they correlated positively with the ratios of immune-stimulatory/immune-inhibitory signatures. It indicated that TMPRSS2 levels had a stronger negative correlation with immune-inhibitory than with immune-stimulatory signatures. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor progression, and worse survival in LUAD. We further validated that TMPRSS2 was downregulated with tumor progression in the LUAD dataset we collected. In vitro and in vivo experiments verified the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1. ConclusionsTMPRSS2 is a tumor suppressor, while its downregulation is a positive biomarker of immunotherapy in LUAD. Our data provide a link between lung cancer and pneumonia caused by SARS-CoV-2 infection.
Response of runoff and suspended load to climate change and reservoir construction in the Lancang River
Authors: Sun Lixia , Sun Zhilin , Li Zongyu , Zheng Haolei , Li Cheng , Xiong Wenhua 
Published: February 2022

Abstract
With the operation of six cascade reservoirs, the flow regime and sediment discharge of the Lancang River have changed greatly. The changes of runoff and suspended load have attracted extensive attention. The hydrological data of Gajiu and Yunjinghong stations in Lancang River from 1964 to 2019 were analyzed by using wavelet analysis, double mass curve and abrupt change analysis. The temporal trends in runoff and suspended load were evaluated. Results revealed that the reduction of suspended load was much more profound than the change of runoff. There was a slight downward trend in annual runoff due to climate change. After the completion of Xiaowan and Nuozhadu reservoirs, the proportion of runoff in flood season decreased by 22.64 and 30.75%, respectively. Wavelet analysis was used to reveal the characteristics of runoff evolution. With the operation of reservoirs, suspended load showed abrupt changes in 1993 and 2008. The amount of suspended load during 2009–2019 decreased by 95.47–98.78% compared with that before the reservoir construction. This paper presents the latest quantitative study on the temporal variation of runoff and suspended load since the completion of Xiaowan and Nuozhadu reservoirs, which is of great importance for guiding the operation of reservoirs and maximizing the value of the whole Lancang-Mekong River basin.
New Trends in 1,4-Dipolar Cycloaddition Reactions. Thermodynamic Control Synthesis
of Model 2'-(isoquinolin-1-yl)-spiro[oxindole-3,3'-pyrrolines]
Authors: Jaber Areej M. , Zahra Jalal A. , Sabri Salim S. , Khanfar Monther A. , Awwadi Firas F. , El-Abadelah Mustafa M. 
Published: February 2022

Background:
A direct synthesis of functionalized spiro[oxindole-3,3'-pyrrolines] is
achieved via thermodynamic control (~60 oC), three-component 1,4-dipolar cycloaddition
reaction involving 3-phenylimidazo[5,1-a]isoquinoline, dimethyl acetylenedicarboxylate, and
N-alkylisatins.

Methods:
Conversely, this one-pot reaction furnished, upon conduction at 25–38 oC, the expected
1,3-oxazepino[7,6-b]indoles as the main kinetic control products. The calculated energy
of the optimized molecular structures of model spiro-oxindole and its isomeric oxazepinoindole
indicate that spiro-oxindole is more stable by 76.1 kJ/mol.

Results:
The structures of the synthesized spiro adducts were evidenced from NMR and MS
spectral data and further confirmed by single-crystal X-ray diffraction. Characteristic features
of the spiro-oxindoles are displaced in their 13C-spectra as diagnostic signals at ~53 and ~70 ppm assigned, respectively,
to the spiro carbon-3 and sp3 CH-2' of the pyrroline ring.

Conclusion:
This unprecedented thermally induced pathway in 1,4-dipolar cycloaddition, utilizing imidazo[5,1-
a]isoquinoline and related congeners, would serve as a new route towards the synthesis of spiro[oxindole-3,3'-
pyrrolines], a class of diverse biological activities. An insight into the thermodynamic control pathway is presented.
Pan-Cancer Analysis of Histone Methyltransferase KMT2D with Potential
Implications for Prognosis and Immunotherapy in Human Cancer
Authors: Luo Guangcheng , Chen Guoning , Chen Peijie , Zhou Jianwen 
Published: February 2022

Background:
Pan-cancer analysis is an efficient tool to obtain a panoramic view of cancer-
related genes and identify their oncogenic processes, facilitating the development of new therapeutic
targets. Lysine methyltransferase 2D (KMT2D), acting as a major enhancer coactivator for
mammalian cells, is one of the most frequently mutated genes across various cancer types and is
considered an oncogene and a rationale for epigenetic therapeutic targets.

Objective:
This study was designed to explore the potential role of KMT2D in human cancer
through a pan-cancer analysis.

Methods:
The expression of KMT2D was assessed in normal tissues and cell lines, and pancancers
from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and
Genotype-Tissue Expression (GTE) datasets were used to explore its correlation with prognosis,
immune cell infiltration, tumor mutation burden, microsatellite instability, and mismatch repair.

Results:
KMT2D expression was heterogeneous across different cancer types. Increased KMT2D
indicated a worse prognosis in adrenocortical carcinoma (ACC), brain lower-grade glioma (LGG),
and mesothelioma (MESO), while patients with high KMT2D expression showed better outcomes
in renal clear cell carcinoma (KIRC). Moreover, KMT2D expression was positively correlated with
immune cell infiltration and negative tumor mutation burden in multiple cancers. In addition, a
significant correlation between KMT2D and immune checkpoint-related genes or mismatch repair
genes was identified.

Conclusions:
These findings support the hypothesis that KMT2D is not only a potential biomarker
for prognosis and immunotherapy response prediction but also an essential immune regulator in
human cancer.
Network Pharmacology Research Indicates that Wu-Mei-Wan Treats Obesity by Inhibiting Th17 Cell Differentiation and Alleviating Metabolic Inflammation
Authors: Huang Panpan , Chen Guang , Cheng Zhe , Xiong Xinyu , Wu Fan , Zhao Yan , Dong Ruolan , Jiang Shujun , Fang Ke 
Published: February 2022

Background:Wu-Mei-Wan (WMW), a traditional Chinese medicine (TCM) formula, has a good effect on the treatment of obesity and has been proven helpful to promote the metabolism of adipose tissue. However, its underlying mechanism remains to be studied. This study aims to explore the potential pharmacological mechanism of WMW in the treatment of obesity.Methods:Network pharmacology was used to sort out the relationship between WMW putative targets and obesity-related drug targets or disease targets, which indicated the mechanism of WMW in treating obesity from two aspects of clinical drugs approved by the Food and Drug Administration (FDA) and obesity-related diseases. Databases such as Traditional Chinese Medicine Systems Pharmacology (TCMSP), PubChem, DrugBank, DisGeNET, and Genecards were used to collect information about targets. String platform was used to convert the data into gene symbol of “homo sapiens”, and perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. With the Human Protein Reference Database (HPRD) as background data, Cytoscape 3.6.0 software was used to construct a new protein-protein interaction (PPI) network. Mechanism diagrams of key pathways were obtained from the KEGG database. AutoDock Vina software was used to conduct molecular docking verification.Results:The number of targets in the overlap between WMW putative targets and obesity-related drug targets accounted for more than 50% of the latter, and HTR3A, SLC6A4, and CYP3A4 were core targets. In obesity-related disease targets-WMW putative targets PPI network, the Th17 cell differentiation pathway, and the IL-17 signaling pathway were key pathways, and the 1st module and the 7th module were central function modules that were highly associated with immunity and inflammation. Molecular docking verified that STAT3, TGFB1, MMP9, AHR, IL1B, and CCL2 were core targets in the treatment of WMW on obesity.Conclusion:WMW has similar effects on lipid and drug metabolism as the current obesity-related drugs, and is likely to treat obesity by inhibiting Th17 cell differentiation and alleviating metabolic inflammation.
Novel PARP Inhibitor DDPF-20 Induces DNA Damage and Inhibits Angiogenesis
through the PI3K/Akt/VEGF Pathway
Authors: Wang Tian , Zhang Dong , Guo Chuanlong , Zhu Wenyong 
Published: February 2022

Background:
Poly (ADP-ribose) polymerase (PARP) plays a key role in DNA damage repair. A novel
compound (E)-N'-(2,3-dibromo-4,5-dihydroxyphenyl)-N-(phenylcarbamothioyl)formimidamide (DDPF-20) with excellent
PARP inhibitory activity was synthesized.

Objective:
In this study, we aimed to clarify the mechanism of the novel PARP inhibitor DDPF-20 against lung cancer
by inducing DNA damage and inhibiting angiogenesis.

Method:
The cytotoxic effect of DDPF-20 on the A549 cell line was determined with an MTT assay. Cell cycle and
apoptosis were determined by a flow cytometer. Moreover, the γH2AX foci were detected by immunofluorescence.
Capillary-like tube formation assay and chick chorioallantoic membrane (CAM) assay were used to detect the angiogenesis
inhibitory effect of DDPF-20. The expressions of related proteins were detected by western blot. The anticancer
activity of DDPF-20 in vivo was also detected.

Results:
With an IC50 value of 52.42 ± 15.13 nM, DDPF-20 inhibited the proliferation, induced G2/M cycle arrest, and
induced apoptosis of human lung cancer A549 cells. Further research showed that DDPF-20 induced DNA doublestrand
breaks (DSBs). Interestingly, DDPF-20 inhibited the tube formation of HUVEC cells, as well as inhibited the
neovascularization of CAM, proving the angiogenesis inhibitory ability of DDPF-20. Mechanism studies proved that
DDPF-20 inhibited the PI3K/Akt/VEGF signaling pathway. In an in vivo study, DDPF-20 inhibited tumor growth of an
A549 xenograft. Analysis of the molecular mechanism underlying this effect revealed that the PI3K/Akt/VEGF pathway
was involved in DDPF-20-induced cell death and inhibited angiogenesis in vivo.

Conclusion:
This study suggested that the novel PARP inhibitor DDPF-20 may have therapeutic potential in treating
lung cancer.
Nanostructured Lipid Carriers: A Promising Carrier in Targeted Drug
Delivery System
Authors: Tiwari Abhishek , Palaria Binita , Tiwari Varsha , Aslam Ramsha , Kumar Ashok , Sahoo Biswa Mohan , Kumar Manish , Singh Sunil , Kumar Suresh 
Published: February 2022

Abstract:
Nanostructured lipid carriers (NLCs) are considered second-generation
lipid-based pharmaceutical formulations in drug delivery systems. It is a more
efficient drug delivery system that includes the development of a nano-particulate
system, and it is superior to the conventional drug delivery system. Among all
available nanoparticles, NLC has gained more attention due to its superior
characteristics, such as being lipophilic, biodegradable, and biocompatible. This
lipid nanoparticulate system is more advantageous over liposomes, microparticles,
emulsions, and solid lipid nanoparticles. NLCs have emerged as a promising carrier
for the delivery of targeted drug substances via oral, parenteral, topical, pulmonary,
transdermal, and ocular routes. These nanocarriers are utilized for the delivery of
both lipophilic as well as hydrophilic drugs. NLCs are composed of a matrix of
physiological lipids, i.e., solid lipid and liquid lipid, emulsifiers, and water. NLCs
provide an opportunity for large-scale production, ease of preparation with
enhanced encapsulation, targeted efficiency, and reduced toxic effects. This review
is focused on the advantages, limitations, methods of preparation, characterization,
and applications of NLCs.
Motivation, self-regulated learning, and their effects on learning outcomes of derivative materials during the Covid-19 pandemic
Authors: Fitria Analisa , Najihah Baiti , Paris M. Amin , Atsnan Muh. Fajaruddin , Nareki Maisea Ledua 
Published: February 2022

The study aims to identify the effect of learning motivation and self-regulated learning on learning achievement in “Derivative” learning materials in Trigonometry Functions. The study was field research using the ex-post facto design and quantitative approach during the Covid-19 Pandemic. The population was all grade XII students of a state Islamic senior high school in South Kalimantan, Indonesia. The samples of 24 students were selected using the purposive sampling technique. The data were gathered using a questionnaire and test and through documentation and interview. The data were analysed using the descriptive statistics and the inferential statistics consisting of normality test, linearity test, multicollinearity test, heteroscedasticity test, and multiple linear regression. The result shows that there is an effect of motivation and learning independence during the Covid-19 pandemic, which contributed 90.9% in increasing mathematics learning outcomes, and the rest was affected by other variables. This result is based on the results of F-test (Fcount = 104.948 Ftable =3.47) at the significance level of 5% with a multiple linear regression model Ῠ= 13.557+0.435 X1+0.395 X2 + ɛ.
Algorithm-Enabled, Personalized Glucose Management for Type 1 Diabetes at the Population Scale: Prospective Evaluation in Clinical Practice
Authors: Scheinker David , Gu Angela , Grossman Joshua , Ward Andrew , Ayerdi Oseas , Miller Daniel , Leverenz Jeannine , Hood Korey , Lee Ming Yeh , Maahs David M , Prahalad Priya 
Published: February 2022

Background
The use of continuous glucose monitors (CGMs) is recommended as the standard of care by the American Diabetes Association for individuals with type 1 diabetes (T1D). Few hardware-agnostic, open-source, whole-population tools are available to facilitate the use of CGM data by clinicians such as physicians and certified diabetes educators.

Objective
This study aimed to develop a tool that identifies patients appropriate for contact using an asynchronous message through electronic medical records while minimizing the number of patients reviewed by a certified diabetes educator or physician using the tool.

Methods
We used consensus guidelines to develop timely interventions for diabetes excellence (TIDE), an open-source hardware-agnostic tool to analyze CGM data to identify patients with deteriorating glucose control by generating generic flags (eg, mean glucose [MG] >170 mg/dL) and personalized flags (eg, MG increased by >10 mg/dL). In a prospective 7-week study in a pediatric T1D clinic, we measured the sensitivity of TIDE in identifying patients appropriate for contact and the number of patients reviewed. We simulated measures of the workload generated by TIDE, including the average number of time in range (TIR) flags per patient per review period, on a convenience sample of eight external data sets, 6 from clinical trials and 2 donated by research foundations.

Results
Over the 7 weeks of evaluation, the clinical population increased from 56 to 64 patients. The mean sensitivity was 99% (242/245; SD 2.5%), and the mean reduction in the number of patients reviewed was 42.6% (182/427; SD 10.9%). The 8 external data sets contained 1365 patients with 30,017 weeks of data collected by 7 types of CGMs. The rates of generic and personalized TIR flags per patient per review period were, respectively, 0.15 and 0.12 in the data set with the lowest average MG (141 mg/dL) and 0.95 and 0.22 in the data set with the highest average MG (207 mg/dL).

Conclusions
TIDE is an open-source hardware-agnostic tool for personalized analysis of CGM data at the clinical population scale. In a pediatric T1D clinic, TIDE identified 99% of patients appropriate for contact using an asynchronous message through electronic medical records while reducing the number of patients reviewed by certified diabetes care and education specialists by 43%. For each of the 8 external data sets, simulation of the use of TIDE produced fewer than 0.25 personalized TIR flags per patient per review period. The use of TIDE to support telemedicine-based T1D care may facilitate sensitive and efficient guideline-based population health management.
The Impact of COVID-19 Lockdown on Daily Activities, Cognitions, and Stress in a Lonely and Distressed Population: Temporal Dynamic Network Analysis
Authors: Haucke Matthias , Heinz Andreas , Liu Shuyan , Heinzel Stephan 
Published: February 2022

Background
The COVID-19 pandemic and its associated lockdown measures impacted mental health worldwide. However, the temporal dynamics of causal factors that modulate mental health during lockdown are not well understood.

Objective
We aimed to understand how a COVID-19 lockdown changes the temporal dynamics of loneliness and other factors affecting mental health. This is the first study that compares network characteristics between lockdown stages to prioritize mental health intervention targets.

Methods
We combined ecological momentary assessments with wrist-worn motion tracking to investigate the mechanism and changes in network centrality of symptoms and behaviors before and during lockdown. A total of 258 participants who reported at least mild loneliness and distress were assessed 8 times a day for 7 consecutive days over a 213-day period from August 8, 2020, through March 9, 2021, in Germany, covering a “no-lockdown” and a “lockdown” stage. COVID-19–related worry, information-seeking, perceived restriction, and loneliness were assessed by digital visual analog scales ranging from 0 to 100. Social activity was assessed on a 7-point Likert scale, while physical activity was recorded from wrist-worn actigraphy devices.

Results
We built a multilevel vector autoregressive model to estimate dynamic networks. To compare network characteristics between a no-lockdown stage and a lockdown stage, we performed permutation tests. During lockdown, loneliness had the highest impact within the network, as indicated by its centrality index (ie, an index to identify variables that have a strong influence on the other variables). Moreover, during lockdown, the centrality of loneliness significantly increased. Physical activity contributed to a decrease in loneliness amid the lockdown stage.

Conclusions
The COVID-19 lockdown increased the central role of loneliness in triggering stress-related behaviors and cognition. Our study indicates that loneliness should be prioritized in mental health interventions during lockdown. Moreover, physical activity can serve as a buffer for loneliness amid social restrictions.
A Web-Based Well-being Program for Health Care Workers (Thrive): Protocol for a Randomized Controlled Trial
Authors: Egan Luke A , Mulcahy Mary , Tuqiri Karen , Gatt Justine M 
Published: February 2022

Background
Mental health has come to be understood as not merely the absence of mental illness but also the presence of mental well-being, and recent interventions have sought to increase well-being in various populations. A population that deserves particular attention is that of health care workers, whose occupations entail high levels of stress, especially given the ongoing COVID-19 pandemic. A neuroscience-based web-based well-being program for health care workers—the Thrive program—has been newly developed to promote habits and activities that contribute to brain health and overall mental well-being.

Objective
This paper describes the protocol for a randomized controlled trial whose objective is to evaluate the Thrive program in comparison with an active control condition to measure whether the program is effective at increasing well-being and decreasing symptoms of psychological distress in health care workers at a designated Australian hospital.

Methods
The trial will comprise two groups (intervention vs active control) and 4 measurement occasions over a 12-week period. A survey will be administered in each of weeks 0, 4, 8, and 12, and the well-being program will be delivered in weeks 1-7 (via web-based video presentations or digital pamphlets). Each of the 4 surveys will comprise a range of questionnaires to measure well-being, psychological distress, and other key variables. The planned analyses will estimate group-by-time interaction effects to test the hypothesis that mental health will increase over time in the intervention condition relative to the active control condition.

Results
The Thrive program was delivered to a small number of wards at the hospital between February 2021 and July 2021, and it will be delivered to the remaining wards from October 2021 to December 2021. A power calculation has recommended a sample size of at least 200 participants in total. A linear mixed model will be used to estimate the interaction effects.

Conclusions
This trial seeks to evaluate a new web-based well-being program for health care workers at a major public hospital. It will contribute to the growing body of research on mental well-being and ways to promote it.

Trial Registration
Australian New Zealand Clinical Trials Registry ACTRN12621000027819; https://tinyurl.com/58wwjut9

International Registered Report Identifier (IRRID)
DERR1-10.2196/34005