bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct Circadian Assessments From Wearable Data Reveal Social Distancing Promoted Internal Desynchrony Between Circadian Markers
Authors: Huang Yitong , Mayer Caleb , Walch Olivia J. , Bowman Clark , Sen Srijan , Goldstein Cathy , Tyler Jonathan , Forger Daniel B.
Published: November 2021

Mobile measures of human circadian rhythms (CR) are needed in the age of chronotherapy. Two wearable measures of CR have recently been validated: one that uses heart rate to extract circadian rhythms that originate in the sinoatrial node of the heart, and another that uses activity to predict the laboratory gold standard and central circadian pacemaker marker, dim light melatonin onset (DLMO). We first find that the heart rate markers of normal real-world individuals align with laboratory DLMO measurements when we account for heart rate phase error. Next, we expand upon previous work that has examined sleep patterns or chronotypes during the COVID-19 lockdown by studying the effects of social distancing on circadian rhythms. In particular, using data collected from the Social Rhythms app, a mobile application where individuals upload their wearable data and receive reports on their circadian rhythms, we compared the two circadian phase estimates before and after social distancing. Interestingly, we found that the lockdown had different effects on the two ambulatory measurements. Before the lockdown, the two measures aligned, as predicted by laboratory data. After the lockdown, when circadian timekeeping signals were blunted, these measures diverged in 70% of subjects (with circadian rhythms in heart rate, or CRHR, becoming delayed). Thus, while either approach can measure circadian rhythms, both are needed to understand internal desynchrony. We also argue that interventions may be needed in future lockdowns to better align separate circadian rhythms in the body.
Experimental Validation of N2 Emission Ratios in Altitude Profiles of Observed Sprites
Authors: Kuo Cheng-Ling , Williams Earle , Adachi Toru , Ihaddadene Kevin , Celestin Sebastien , Takahashi Yukihiro , Hsu Rue-Ron , Frey Harald U. , Mende Stephen B. , Lee Lou-Chuang
Published: November 2021

Recent efforts to compare the sprite ratios with theoretical results have not been successfully resolved due to a lack of theoretical results for sprite streamers in varying altitudes. Advances in the predicted emission ratios of sprite streamers with a simple analytic equation have opened up the possibility for direct comparisons of theoretical results with sprite observations. The study analyzed the blue-to-red ratios measured by the ISUAL array photometer with the analytical expression for the sprite emission ratio derived from the modeling of downward sprite streamers. Our statistical studies compared sprite halos and carrot sprites where the sprite halos showed fair agreement with the predicted ratios from the sprite streamer simulation. But carrot sprites had lower emission ratios. Their estimated electric field has a lower bound of greater than 0.4 times the conventional breakdown electric field (Ek). It was consistent with the results of remote electromagnetic field measurements for short delayed or big/bright sprites. An unexpectedly lower ratio in carrot sprites occurred since sprite beads or glow in carrot sprites may exist and contribute additional red emission.
Occurrences of Deep-Seated Creeping Landslides in Accordance with Hydrological Water Storage in Catchments
Authors: Kuo Chih-Yu , Lin Shen-En , Chen Rou-Fei , Hsu Ya-Ju , Chang Kuo-Jen , Lee Shin-Ping , Wu Rou-Ying , Lin Ching-Weei , Chan Ya-Hsin
Published: November 2021

Rainfall is one of the most important triggers of both shallow debris flows and deep-seated landslides. The triggering mechanism involves the process of water infiltration into the failure zone. For deep-seated landslides, the deeper and more extensive failure surfaces delay the effect of the process and thus delay landslide initiations. The delay is difficult to assess, especially if the sites only have scarce or insufficient monitoring data. Under these circumstances, we illustrate that the occurrences of landslides can be estimated by their correlations with the phenomenological water storage index (WSI) of a given catchment. In the present study, a total of five deep-seated landslides in TienChih (4) and SiangYang (1) are investigated. The displacements of the landslides were recorded by global positioning system (GPS) and the WSI was modelled using the tank model. The result demonstrates that the WSI correlates closer in time to the landslide motion than the rainfall, and the WSI thresholds for the landslides are inferred. Thus, this technique can be applied as an associated method to evaluate landslide initiation.
Changes in Dry-Season Water Availability and Attributions in the Yellow River Basin, China
Authors: Zhao Fubo , Ma Shuai , Wu Yiping
Published: November 2021

Global warming will significantly change patterns of precipitation (P) and evapotranspiration (E) and thus the surface water availability (P minus E, P–E). Changes in P–E will challenge freshwater supply, food security, and sustainability of the ecosystems. Therefore, understanding the spatiotemporal change in P–E and its drivers is key for water resources management. Here, we quantified the changes in water availability during the driest month of the year and identified its drivers in the Yellow River Basin (YRB), China, during 1982–2016. Our results showed that 89.6% of the YRB showed declining dry-season water availability in 2000–2016 compared with 1982–1999, although the total dry-season water resources (defined as the proportion of the sum of monthly P–E to the P) remained nearly unchanged due to the increased P. Changes in seasonal P and E contributed to 87.0 and 99.0% declines in dry-season water availability, respectively, demonstrating the key role of E in net seasonal water fluxes. Increased air temperature (41.8%), vegetation greening (30.8%), and vapor pressure deficit (19.2%) were the main factors driving changes in E in the YRB during the study period. Our study highlighted a drier dry season in the YRB during 1982–2016 and illustrated that climate and vegetation changes played important roles in driving changes in dry-season water availability. Seasonal water fluxes must be considered in future water resources management in the YRB, especially in the context of climate warming and revegetation programs.
Identification of Six Prognostic Genes in EGFR–Mutant Lung Adenocarcinoma Using Structure Network Algorithms
Authors: Zhang Haomin , Lu Di , Li Qinglun , Lu Fengfeng , Zhang Jundong , Wang Zining , Lu Xuechun , Wang Jinliang
Published: November 2021

This study aims to determine hub genes related to the incidence and prognosis of EGFR-mutant (MT) lung adenocarcinoma (LUAD) with weighted gene coexpression network analysis (WGCNA). From The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we used 253 EGFR-MT LUAD samples and 38 normal lung tissue samples. At the same time, GSE19188 was additionally included to verify the accuracy of the predicted gene. To discover differentially expressed genes (DEGs), the R package “limma” was used. The R packages “WGCNA” and “survival” were used to perform WGCNA and survival analyses, respectively. The functional analysis was carried out with the R package “clusterProfiler.” In total, 1450 EGFR-MT–specific DEGs were found, and 7 tumor-related modules were marked with WGCNA. We found 6 hub genes in DEGs that overlapped with the tumor-related modules, and the overexpression level of B3GNT3 was significantly associated with the worse OS (overall survival) of the EGFR-MT LUAD patients (p < 0.05). Functional analysis of the hub genes showed the metabolism and protein synthesis–related terms added value. In conclusion, we used WGCNA to identify hub genes in the development of EGFR-MT LUAD. The established prognostic factors could be used as clinical biomarkers. To confirm the mechanism of those genes in EGFR-MT LUAD, further molecular research is required.
The New Old CD8+ T Cells in the Immune Paradox of Pregnancy
Authors: Hardardottir Lilja , Bazzano Maria Victoria , Glau Laura , Gattinoni Luca , Köninger Angela , Tolosa Eva , Solano Maria Emilia
Published: November 2021

CD8+ T cells are the most frequent T cell population in the immune cell compartment at the feto-maternal interface. Due to their cytotoxic potential, the presence of CD8+ T cells in the immune privileged pregnant uterus has raised considerable interest. Here, we review our current understanding of CD8+ T cell biology in the uterus of pregnant women and discuss this knowledge in relation to a recently published immune cell Atlas of human decidua. We describe how the expansion of CD8+ T cells with an effector memory phenotype often presenting markers of exhaustion is critical for a successful pregnancy, and host defense towards pathogens. Moreover, we review new evidence on the presence of long-lasting immunological memory to former pregnancies and discuss its impact on prospective pregnancy outcomes. The formation of fetal-specific memory CD8+ T cell subests in the uterus, in particular of tissue resident, and stem cell memory cells requires further investigation, but promises interesting results to come. Advancing the knowledge of CD8+ T cell biology in the pregnant uterus will be pivotal for understanding not only tissue-specific immune tolerance but also the etiology of complications during pregnancy, thus enabling preventive or therapeutic interventions in the future.
IL-22 Binding Protein (IL-22BP) in the Regulation of IL-22 Biology
Authors: Zenewicz Lauren A.
Published: November 2021

Cytokines are powerful mediators of inflammation. Consequently, their potency is regulated in many ways to protect the host. Several cytokines, including IL-22, have coordinating binding proteins or soluble receptors that bind to the cytokine, block the interaction with the cellular receptor, and thus prevent cellular signaling. IL-22 is a critical cytokine in the modulation of tissue responses during inflammation and is highly upregulated in many chronic inflammatory disease patients, including those with psoriasis, rheumatoid arthritis, and inflammatory bowel disease (IBD). In healthy individuals, low levels of IL-22 are secreted by immune cells, mainly in the gastrointestinal (GI) tract. However, much of this IL-22 is likely not biologically active due to the high levels of IL-22 binding protein (IL-22BP) produced by intestinal dendritic cells (DCs). IL-22BP is a soluble receptor homolog that binds to IL-22 with greater affinity than the membrane spanning receptor. Much is known regarding the regulation and function of IL-22 in health and disease. However, less is known about IL-22BP. In this review, we will focus on IL-22BP, including its regulation, role in IL-22 biology and inflammation, and promise as a therapeutic. IL-22 can be protective or pathogenic, depending on the context of inflammation. IL-22BP also has divergent roles. Ongoing and forthcoming studies will expand our knowledge of IL-22BP and IL-22 biology, and suggest that IL-22BP holds promise as a way to regulate IL-22 biology in patients with chronic inflammatory disease.
Impaired Functional T-Cell Response to SARS-CoV-2 After Two Doses of BNT162b2 mRNA Vaccine in Older People
Authors: Demaret Julie , Corroyer-Simovic Bénédicte , Alidjinou Enagnon Kazali , Goffard Anne , Trauet Jacques , Miczek Sophie , Vuotto Fanny , Dendooven Arnaud , Huvent-Grelle Dominique , Podvin Juliette , Dreuil Daniel , Faure Karine , Deplanque Dominique , Bocket Laurence , Duhamel Alain , Labreuche Julien , Sobaszek Annie , Hisbergues Michael , Puisieux Francois , Labalette Myriam , Lefèvre Guillaume
Published: November 2021

Long-term care facility (LTCF) older residents display physiological alterations of cellular and humoral immunity that affect vaccine responses. Preliminary reports suggested a low early postvaccination antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study was to focus on the specific T-cell response. We quantified S1-specific IgG, neutralizing antibody titers, total specific IFNγ-secreting T cells by ELISpot, and functionality of CD4+- and CD8+-specific T cells by flow cytometry, after two doses of the BNT162b2 vaccine in younger and older people, with and without previous COVID-19 infection (hereafter referred to as COVID-19-recovered and COVID-19-naive subjects, respectively). Frailty, nutritional, and immunosenescence parameters were collected at baseline in COVID-19-naive older people. We analyzed the immune response in 129 young adults (median age 44.0 years) and 105 older residents living in a LCTF (median age 86.5 years), 3 months after the first injection. Humoral and cellular memory responses were dramatically impaired in the COVID-19-naive older (n = 54) compared with the COVID-19-naive younger adults (n = 121). Notably, older participants’ neutralizing antibodies were 10 times lower than the younger’s antibody titers (p < 0.0001) and LCTF residents also had an impaired functional T-cell response: the frequencies of IFNγ+ and IFNγ+IL-2+TNFα+ cells among specific CD4+ T cells, and the frequency of specific CD8+ T cells were lower in COVID-19-naive older participants than in COVID-19-naive young adults (p < 0.0001 and p = 0.0018, respectively). However, COVID-19-recovered older participants (n = 51) had greater antibody and T-cell responses, including IFNγ+ and IFNγ+IL-2+TNFα+-specific CD4+ T cells (p < 0.0001), as well as TNFα+-specific CD8+ T cells (p < 0.001), than COVID-19-naive older adults. We also observed that “inflammageing” and particularly high plasma levels of TNFα was associated to poor antibody response in the older participants. In conclusion, our results show that the COVID-19-naive older people had low counts and impaired specific CD4+ and CD8+ T cells, in addition to impaired antibody response, and that specific studies are warranted to assess the efficiency of SARS-CoV-2 mRNA-based vaccines, as in other immunocompromised subjects. Our study also shows that, despite their physiological alterations of immunity, vaccination is highly efficient in boosting the prior natural memory response in COVID-19-recovered older people.
Development and Application of the Placebo Response Model in Clinical Trials for Primary Sjögren’s Syndrome
Authors: Wang ZHI-Zhou , Zheng Qing-Shan , Liu Hong-Xia , Li Lu-Jin
Published: November 2021

This study aimed to develop a placebo response model for pharmaceutical clinical trials of primary Sjogren’s syndrome,and to quantitatively analyze the distribution and related factors influencing the placebo response to further optimize the design of clinical trials and evaluate the results of single-arm clinical trials. Public databases, including PubMed, Embase, and Cochrane Library were searched for reports on randomized placebo-controlled trials for Sjögren’s syndrome which used the change from baseline in ESSDAI score as the primary outcome. The model-based meta-analysis method was used to evaluate the time course and the related influencing factors of the placebo response for ESSDAI in such clinical trials. A virtual placebo control group was constructed based on the final placebo response model to determine the treatment efficacy of belimumab and cyclosporine A for primary Sjögren’s syndrome in a single-arm study. A total of 12 studies involving 450 subjects were included in the analysis. The established model described the time-course characteristics of the changes in ESSDAI score from the baseline in the 48 weeks placebo group. We found that the onset time of placebo response was approximately 12 weeks, and its efficacy plateaued at 48 weeks. The baseline ESSDAI score had a significant effect on the maximum value of the placebo response; the maximum value of the placebo response decreased by 0.552 for every 1 score rise in the baseline ESSDAI score. The efficacy of belimumab and cyclosporine A in the single-arm trial was comparable to that of the placebo response at the same baseline; no significant therapeutic advantage was observed. The placebo response model established in this study could provide a basis for designing clinical trials for primary Sjogren’s syndrome in the future. It may also provide a reliable external efficacy control standard for single-arm clinical trials.
Are Temperature Suitability and Socioeconomic Factors Reliable Predictors of Dengue Transmission in Brazil?
Authors: Simon Lorena M. , Rangel Thiago F.
Published: November 2021

Dengue is an ongoing problem, especially in tropical countries. Like many other vector-borne diseases, the spread of dengue is driven by a myriad of climate and socioeconomic factors. Within developing countries, heterogeneities on socioeconomic factors are expected to create variable conditions for dengue transmission. However, the relative role of socioeconomic characteristics and their association with climate in determining dengue prevalence are poorly understood. Here we assembled essential socioeconomic factors over 5570 municipalities across Brazil and assessed their effect on dengue prevalence jointly with a previously predicted temperature suitability for transmission. Using a simultaneous autoregressive approach (SAR), we showed that the variability in the prevalence of dengue cases across Brazil is primarily explained by the combined effect of climate and socioeconomic factors. At some dengue seasons, the effect of temperature on transmission potential showed to be a more significant proxy of dengue cases. Still, socioeconomic factors explained the later increase in dengue prevalence over Brazil. In a heterogeneous country such as Brazil, recognizing the transmission drivers by vectors is a fundamental issue in effectively predicting and combating tropical diseases like dengue. Ultimately, it indicates that not considering socioeconomic factors in disease transmission predictions might compromise efficient surveillance strategies. Our study shows that sanitation, urbanization, and GDP are regional indicators that should be considered along with temperature suitability on dengue transmission, setting effective directions to mosquito-borne disease control.
Identifying Black Corals and Octocorals From Deep-Sea Imagery for Ecological Assessments: Trade-Offs Between Morphology and Taxonomy
Authors: Untiedt Candice B. , Williams Alan , Althaus Franziska , Alderslade Phil , Clark Malcolm R.
Published: November 2021

An increased reliance on imagery as the source of biodiversity data from the deep sea has stimulated many recent advances in image annotation and data management. The form of image-derived data is determined by the way faunal units are classified and should align with the needs of the ecological study to which it is applied. Some applications may require only low-resolution biodiversity data, which is easier and cheaper to generate, whereas others will require well-resolved biodiversity measures, which require a larger investment in annotation methods. We assessed these trade-offs using a dataset of 5 939 images and physical collections of black and octocorals taken during surveys from a seamount area in the southwest Pacific Ocean. Coral diversity was greatly underestimated in images: only 55 black and octocoral ‘phototaxa’ (best-possible identifications) were consistently distinguishable out of a known 210 species in the region (26%). Patterns of assemblage composition were compared between the phototaxa and a standardized Australian classification scheme (“CATAMI”) that uses morphotypes to classify taxa. Results were similar in many respects, but the identities of dominant, and detection of rare but locally abundant, coral entities were achieved only when annotation was at phototaxon resolution, and when faunal densities were recorded. A case study of data from 4 seamounts compared three additional classification schemes. Only the two with highest resolution – phototaxon and a combined phototaxon-morphological scheme – were able to distinguish black and octocoral communities on unimpacted vs. impacted seamounts. We conclude that image annotation schemes need to be fit-for-purpose. Morphological schemes such as CATAMI may perform well and are most easily standardized for cross-study data sharing, but high resolution (and more costly) annotation schemes are likely necessary for some ecological and management-based applications including biodiversity inventory, change detection (monitoring) – and to develop automated annotation using machine learning.
The Evolution of Regulatory Elements in the Emerging Promoter-Variant Strains of HIV-1 Subtype C
Authors: Bhange Disha , Prasad Nityanand , Singh Swati , Prajapati Harshit Kumar , Maurya Shesh Prakash , Gopalan Bindu Parachalil , Nadig Sowmya , Chaturbhuj Devidas , Jayaseelan Boobalan , Dinesha Thongadi Ramesh , Ahamed Syed Fazil , Singh Navneet , Brahmaiah Anangi , Mehta Kavita , Gohil Yuvrajsinh , Balakrishnan Pachamuthu , Das Bimal Kumar , Dias Mary , Gangakhedkar Raman , Mehendale Sanjay , Paranjape Ramesh S , Saravanan Shanmugam , Shet Anita , Solomon Sunil Suhas , Thakar Madhuri , Ranga Udaykumar
Published: November 2021

In a multicentric, observational, investigator-blinded, and longitudinal clinical study of 764 ART-naïve subjects, we identified nine different promoter variant strains of HIV-1 subtype C (HIV-1C) emerging in the Indian population, with some of these variants being reported for the first time. Unlike several previous studies, our work here focuses on the evolving viral regulatory elements, not the coding sequences. The emerging viral strains contain additional copies of the existing transcription factor binding sites (TFBS), including TCF-1α/LEF-1, RBEIII, AP-1, and NF-κB, created by sequence duplication. The additional TFBS are genetically diverse and may blur the distinction between the modulatory region of the promoter and the viral enhancer. In a follow-up analysis, we found trends, but no significant associations between any specific variant promoter and prognostic markers, probably because the emerging viral strains might not have established mono infections yet. Illumina sequencing of four clinical samples containing a coinfection indicated the domination of one strain over the other and establishing a stable ratio with the second strain at the follow-up time points. Since a single promoter regulates viral gene expression and constitutes the master regulatory circuit with Tat, the acquisition of additional and variant copies of the TFBS may significantly impact viral latency and latent reservoir characteristics. Further studies are urgently warranted to understand how the diverse TFBS profiles of the viral promoter may modulate the characteristics of the latent reservoir, especially following the initiation of antiretroviral therapy.
Caffeic Acid Supplement Alleviates Colonic Inflammation and Oxidative Stress Potentially Through Improved Gut Microbiota Community in Mice
Authors: Wan Fan , Zhong Ruqing , Wang Mengyu , Zhou Yexun , Chen Yuxia , Yi Bao , Hou Fujiang , Liu Lei , Zhao Yong , Chen Liang , Zhang Hongfu
Published: November 2021

Caffeic acid (CA) is one of the major phenolic acids of coffee with multiple biological activities. Our previous study found that 500 mg/kg of chlorogenic acid (CGA) had the potential capacity of alleviating colonic inflammation. Moreover, CGA can be degraded into caffeic acid (CA) by the gut microbiota in the colon. Therefore, we hypothesize that CA can exert protective effects on colonic inflammation. To test the hypothesis, 251 mg/kg CA was supplemented to DSS-induced colitis mice. The results showed that CA treatment recovered DSS-induced disease activity index (DAI), colon length, and histopathology scores of colon tissue. Additionally, CA treatment significantly decreased pro-inflammatory cytokines and malondialdehyde (MDA) levels and increased the level of IL-10, total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in serum. qPCR results indicated that CA treatment dramatically downregulated mRNA expression of IL-1β, IL-6, and TNF-α as well as upregulated SOD1, GPX1, GPX2, CAT, and IL-10. In addition, CA supplementation significantly increased mRNA expression of Nrf-2, HO-1, and NQO1, which showed its antioxidant and anti-inflammatory capacities potentially by activating the Nrf-2/HO-1 pathway. Moreover, CA supplementation prevented gut barrier damage by enhancing Occludin gene expression. Furthermore, CA supplementation altered the gut microbiome composition by decreasing the relative abundance of Bacteroides and Turicibacter, and enhancing the relative abundance of Alistipes and Dubosiella. Meanwhile, CA supplementation increases the abundance of Dubosiella and Akkermansia. In conclusion, CA supplementation could effectively alleviate DSS-induced colitis by improving the defense against oxidative stress and inflammatory response.
Participation of Acyl-Coenzyme A Synthetase FadD4 of Pseudomonas aeruginosa PAO1 in Acyclic Terpene/Fatty Acid Assimilation and Virulence by Lipid A Modification
Authors: Martínez-Alcantar Lorena , Orozco Gabriela , Díaz-Pérez Alma Laura , Villegas Javier , Reyes-De la Cruz Homero , García-Pineda Ernesto , Campos-García Jesús
Published: November 2021

The pathogenic bacterium Pseudomonas aeruginosa possesses high metabolic versatility, with its effectiveness to cause infections likely due to its well-regulated genetic content. P. aeruginosa PAO1 has at least six fadD paralogous genes, which have been implicated in fatty acid (FA) degradation and pathogenicity. In this study, we used mutagenesis and a functional approach in P. aeruginosa PAO1 to determine the roles of the fadD4 gene in acyclic terpene (AT) and FA assimilation and on pathogenicity. The results indicate that fadD4 encodes a terpenoyl-CoA synthetase utilized for AT and FA assimilation. Additionally, mutations in fadD paralogs led to the modification of the quorum-sensing las/rhl systems, as well as the content of virulence factors pyocyanin, biofilm, rhamnolipids, lipopolysaccharides (LPS), and polyhydroxyalkanoates. In a Caenorhabditis elegans in vivo pathogenicity model, culture supernatants from the 24-h-grown fadD4 single mutant increased lethality compared to the PAO1 wild-type (WT) strain; however, the double mutants fadD1/fadD2, fadD1/fadD4, and fadD2/fadD4 and single mutant fadD2 increased worm survival. A correlation analysis indicated an interaction between worm death by the PAO1 strain, the fadD4 mutation, and the virulence factor LPS. Fatty acid methyl ester (FAME) analysis of LPS revealed that a proportion of the LPS and FA on lipid A were modified by the fadD4 mutation, suggesting that FadD4 is also involved in the synthesis/degradation and modification of the lipid A component of LPS. LPS isolated from the fadD4 mutant and double mutants fadD1/fadD4 and fadD2/fadD4 showed a differential behavior to induce an increase in body temperature in rats injected with LPS compared to the WT strain or from the fadD1 and fadD2 mutants. In agreement, LPS isolated from the fadD4 mutant and double mutants fadD1/fadD2 and fadD2/fadD4 increased the induction of IL-8 in rat sera, but IL1-β cytokine levels decreased in the double mutants fadD1/fadD2 and fadD1/fadD4. The results indicate that the fadD genes are implicated in the degree of pathogenicity of P. aeruginosa PAO1 induced by LPS-lipid A, suggesting that FadD4 contributes to the removal of acyl-linked FA from LPS, rendering modification in its immunogenic response associated to Toll-like receptor TLR4. The genetic redundancy of fadD is important for bacterial adaptability and pathogenicity over the host.
Leisure Activities and Their Relationship With MRI Measures of Brain Structure, Functional Connectivity, and Cognition in the UK Biobank Cohort
Authors: Anatürk Melis , Suri Sana , Smith Stephen M. , Ebmeier Klaus P. , Sexton Claire E.
Published: November 2021

Introduction:This study aimed to evaluate whether engagement in leisure activities is linked to measures of brain structure, functional connectivity, and cognition in early old age.

Methods:We examined data collected from 7,152 participants of the United Kingdom Biobank (UK Biobank) study. Weekly participation in six leisure activities was assessed twice and a cognitive battery and 3T MRI brain scan were administered at the second visit. Based on responses collected at two time points, individuals were split into one of four trajectory groups: (1) stable low engagement, (2) stable weekly engagement, (3) low to weekly engagement, and (4) weekly to low engagement.

Results:Consistent weekly attendance at a sports club or gym was associated with connectivity of the sensorimotor functional network with the lateral visual (β = 0.12, 95%CI = [0.07, 0.18], FDRq= 2.48 × 10–3) and cerebellar (β = 0.12, 95%CI = [0.07, 0.18], FDRq= 1.23 × 10–4) networks. Visiting friends and family across the two timepoints was also associated with larger volumes of the occipital lobe (β = 0.15, 95%CI = [0.08, 0.21], FDRq= 0.03). Additionally, stable and weekly computer use was associated with global cognition (β = 0.62, 95%CI = [0.35, 0.89], FDRq= 1.16 × 10–4). No other associations were significant (FDRq> 0.05).

Discussion:This study demonstrates that not all leisure activities contribute to cognitive health equally, nor is there one unifying neural signature across diverse leisure activities.
Amine-Coated Carbon Dots (NH2-FCDs) as Novel Antimicrobial Agent for Gram-Negative Bacteria
Authors: Devkota Asmita , Pandey Anju , Yadegari Zeinab , Dumenyo Korsi , Taheri Ali
Published: November 2021

Multidrug resistance (MDR) is a major concern in battling infectious bacterial diseases. The overuse of antibiotics contributes to the emergence of resistance by eradicating the drug-sensitive strains, leaving behind the resistant strains that multiply without any competition. Nanoparticles are becoming popular as novel antimicrobial agents that follow a different mode of action from standard antibiotics and are therefore desirable against MDR bacteria. In this study, we synthesized carbon dots from different precursors including glucosamine HCL (GlcNH2·HCl) and 4,7,10-trioxa-1,13-tridecanediamine (TTDDA, and studied their antimicrobial effects in a diverse list of Gram-negative bacteria including Escherichia coli, Pseudomonas syringae, Salmonella enterica subsp. enterica serovar Typhimurium, Pectobacterium carotovorum, Agrobacterium tumefaciens, and Agrobacterium rhizogenes. We demonstrated the antimicrobial properties of these carbon dots against these bacteria and provided the optimum concentration and incubation times for each bacterial species. Our findings indicated that not all carbon dots carry antimicrobial properties, and there is also a variation between different bacterial species in their resistance against these carbon dots.
Night-Time Non-dipping Blood Pressure and Heart Rate: An Association With the Risk of Silent Small Vessel Disease in Patients Presenting With Acute Ischemic Stroke
Authors: Akhtar Naveed , Al-Jerdi Salman , Kamran Saadat , Singh Rajvir , Babu Blessy , Abdelmoneim Mohamed S. , Morgan Deborah , Joseph Sujatha , Francis Reny , Shuaib Ashfaq
Published: November 2021

Background and Purpose: Nocturnal non-dipping blood pressure and heart rate are associated with an increased risk of cardiovascular disease. The effects of such variance on cerebrovascular disease have not been well studied.

Methods: The 24-h ambulatory blood pressure (ABPM) and heart rate were monitored with B-pro in patients with acute stroke within the initial week of hospital admission. The risk factor profiles, clinical presentation, imaging, and short-term prognosis were compared in nocturnal dippers and non-dippers (more than 10% nocturnal decrease) of blood pressure and heart rate.

Results: We enrolled 234 patients in whom ABPM and MRI data were available. Heart rate data were available in 180 patients. Lacunar sub-cortical stroke was the most common acute lesion (58.9%), while hypertension (74%) and diabetes (41.5%) were the most common associated risk factors. ABPM revealed non-dipping in 69% of patients. On univariate analysis, Small Vessel Disease (SVD) was significantly more frequent in non-dippers vs. dippers (BP: 56.8 vs. 40.3% p = 0.02; heart rate: 57.9 vs. 40.7% p = 0.03). Silent strokes were also more frequent in non-dippers vs. dippers (BP: 40.7 vs. 26.4% p = 0.35; heart rate: 44.6 vs. 25.4% p = 0.01). Multivariate analysis revealed SVD to be significantly related to age, hypertension, blood pressure non-dipping, and severity of symptoms at index event.

Conclusions: The presence of nocturnal non-dipping of blood pressure and heart rate are associated with an increased risk of silent stroke and SVD. Increased use of ABPM may allow for improved diagnosis of non-dippers.
Impact of Tumor–Stroma Ratio on the Prognosis of Colorectal Cancer: A Systematic Review
Authors: Gao Jinlai , Shen Zhangguo , Deng Zaixing , Mei Lina
Published: November 2021

Background

It is critical to develop a reliable and cost-effective prognostic tool for colorectal cancer (CRC) stratification and treatment optimization. Tumor–stroma ratio (TSR) may be a promising indicator of poor prognosis in CRC patients. As a result, we conducted a systematic review on the predictive value of TSR in CRC.

Methods

This study was carried out according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline. An electronic search was completed using commonly used databases PubMed, CENTRAL, Cochrane Central Register of Controlled Trials, and Google scholar till the last search up to May 30, 2021. STATA version 13 was used to analyze the data.

Results

A total of 13 studies [(12 for disease-free survival (DFS) and nine studies for overall survival (OS)] involving 4,857 patients met the inclusion criteria for the systematic review in the present study. In individuals with stage II CRC, stage III CRC, or mixed stage CRC, we observed a significantly higher pooled hazard ratio (HR) in those with a low TSR/greater stromal content (HR, 1.54; 95% CI: 1.20 to 1.88), (HR, 1.90; 95% CI: 1.35 to 2.45), and (HR, 1.70; 95% CI: 1.45 to 1.95), respectively, for predicting DFS. We found that a low TSR ratio had a statistically significant predictive relevance for stage II (HR, 1.43; 95% CI: 1.09 to 1.77) and mixed stages of CRC (HR, 1.65; 95% CI: 1.31 to 2.0) for outcome OS.

Conclusion

In patients with CRC, low TSR was found to be a prognostic factor for a worse prognosis (DFS and OS).
The Survival Benefit for Optimal Glycemic Control in Advanced Non-Small Cell Lung Cancer Patients With Preexisting Diabetes Mellitus
Authors: Qian Jie , Wang Weimin , Wang Lin , Lu Jun , Zhang Lele , Zhang Bo , Wang Shuyuan , Nie Wei , Zhang Yanwei , Lou Yuqing , Han Baohui
Published: November 2021

Background

Diabetes mellitus (DM) is a frequent comorbidity in patients with cancer. This study aimed to evaluate the prognosis of advanced non-small cell lung cancer (NSCLC) patients with DM and to assess whether an optimal glycemic control improves overall survival (OS).

Methods

A total of 1279 advanced NSCLC patients including 300 (23.5%) with preexisting DM were retrospectively reviewed. The continuous relationship between glycated hemoglobin A1C (HbA1c) level and OS was analyzed by restricted cubic spline (RCS) function. Optimal HbA1c cut-off point was determined using X-tile analysis. Survival was analyzed with the Kaplan–Meier method and compared among groups stratified by diabetes status and HbA1c. Multivariable Cox proportional hazards regression analysis was employed to identify prognostic factors for OS after adjusting for baseline characteristics.

Results

DM and non-DM patients had similar OS (median (95% CI): 22.85 (20.05-26.73) vs. 22.22 (20.35-24.76) months, P=0.950). The multivariate Cox regression analyses showed that DM status was not a prognostic factor for OS (HR: 0.952, 95% CI: 0.808-1.122, P=0.559). However, there existed a non-linear but generally positive relationship between the elevated HbA1c level and increased risk of overall mortality. HbA1c > 6.6% was a negative prognostic factor for OS (HR: 1.593, 95% CI: 1.113-2.280, P=0.011). The median OS (95% CI) for nondiabetic patients, DM patients with HbA1c ≤6.6% and those with HbA1c > 6.6% was 22.22 (20.01-24.43), 25.28 (21.79-28.77) and 15.45 (7.57-23.33) months, respectively. Well-controlled DM patients had a comparable crude OS (HR (95% CI): 0.90 (0.76-1.08), P=0.273] compared to nondiabetic patients while patients with HbA1c>6.6% had a worse crude OS than patients without DM (HR (95% CI): 1.70 (1.24-2.34), P=0.001]. The survival benefit of good HbA1c control was prominent in all subgroups.

Conclusion

Impaired glycemic level negatively affects survival for patients with advanced NSCLC while proper glycemic control with HbA1c ≤6.6% improves the OS.
Hemorrhage During Induction Chemotherapy in Neuroblastoma: Additional Risk Factors in High-Risk Patients
Authors: Voglino Valerio , Persano Giorgio , Crocoli Alessandro , Castellano Aurora , Serra Annalisa , Giordano Ugo , Natali Gian Luigi , Di Paolo Pier Luigi , Martucci Cristina , Stracuzzi Alessandra , Inserra Alessandro
Published: November 2021

Background: Neuroblastoma is the most common solid extracranial tumor in children. Patients affected by neuroblastoma are stratified into low, intermediate, and high risk in terms of event-free and overall survival. Some high-risk patients have an additional risk of acute hemorrhagic complications during induction chemotherapy.

Aim: To find easily and rapidly assessed parameters that help clinicians identify those patients affected by high-risk neuroblastoma who have an additional risk of hemorrhagic complications.

Methods: The clinical notes of patients diagnosed with high-risk neuroblastoma from January 2013 until February 2021 were retrospectively reviewed. Clinical, demographic and laboratory data, biological characteristics of the tumor, and information about treatment and hospital stay were identified.

Results: In the examined period, 44 patients were diagnosed with high-risk neuroblastoma. Four of these patients had hemorrhagic complications within 2–7 days after the initiation of induction chemotherapy; two patients had hemothorax, one patient had hemoperitoneum and one patient had hemothorax and hemoperitoneum. The patient with isolated hemoperitoneum was treated with blood components transfusions, clotting factors and colloids infusions; the three patients with hemothorax underwent thoracostomy tube placement and respiratory support. At initial presentation, patients who suffered from hemorrhagic complications had a higher degree of hypertension (stage 2, p = 0.0003), higher levels of LDH (median 3,745 U/L, p = 0.009) and lower levels of hemoglobin (mean 7.6 gr/dl, p = 0.0007) compared to other high-risk patients.

Conclusions: A subgroup of “additional” high-risk patients can be identified within the high-risk neuroblastoma patients based on mean arterial pressure, LDH levels and hemoglobin levels at presentation. Further studies to define cut-off values and optimal management strategies for these patients are needed.
VDR Signaling via the Enzyme NAT2 Inhibits Colorectal Cancer Progression
Authors: Zhu Chaojun , Wang Zihuan , Cai Jianqun , Pan Chunqiu , Lin Simin , Zhang Yue , Chen Yuting , Leng Mengxin , He Chengcheng , Zhou Peirong , Wu Changjie , Fang Yuxin , Li Qingyuan , Li Aimin , Liu Side , Lai Qiuhua
Published: November 2021

Recent epidemiological and preclinical evidence indicates that vitamin D3 inhibits colorectal cancer (CRC) progression, but the mechanism has not been completely elucidated. This study was designed to determine the protective effects of vitamin D3 and identify crucial targets and regulatory mechanisms in CRC. First, we confirmed that 1,25(OH)2D3, the active form of vitamin D3, suppressed the aggressive phenotype of CRC in vitro and in vivo. Based on a network pharmacological analysis, N-acetyltransferase 2 (NAT2) was identified as a potential target of vitamin D3 against CRC. Clinical data of CRC patients from our hospital and bioinformatics analysis by online databases indicated that NAT2 was downregulated in CRC specimens and that the lower expression of NAT2 was correlated with a higher metastasis risk and lower survival rate of CRC patients. Furthermore, we found that NAT2 suppressed the proliferation and migration capacity of CRC cells, and the JAK1/STAT3 signaling pathway might be the underlying mechanism. Moreover, Western blot and immunofluorescence staining assays demonstrated that 1,25(OH)2D3 promoted NAT2 expression, and the chromatin immunoprecipitation assay indicated that the vitamin D receptor (VDR) transcriptionally regulated NAT2. These findings expand the potential uses of vitamin D3 against CRC and introduce VDR signaling via the enzyme NAT2 as a potential diagnostic and therapeutic target for CRC.
Inhibitory Effect of Punicalagin on Inflammatory and Angiogenic Activation of Human Umbilical Vein Endothelial Cells
Authors: Liu Wei , Ou Yanghui , Yang Yumeng , Zhang Xuemei , Huang Liqi , Wang Xiaohua , Wu Buling , Huang Mingcheng
Published: November 2021

Punicalagin, a major ellagitannin isolated from pomegranate, is proved to have various pharmacological activities with an undefined therapy mechanism. The objective of this research was to demonstrate the effect of punicalagin on anti-inflammatory and angiogenic activation in human umbilical vein endothelial cells (HUVECs) and their potential mechanisms. Endothelial-leukocyte adhesion assay was applied to evaluate primary cultures of HUVECs activation following tumor necrosis factor alpha (TNF-α) treatment. The endothelial cell proliferation, migration, permeability and tube formation were assessed by EdU assay, wound migration assay, trans-endothelial electrical resistances (TEER) assay, and capillary-like tube formation assay, respectively. In addition, the expression of relevant proteins was assessed using Western blot analysis. We confirmed that punicalagin could reduce the adhesion of human monocyte cells to HUVECs in vitro and in vivo. Further, punicalagin decreased the expression of mRNA and proteins of ICAM-1 and VCAM-1 in HUVECs. Moreover, punicalagin inhibited permeability, proliferation, migration, and tube formation in VEGF-induced HUVECs, suppressed IKK-mediated activation of NF-κB signaling in TNF-α-induced endothelial cells, and inhibited vascular endothelial growth factor receptor 2 (VEGFR2) activation and downstream p-PAK1. Our findings indicated that punicalagin might have a protective effect on HUVECs activation, which suggested that punicalagin functions through an endothelial mediated mechanism for treating various disorders such as, cancer, rheumatoid arthritis, and cardiovascular disease.
Identification of Novel Type Three Secretion System (T3SS) Inhibitors by Computational Methods and Anti-Salmonella Evaluations
Authors: Wang Yonghui , Hou Meihui , Kan Zhaodong , Zhang Guanghui , Li Yunxia , Zhou Lei , Wang Changfa
Published: November 2021

Three type III secretion system (T3SS) inhibitors (compounds 5, 19, and 32) were identified by virtual screening and biological evaluation. These three compounds were evaluated against a panel of Salmonella species strains including S. enteritidis, S. typhi, S. typhimurium, S. paratyphi, and S. abortus equi, and their minimum inhibitory concentrations ranged from 1 to 53 μg/ml. Especially, these compounds showed comparable activity as the of the positive control gatifloxacin towards S. abortus equi. The present results suggest that these new T3SS inhibitors could be used as a potential lead molecule for drug development of anti-Salmonella.
Functional Nanomedicines for Targeted Therapy of Bladder Cancer
Authors: Tang Chao , Liu Heng , Fan Yanpeng , He Jiahao , Li Fuqiu , Wang Jin , Hou Yuchuan
Published: November 2021

Bladder cancer is one of most common malignant urinary tract tumor types with high incidence worldwide. In general, transurethral resection of non-muscle-invasive bladder cancer followed by intravesical instillation of chemotherapy is the standard treatment approach to minimize recurrence and delay progression of bladder cancer. However, conventional intravesical chemotherapy lacks selectivity for tumor tissues and the concentration of drug is reduced with the excretion of urine, leading to frequent administration and heavy local irritation symptoms. While nanomedicines can overcome all the above shortcomings and adhere to the surface of bladder tumors for a long time, and continuously and efficiently release drugs to bladder cancers. The rapid advances in targeted therapy have led to significant improvements in drug efficacy and precision of targeted drug delivery to eradicate tumor cells, with reduced side-effects. This review summarizes the different available nano-systems of targeted drug delivery to bladder cancer tissues. The challenges and prospects of targeted therapy for bladder cancer are additionally discussed.
Hierarchical Modeling of the Liver Vascular System
Authors: Torres Rojas Aimee M. , Lorente Sylvie , Hautefeuille Mathieu , Sanchez-Cedillo Aczel
Published: November 2021

The liver plays a key role in the metabolic homeostasis of the whole organism. To carry out its functions, it is endowed with a peculiar circulatory system, made of three main dendritic flow structures and lobules. Understanding the vascular anatomy of the liver is clinically relevant since various liver pathologies are related to vascular disorders. Here, we develop a novel liver circulation model with a deterministic architecture based on the constructal law of design over the entire scale range (from macrocirculation to microcirculation). In this framework, the liver vascular structure is a combination of superimposed tree-shaped networks and porous system, where the main geometrical features of the dendritic fluid networks and the permeability of the porous medium, are defined from the constructal viewpoint. With this model, we are able to emulate physiological scenarios and to predict changes in blood pressure and flow rates throughout the hepatic vasculature due to resection or thrombosis in certain portions of the organ, simulated as deliberate blockages in the blood supply to these sections. This work sheds light on the critical impact of the vascular network on mechanics-related processes occurring in hepatic diseases, healing and regeneration that involve blood flow redistribution and are at the core of liver resilience.