bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac Monitoring and Heart Failure in Advanced Breast Cancer Patients Treated With Trastuzumab in Ontario, Canada
Authors: Rushton Moira , Kappel Coralea , Lima Isac , Tuna Meltem , Pritchard Kathleen , Hawken Steven , Dent Susan
Published: May 2022

Background

Trastuzumab has improved patient outcomes in HER2 + breast cancer (BC) but carries a risk of cardiotoxicity. Routine cardiac imaging is recommended for advanced breast cancer (aBC) patients during trastuzumab treatment despite a lack of evidence that this improves patient outcomes. This study was conducted to understand predictive factors for cardiac events and determine the impact of cardiovascular monitoring in aBC.

Methods

This retrospective population-based cohort study included aBC patients treated with trastuzumab (all lines), in Ontario, Canada from 2007 to 2017. The overall cohort was divided into two groups; those who developed a cardiac event (CE) vs. those who did not. Patients with pre-existing heart disease were excluded. Logistic regression was performed to identify patient characteristics associated with an increased risk of CE.

Results

Of 2,284 patients with HER2 + aBC treated with trastuzumab, 167 (7.3%) developed a CE. Median age at first dose of trastuzumab was 57 (IQR 49–66); 61 (IQR 51–70) for patients with a CE. Median number of cycles was 16 (IQR 7–32); 21 (IQR 8–45) for patients with a CE (p < 0.01). Twelve (0.5%) patients died of cardiac causes; all had a prior CE. Increased risk of CEs was associated with age > 60 (OR 5.21, 95% CI 1.83–14.84, p = 0.05) and higher number cycles of trastuzumab (OR 1.01; 95% CI 1–101, p = 0.028).

Conclusion

This is the first population-based study to report on CEs and cardiac monitoring in HER2 + aBC patients during trastuzumab-based therapy. Older age and longer treatment with trastuzumab were associated with an increased risk of a CE.
Anxiety Predicts Poor Prognosis in Patients With Hypertrophic Cardiomyopathy
Authors: He Chao-Jie , Zhai Chang-Lin , Huang Shao-Dai , Fan Hong-Yan , Qian Ye-Zhou , Zhu Chun-Yan , Hu Hui-Lin
Published: May 2022

Background

Hypertrophic cardiomyopathy (HCM) is the prevalent inherited cardiomyopathy and a major contributor to sudden death and heart failure in young adults. Although depression has been associated with poor prognosis in patients with cardiovascular disease, the relationship between anxiety and HCM clinical outcomes has not been addressed. We aimed to determine the prevalence of anxiety symptoms in patients with HCM and the association between anxiety and adverse prognosis in this population.

Methods

A total of 793 patients with HCM were prospectively enrolled and followed up for a mean of 4.1 years from March 2014 to January 2018. The primary endpoint was sudden cardiac death (SCD) events, and the secondary endpoint was HCM-related heart failure events. Anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) during outpatient visits or hospital stays.

Results

Elevated scores on the HADS anxiety subscale (HADS-A ≥ 8) were defined as clinically significant anxiety. SCD and HCM-related heart failure events occurred in 76 and 149 patients, respectively, during the follow-up period. Kaplan–Meier survival curves demonstrated the significant association of anxiety with SCD events (log-rank P = 0.012) and HCM-related heart failure events (log-rank P = 0.001). Multivariable Cox regression analysis showed anxiety as a predictor of SCD events and HCM-related heart failure events (adjusted hazard ratio [HR] = 1.42, 95% confidence interval [CI] = 1.12–2.04, P = 0.03; adjusted HR = 2.9,2 95% CI = 1.73–4.03, P < 0.001), independent of conventional risk factors and depression. Besides, patients with comorbid anxiety and depression showed a fourfold higher risk of heart failure events and 3.5-fold higher risk of SCD versus those with neither (adjusted HR = 4.08, 95% CI = 2.76–5.91, P < 0.001; adjusted HR = 3.52, 95% CI = 2.24–4.67, P < 0.001, respectively).

Conclusions

Anxiety was prevalent among Chinese patients with HCM, and it was independently associated with a higher risk of SCD and HCM-related heart failure events, particularly when comorbid with depression. Psychological assessment and intervention should be considered to alleviate anxiety symptoms in this population.

Clinical Trial Registration

http://www.chictr.org.cn, identifier: ChiCTR2000040759.
Engagement in Digital Health App-Based Prevention Programs Is Associated With Weight Loss Among Adults Age 65+
Authors: Auster-Gussman Lisa A. , Lockwood Kimberly G. , Graham Sarah A. , Pitter Viveka , Branch OraLee H.
Published: May 2022

Background

Digital health programs have been shown to be feasible and effective for the prevention of chronic diseases such as diabetes. Contrary to expectations, findings also suggest that older adults have higher levels of engagement with digital health programs than younger adults. However, there is a paucity of research examining outcomes among older adults in digital health programs and whether higher engagement is related to better outcomes.

Methods

We examined weight loss outcomes for 538 users aged 65 and older participating in one of two app-based prevention programs called the Diabetes Prevention Program and the Prevention Program, respectively. Both programs were available on a single artificial intelligence (AI)-powered digital health platform and shared a common goal of weight loss. We also examined the relationship between key engagement metrics (i.e., conversing with the AI-powered coach, weigh-ins, and initiating educational lessons early in the program) and weight loss outcomes.

Results

The average weight loss of all enrollees having a weight measurement after after the 9th week was 4.51%, and the average weight loss of the Diabetes Prevention Program enrollees meeting a minimum engagement level was 8.56%. Greater weight loss was associated with a greater number of days with AI-powered coaching conversations (p = 0.03), more weigh-ins (p = 0.00), and early educational lesson initiation (p = 0.02).

Conclusions

Digital health programs powered by AI offer a promising solution for health management among older adults. The results show positive health outcomes using app-based prevention programs, and all three engagement metrics were independently associated with weight loss.
Geochemical Composition of Surface Sediments in the Bashang Area, North China and its Environmental Significance
Authors: Liu Linjing , Jiang Gaolei , Mao Xin , Zhao Hongmei , Zhao Yongjie , Li Yuecong , Zhao Hua , Bi Zhiwei
Published: May 2022

The geochemical characteristics of sediments are important for reconstructing paleoclimatic and paleoenvironmental conditions in the Asian summer monsoon marginal area. However, robust reconstructions require an understanding of the key factors and mechanisms governing the spatial variations in the composition and ratio of chemical elements in the modern sediments of the Asian summer monsoon marginal area. In this study, 128 surface sediment samples were collected from the Bashang area, which is situated in the Asian summer monsoon marginal area, and examined for their major and trace element compositions and grain size. Principal component analysis (PCA) and redundancy analysis (RDA) were used to analyse the relationship between geochemical data and modern temperature and precipitation data. The results showed that the CIA values of sediments in the Bashang area are mainly affected by temperature rather than precipitation and the Rb/Sr value in the study area reflects the level of precipitation in the corresponding period and the temperature controlling the leaching and weathering. In addition, SiO2/Al2O3 and Zr/Ti ratios have good positive relationships with the coarse-grained fraction of sediments and thus can be used as grain size proxies. We propose that the exact environmental significance indicated by these proxies should be stated explicitly before using them as proxies for paleoenvironmental reconstructions of the Asian summer monsoon marginal area.
Late Quaternary Activity: Kouma Fault
Authors: He Weimin , Wei Leihua , Xu Shuya , Wan Senlin , Yang Jie , Liu Mingjun
Published: May 2022

The Kouma Fault, located at the northern foot of the Mangshan Mountain in Luoyang City, Henan Province, China, is an active fault newly discovered in the field seismic geological survey. The Kouma Fault is a normal fault that is approximately 30 km in length, near the east-west strike, and the north dip. The study on the nature of the Quaternary activity of the Kouma Fault is of great significance to the potential seismic source zone division, urban and rural land planning, site selection for major projects, the assessment and prevention of earthquake disaster risk. Through a series of seismic geological surveys, 12 fault outcrops were discovered, which were all distributed on the slopes of the loess gullies. The Kouma Fault cuts loess, clay, sand, and gravel. The fault planes and scratch can be seen clearly. The filling in the fault zone is dominated by clay, loess, and pebbles, among others. When the width of the fault zone is smaller (10–30 cm), most clay in the zone is laminated in occurrence. The laminated surface is almost parallel to the fault plane and the long axis direction of pebbles in the fault zone is almost parallel to the fault plane. When the width of the fault zone is greater (for instance, 1.6 m), the clay and loess in the fault zone are massive. The composite drilling geological section and trench reveal two paleoseismic events of the Kouma Fault, the paleoseismic event I occurred at the fault in the Middle Pleistocene; the paleoseismic event II occurred at the fault in the later period of the Late Pleistocene, and the vertical offset of the upper Pleistocene bottom boundary is 13.57 m. Based on the OSL age data in the fault G1 outcrop of the fault and TC1 and TC2 trenches, the latest activity age of the Kouma Fault may be defined within the range of (38.84 ± 4.69) to (40.90 ± 4.45) kaB.P. The latest active age of the Kouma fault is the late of Late Pleistocene. The average vertical slip rate of the fault during the Late Pleistocene has been 0.11 mm/a.
The Effects of Undergraduate Research Experiences as Reported by Texas A&M University System Louis Stokes Alliance for Minority Participation Students
Authors: Preuss Michael , Merriweather Samuel , Avila John , Butler-Purry Karen , Watson Karan , Walton Shannon , Obiomon Pamela , Pezold Frank , Murry Jasmine , Roth Michele , Kelley Judy , Lamm Harriet
Published: May 2022

In 1991, the Texas A&M University System was one of the first six Louis Stokes Alliance for Minority Participation (LSAMP) awardees. In the three decades of programming, several high impact practices (HIP) have been emphasized. One of them, undergraduate research (UR), is discussed. All members of the Alliance are part of the Texas A&M University System and undergraduate research was supported through a variety of initiatives on the Alliance campuses. Data presented chronicle student perspectives. Topics addressed are the impact of involvement in undergraduate research on academic outcomes, interest in further engagement with research, interest in graduate school, and career goals as well as the patterns of research engagement participants experienced and the forms of learning that resulted. These materials are presented regarding an audience that was overwhelmingly underrepresented minority students all of whom were pursuing science, technology, engineering, or mathematics (STEM) degrees. Students reported UR influenced their academic outcomes, further engagement with research, interest in graduate school, and career goals while facilitating learning and skill development. These findings, for URM students from institutions with three different Carnegie classifications that are a predominantly white institution, two Hispanic-serving institutions (HSIs), and a historically Black college or university (HBCU), parallel outcomes reported in the literature for investigations focused on general student populations suggesting that UR benefits are generalizable regardless of institution type and ethnicity/race of the participant. Findings also suggest that these patterns apply regardless of the student’s year in school. Material presented details the research elements commonly included in TAMUS LSAMP UR experiences and in which areas students reported the most learning. Thus, this document touches on topics important in addressing development of an adequate, well-trained, and diverse STEM workforce. It also confirms the efficacy of a highly replicable approach to facilitating a HIP, undergraduate research, with students from underrepresented groups.
“EdTech Integration Framework in Schools”: Systematic Review of the Literature
Authors: Sosa-Díaz María José , Sierra-Daza María Caridad , Arriazu-Muñoz Rubén , Llamas-Salguero Fátima , Durán-Rodríguez Noelia
Published: May 2022

The process of integration of Information and Communication Technologies (ICT) in the Educational System is a dynamic process influenced by multiple interdependent factors. The most relevant studies published to date have highlighted the following as systemic levels of ICT integration: teachers, schools, and educational policy. The general objective of this work is to carry out a Systematic Literature Review (SLR) on the strategic planning of technology in primary and secondary schools from 2010 to 2021. This study is supported by a qualitative methodology based on a SLR, guided by the PRISMA protocol. For this purpose, a keyword-based document search was carried out in three databases: Eric, Scopus, and WOS. For the collection of information, the criteria applied for the inclusion of papers was by date (last 12 years) and type of document (journal articles). A total of 6,187 scientific journal articles were initially included in the CADIMA platform, where finally, after screening, 42 articles were selected that met the established criteria: studies with teachers and students in the educational stages of Primary and Secondary Education, excluding Higher Education. Empirical studies with quantitative and/or qualitative methods are also included, discarding theoretical studies. Research on digital technologies from a general perspective is also considered relevant, excluding studies on specific technologies. This SLR concludes by providing an explanatory theoretical model, defining the integration of ICT in educational centres as a complex, systemic and ecological process, where legislative and organisational structures, such as leadership, strategic planning, and collaboration among professionals, are essential elements. Therefore, the incorporation of technology in the classroom requires a redefinition of the organisational culture of schools.

Systematic Review Registration: [zenodo.org], identifier [6343639].
Deficiency of RARα Suppresses Decidualization via Downregulating CEBPB Transcription in Women With Recurrent Implantation Failure
Authors: Huang Caiyi , Zhang Qian , Ni Tianxiang , Zhou Tingting , Lv Chunzi , Li Yan , Yan Junhao , Chen Zi-Jiang
Published: May 2022

Background

Recurrent implantation failure (RIF) is a disease associated with endometrial receptivity dysfunction. Retinoic acid receptor alpha (RARα) is an important protein in many biological processes, such as differentiation and development. However, the exact underlying mechanism whereby RARα affects RIF remains unknown. This study investigated RARα expression and its contribution in the mid-luteal phase endometria of patients with RIF.

Methods

The expression levels of RARα and CCAAT/enhancer-binding protein (C/EBP) β in the endometria of the RIF and normal group were investigated using western blotting and immunohistochemistry. In in vitro experiments, immortal telomerase-transformed human endometrial stromal cells (T-HESCs) were incubated with medroxyprogesterone-17-acetate (MPA) and cyclic adenosine monophosphate (cAMP) for 4 days to induce decidualization. The expression levels of the decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein-1 (IGFBP-1) were determined using quantitative polymerase chain reaction. RARα was knocked down using a small interfering RNA, and C/EBPβ was overexpressed from an adenoviral vector. The transcriptional regulation of CEBPB by RARα was determined by chromatin immunoprecipitation (ChIP) assay and luciferase assays.

Results

We found that the expression levels of RARα decreased in the mid-luteal endometria of RIF patients. After 4 days of decidualization induction in vitro, RARα knockdown impaired the decidualization of T-HESCs and downregulated the expression of C/EBPβ. The restoration of C/EBPβ expression rescued the RARα knockdown-induced suppression of T-HESC decidualization. In ChIP analysis of lysates from decidualized T-HESCs, the CEBPB promoter region was enriched in chromatin fragments pulled down using an anti-RARα antibody. However, the relationship between CEBPB transcription and RARα expression levels was only observed when the decidualization of T-HESCs was induced by the addition of cAMP and MPA. To identify the binding site of RARα/retinoid X receptor α, we performed luciferase assays. Mutation of the predicted binding site in CEBPB (-2,009/-1,781) decreased the transcriptional activity of the reporter. To confirm this mechanism, the expression levels of C/EBPβ in the mid-luteal endometria of RIF patients were determined and found to decrease with decreased RARα expression levels.

Conclusion

A deficiency of RARα expression in the mid-luteal endometrium inhibits decidualization due to the downregulation of CEBPB transcription. This is a potential mechanism contributing to RIF.
Hyperuricemia is Associated With 2- and 5-Year Adverse Outcomes in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention
Authors: Tang Xiao-Fang , He Chen , Zhu Pei , Zhang Che , Song Ying , Xu Jing-Jing , Yao Yi , Xu Na , Jiang Ping , Jiang Lin , Gao Zhan , Zhao Xue-yan , Gao Li-jian , Song Lei , Yang Yue-Jin , Gao Run-Lin , Xu Bo , Yuan Jin-Qing
Published: May 2022

Background

Hyperuricemia has recently been identified as a risk factor of cardiovascular diseases; however, prognostic value of hyperuricemia in patients with ST-segment elevation myocardial infarction (STEMI) remained unclear. Simultaneously, the mechanism of this possible relationship has not been clarified. At present, some views believe that hyperuricemia may be related to the inflammatory response. Our study aimed to investigate the association between hyperuricemia and long-term poor prognosis and inflammation in STEMI patients undergoing percutaneous coronary intervention (PCI).

Methods

A total of 1,448 consecutive patients with STEMI were studied throughout 2013 at a single center. The primary endpoint was all-cause death at 2- and 5-year follow-up. Inflammatory biomarkers were collected on admission of those patients: high sensitive C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), and white blood cell (WBC) count.

Results

Hyperuricemia was associated with higher 2- and 5-year all-cause death in STEME patients compared to normouricemia (5.5% vs. 1.4%, P <0.001; 8.0% vs 3.9%, P = 0.004; respectively). After multivariable adjustment, hyperuricemia was still an independent predictor of 2-year all-cause death (hazard ratio (HR) =4.332, 95% confidence interval (CI): 1.990–9.430, P <0.001) and 5-year all-cause death (HR =2.063, 95% CI: 1.186–3.590, P =0.010). However, there was no difference in hs-CRP, ESR, and WBC count on admission in STEMI patients with hyperuricemia compared to normouricemia (P >0.05).

Conclusions

Hyperuricemia was associated with higher risks of 2- and 5-year all-cause deaths in patients with STEMI undergoing PCI. However, this study did not find a correlation between hyperuricemia and inflammatory responses in newly admitted STEMI patients.
Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease
Authors: Yang Yang , Xu Gaosi
Published: May 2022

In the existing stages of diabetic kidney disease (DKD), the first stage of DKD is called the preclinical stage, characterized by glomerular hyperfiltration, an abnormally elevated glomerular filtration rate. Glomerular hyperfiltration is an independent risk factor for accelerated deterioration of renal function and progression of nephropathy, which is associated with a high risk for metabolic and cardiovascular disease. It is imperative to understand hyperfiltration and identify potential treatments to delay DKD progress. This paper summarizes the current mechanisms of hyperfiltration in early DKD. We pay close attention to the effect of glucose reabsorption mediated by sodium–glucose cotransporters and renal growth on hyperfiltration in DKD patients, as well as the mechanisms of nitric oxide and adenosine actions on renal afferent arterioles via tubuloglomerular feedback. Furthermore, we also focus on the contribution of the atrial natriuretic peptide, cyclooxygenase, renin–angiotensin–aldosterone system, and endothelin on hyperfiltration. Proposing potential treatments based on these mechanisms may offer new therapeutic opportunities to reduce the renal burden in this population.
Identification and Verification of Diagnostic Biomarkers for Glomerular Injury in Diabetic Nephropathy Based on Machine Learning Algorithms
Authors: Han Hongdong , Chen Yanrong , Yang Hao , Cheng Wei , Zhang Sijing , Liu Yunting , Liu Qiuhong , Liu Dongfang , Yang Gangyi , Li Ke
Published: May 2022

Diabetic nephropathy (DN) is regarded as the leading cause of end-stage renal disease worldwide and lacks novel therapeutic targets. To screen and verify special biomarkers for glomerular injury in patients with DN, fifteen datasets were retrieved from the Gene Expression Omnibus (GEO) database, correspondingly divided into training and testing cohorts and then merged. Using the limma package, 140 differentially expressed genes (DEGs) were screened out between 81 glomerular DN samples and 41 normal ones from the training cohort. With the help of the ConsensusClusterPlus and WGCNA packages, the 81 glomerular DN samples were distinctly divided into two subclusters, and two highly associated modules were identified. By using machine learning algorithms (LASSO, RF, and SVM-RFE) and the Venn diagram, two overlapping genes (PRKAR2B and TGFBI) were finally determined as potential biomarkers, which were further validated in external testing datasets and the HFD/STZ-induced mouse models. Based on the biomarkers, the diagnostic model was developed with reliable predictive ability for diabetic glomerular injury. Enrichment analyses indicated the apparent abnormal immune status in patients with DN, and the two biomarkers played an important role in the immune microenvironment. The identified biomarkers demonstrated a meaningful correlation between the immune cells’ infiltration and renal function. In conclusion, two robust genes were identified as diagnostic biomarkers and may serve as potential targets for therapeutics of DN, which were closely associated with multiple immune cells.
Microbial Infection and Antibiotic Susceptibility of Diabetic Foot Ulcer in China: Literature Review
Authors: Du Fang , Ma Jing , Gong Hongping , Bista Raju , Zha Panpan , Ren Yan , Gao Yun , Chen Dawei , Ran Xingwu , Wang Chun
Published: May 2022

Objective

To investigate the microbial spectrum isolated from foot ulcers among diabetic patients in China, which was conducted to help clinicians choose optimal antibiotics empirically.

Method

The PubMed, MEDLINE, Web of Science, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), WanFang, and VIP databases were searched for studies published between 2015 to 2019, that report primary data on diabetic foot infection (DFI) and antibiotic susceptibility in China.

Result

A total of 63 articles about DFI and antibiotic susceptibility tests among diabetic patients in China were included. There were 11,483 patients with an average age of 60.2 ± 10.1 years and a mean course of 10.6 ± 5.0 years between 2010 and 2019, covering most geographical regions of China. The prevalence of Gram-positive (GP) bacteria (43.4%) was lower than that of Gram-negative (GN) (52.4%). The most prevalent pathogens isolated were Staphylococcus aureus (17.7%), Escherichia coli (10.9%), Pseudomonas aeruginosa (10.5%), Klebsiella pneumoniae (6.2%), Staphylococcus epidermidis (5.3%), Enterococcus faecalis (4.9%), and fungus (3.7%). The prevalence of polymicrobial infection was 22.8%. GP bacteria were sensitive to linezolid, vancomycin, and teicoplanin. More than 50% of GN bacteria were resistant to third-generation cephalosporins, while the resistance rates of piperacillin/tazobactam, amikacin, meropenem, and imipenem were relatively low. Among the 6017 strains of the isolated organisms, 20% had multi-drug resistance (MDR). Staphylococcus aureus (30.4%) was the most predominant MDR bacteria, followed by extended-spectrum β-lactamase (ESBL) (19.1%).

Conclusion

The microbial infection of foot ulcers among diabetic patients in China is diverse. The microbial spectrum is different in different geographic regions and Staphylococcus aureus is the predominant bacteria. Polymicrobial and MDR bacterial infections on the foot ulcers are common. This study could be valuable in guiding the empirical use of antibiotics for diabetic foot infections.
Artificial Intelligence-Aided Meta-Analysis of Toxicological Assessment of Agrochemicals in Bees
Authors: Bernardes Rodrigo Cupertino , Botina Lorena Lisbetd , Araújo Renan dos Santos , Guedes Raul Narciso Carvalho , Martins Gustavo Ferreira , Lima Maria Augusta Pereira
Published: May 2022

The lack of consensus regarding pollinator decline in various parts of the planet has generated intense debates in different spheres. Consequently, much research has attempted to identify the leading causes of this decline, and a multifactorial synergism (i.e., different stressors acting together and mutually potentiating the harmful effects) seems to be the emerging consensus explaining this phenomenon. The emphasis on some stressor groups such as agrochemicals, and pollinators such as the honey beeApis mellifera, can hide the real risk of anthropogenic stressors on pollinating insects. In the present study, we conducted a systematic review of the literature to identify general and temporal trends in publications, considering the different groups of pollinators and their exposure to agrochemicals over the last 76 years. Through an artificial intelligence (AI)-aided meta-analysis, we quantitatively assessed trends in publications on bee groups and agrochemicals. Using AI tools through machine learning enabled efficient evaluation of a large volume of published articles. Toxicological assessment of the impact of agrochemicals on insect pollinators is dominated by the order Hymenoptera, which includes honey bees. Although honey bees are well-explored, there is a lack of published articles exploring the toxicological assessment of agrochemicals for bumble bees, solitary bees, and stingless bees. The data gathered provide insights into the current scenario of the risk of pollinator decline imposed by agrochemicals and serve to guide further research in this area.

Systematic Review Registration

https://asreview.nl/.
Zambian Mole-Rats: 33 Years on the Scene and What We Still Do Not Know and How We Could Learn It
Authors: Burda Hynek
Published: May 2022

This article surveys more than three decades of research on Zambian mole-rats (genus Fukomys, Bathyergidae), pointing out some unanswered questions and untested hypotheses and suggesting approaches to address them. These research proposals range from sensory ecology topics, the main research field, covering different (even not yet identified) senses, orientation in time and space, communication, studies on aging, population dynamics, and the survival strategies of mole-rats during yearly floodings in the Kafue Flats. Discussion includes cryptozoological investigation into the existence of strange mole-rat species in some Zambian localities as reported by local communities, the study of mole-rats in assumed contact (hybrid?) zones of special interest, (cyto)genetic studies of hybrids of selected species, and a non-invasive study of population and family structure and dynamics with help of endoscopes. In each case, there is a rationale, reasoning, hypothesis, and suggested methodical approach.
Child-Onset Cerebellar Ataxia Caused by Two Compound Heterozygous Variants in ADPRS Gene: A Case Report
Authors: Ma Jiehui , Qian Qiaoqiao , Yan Shuang , Dou Haoyu , Li Cheng , Sun Dan
Published: May 2022

Background: Gene variants of ADP-ribosylserine hydrosylase, also known as ADP-ribosylhydrolase-like 2 (ADPRS or ADPRLH2; OMIM: 610624), can cause stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS, OMIM: 618170), an ultra-rare neurodegenerative autosomal recessive disorder. ADPRS encodes ADP-ribosylhydrolase 3, which removes poly(ADP-ribose) polymers, whose posttranslational addition occurs under stressful conditions.

Case Presentation: After a respiratory tract infection, a 30-month-old male patient presented with unsteady gait that rendered walking impossible without external help. Neurological examination revealed acute cerebellar ataxia, electroencephalogram results were abnormal, and brain magnetic resonance imaging revealed slightly widened cerebellar sulci. Laboratory tests showed decreased levels of thyroid-stimulating hormone, and increased levels of plasma lactic acid and serum cardiac enzymes. The cerebrospinal fluid glucose test was positive. Four months after onset, the patient died of sudden convulsions. Using whole exome sequencing, we identified two novel compound heterozygous ADPRS variants: NM_017825.3:c.580C>T (p.Gln194Ter) and NM_017825.3:c.803-1G>A. RNA sequencing indicated that the former mutation might cause nonsense-mediated mRNA decay. The c.803-1G>A variant was found to be a splice-site mutation that leads to the transcriptional retention of intron 5. According to the guidelines of the American College of Medical Genetics and Genomics, the two variants were classified as pathogenic.

Conclusion: We present the first report of the existence of two compound heterozygous variants of ADPRS, which leads to CONDSIAS.
An Adaptive and Robust Test for Microbial Community Analysis
Authors: Chen Qingyu , Lin Shili , Song Chi
Published: May 2022

In microbiome studies, researchers measure the abundance of each operational taxon unit (OTU) and are often interested in testing the association between the microbiota and the clinical outcome while conditional on certain covariates. Two types of approaches exists for this testing purpose: the OTU-level tests that assess the association between each OTU and the outcome, and the community-level tests that examine the microbial community all together. It is of considerable interest to develop methods that enjoy both the flexibility of OTU-level tests and the biological relevance of community-level tests. We proposed MiAF, a method that adaptively combines p-values from the OTU-level tests to construct a community-level test. By borrowing the flexibility of OTU-level tests, the proposed method has great potential to generate a series of community-level tests that suit a range of different microbiome profiles, while achieving the desirable high statistical power of community-level testing methods. Using simulation study and real data applications in a smoker throat microbiome study and a HIV patient stool microbiome study, we demonstrated that MiAF has comparable or better power than methods that are specifically designed for community-level tests. The proposed method also provides a natural heuristic taxa selection.
First Report on CRISPR/Cas9-Based Genome Editing in the Destructive Invasive Pest Tuta Absoluta (Meyrick) (Lepidoptera: Gelechiidae)
Authors: Ji Shun-Xia , Bi Si-Yan , Wang Xiao-Di , Wu Qiang , Tang Yan-Hong , Zhang Gui-Fen , Wan Fang-Hao , Lü Zhi-Chuang , Liu Wan-Xue
Published: May 2022

The tomato leaf miner Tuta absoluta (Meyrick) is one of the world’s most destructive pests of tomato, and because of its severe economic impacts, as well as the development of pesticide resistance, the species has been intensively studied, especially in regard to the identification of targets for T. absoluta control. However, functional genomic studies of T. absoluta have been constrained by a lack of effective genetic tools. Therefore, the aim of the present study was to develop a CRISPR/Cas9 zygote microinjection protocol for generating heritable mutations in T. absoluta, using the ommochrome synthesis gene cinnabar as an easily evaluated target gene. The injection of fertilised eggs with Cas9 protein and four sgRNAs, which targeted cinnabar exon 3, resulted in a mutagenesis rate of 31.9% for eggs reaching adulthood, and cinnabar mutagenesis resulted in either red or mosaic eye colour phenotypes. As such, this study is the first to report a complete and detailed CRISPR/Cas9 workflow for the efficient genome editing of the globally important invasive pest T. absoluta. The application of this robust genome-editing tool to T. absoluta will greatly facilitate the discovery of suitable RNAi control targets and the subsequent development of novel control strategies.
Preferences for Multipurpose Technology and Non-oral Methods of Antiretroviral Therapy Among Women Living With HIV in Western Kenya: A Survey Study
Authors: Bernard Caitlin , Jakait Beatrice , Fadel William F. , Mocello A. Rain , Onono Maricianah A. , Bukusi Elizabeth A. , Wools-Kaloustian Kara K. , Cohen Craig R. , Patel Rena C.
Published: May 2022

Introduction

Understanding interests in and preferences for multipurpose technology (MPT) for the co-administration of contraception and antiretroviral therapy (ART) and alternative, non-oral ART methods among women living with HIV (WLHIV) is vital to successful implementation of future treatment options, such as long-acting injectable ART.

Methods

Between May 2016 and March 2017 we conducted a cross-sectional telephone survey of 1,132 WLHIV of reproductive potential with prior experience using intermediate- or long-acting contraceptive methods in western Kenya. We present descriptive statistics and multinomial logistic regression to evaluate predictors of interest in specific MPT and non-oral ART methods.

Results

Two-thirds (67%) reported interest in MPT, with the most common reason for interest being ease of using a single medication for both purposes of HIV treatment and pregnancy prevention (26%). Main reasons for lack of interest in MPT were need to stop/not use contraception while continuing ART (21%) and risk of side effects (16%). Important characteristics of MPT were effectiveness for pregnancy prevention (26%) and HIV treatment (24%) and less than daily dosing (19%). Important characteristics of non-oral ART methods were less than daily dosing (47%), saving time accessing ART (16%), and effectiveness of HIV treatment (15%). The leading preferred methods for both MPT and non-oral ART were injectables (50 and 54%) and implants (32 and 31%). Prior use of a contraceptive implant or injectable predicted interest in similar methods for both MPT and non-oral ART methods, while this relationship did not appear to vary between younger vs. older WLHIV.

Discussion

Most WLHIV in western Kenya are interested in MPT for HIV treatment and contraception. Prior exposure to contraceptive implants or injectables appears to predict interest in similar methods of MPT and non-oral ART. Developers of MPT and non-oral ART methods should strongly consider WLHIV's preferences, including their changing reproductive desires.
Phosphatidylcholine Liposomes Down-Modulate CD4 Expression Reducing HIV Entry in Human Type-1 Macrophages
Authors: De Santis Federica , Lopez Ana Borrajo , Virtuoso Sara , Poerio Noemi , Saccomandi Patrizia , Olimpieri Tommaso , Duca Leonardo , Henrici De Angelis Lucia , Aquilano Katia , D’Andrea Marco Maria , Aquaro Stefano , Borsetti Alessandra , Ceccherini-Silberstein Francesca , Fraziano Maurizio
Published: May 2022

A strategy adopted to combat human immunodeficiency virus type-1 (HIV-1) infection is based on interfering with virus entry into target cells. In this study, we found that phosphatidylcholine (PC) liposomes reduced the expression of the CD4 receptor in human primary type-1 macrophages but not in CD4+T cells. The down-regulation was specific to CD4, as any effect was not observed in CCR5 membrane expression. Moreover, the reduction of membrane CD4 expression required the Ca2+-independent protein kinase C (PKC), which in turn mediated serine phosphorylation in the intracytoplasmic tail of the CD4 receptor. Serine phosphorylation of CD4 was also associated with its internalization and degradation in acidic compartments. Finally, the observed CD4 downregulation induced by PC liposomes in human primary macrophages reduced the entry of both single-cycle replication and replication competent R5 tropic HIV-1. Altogether, these results show that PC liposomes reduce HIV entry in human macrophages and may impact HIV pathogenesis by lowering the viral reservoir.
Mycobacterium tuberculosis-Induced Upregulation of the COX-2/mPGES-1 Pathway in Human Macrophages Is Abrogated by Sulfasalazine
Authors: Wang Wenfei , Ning Yuping , Wang Yejun , Deng Guofang , Pace Simona , Barth Stefanie A. , Menge Christian , Zhang Kehong , Dai Youchao , Cai Yi , Chen Xinchun , Werz Oliver
Published: May 2022

Macrophages are the primary human host cells of intracellular Mycobacterium tuberculosis (M.tb) infection, where the magnitude of inflammatory reactions is crucial for determining the outcome of infection. Previously, we showed that the anti-inflammatory drug sulfasalazine (SASP) significantly reduced the M.tb bactericidal burden and histopathological inflammation in mice. Here, we asked which genes in human inflammatory macrophages are affected upon infection with M.tb and how would potential changes impact the functional state of macrophages. We used a flow cytometry sorting system which can distinguish the dead and alive states of M.tb harbored in human monocyte-derived macrophages (MDM). We found that the expression of cyclooxygenase-2 and microsomal prostaglandin E2 synthase (mPGES)-1 increased significantly in tagRFP+ MDM which were infected with alive M.tb. After exposure of polarized M1-MDM to M.tb (H37Rv strain)-conditioned medium (MTB-CM) or to the M.tb-derived 19-kD antigen, the production of PGE2 and pro-inflammatory cytokines increased 3- to 4-fold. Upon treatment of M1-MDM with SASP, the MTB-CM-induced expression of COX-2 and the release of COX products and cytokines decreased. Elevation of PGE2 in M1-MDM upon MTB-CM stimulation and modulation by SASP correlated with the activation of the NF-κB pathway. Together, infection of human macrophages by M.tb strongly induces COX-2 and mPGES-1 expression along with massive PGE2 formation which is abrogated by the anti-inflammatory drug SASP.
Bomidin: An Optimized Antimicrobial Peptide With Broad Antiviral Activity Against Enveloped Viruses
Authors: Liu Rongrong , Liu Ziyu , Peng Haoran , Lv Yunhua , Feng Yunan , Kang Junjun , Lu Naining , Ma Ruixue , Hou Shiyuan , Sun Wenjie , Ying Qikang , Wang Fang , Gao Qikang , Zhao Ping , Zhu Cheng , Wang Yixing , Wu Xingan
Published: May 2022

The rapid evolution of highly infectious pathogens is a major threat to global public health. In the front line of defense against bacteria, fungi, and viruses, antimicrobial peptides (AMPs) are naturally produced by all living organisms and offer new possibilities for next-generation antibiotic development. However, the low yields and difficulties in the extraction and purification of AMPs have hindered their industry and scientific research applications. To overcome these barriers, we enabled high expression of bomidin, a commercial recombinant AMP based upon bovine myeloid antimicrobial peptide-27. This novel AMP, which can be expressed in Escherichia coli by adding methionine to the bomidin sequence, can be produced in bulk and is more biologically active than chemically synthesized AMPs. We verified the function of bomidin against a variety of bacteria and enveloped viruses, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), herpes simplex virus (HSV), dengue virus (DENV), and chikungunya virus (CHIKV). Furthermore, based on the molecular modeling of bomidin and membrane lipids, we elucidated the possible mechanism by which bomidin disrupts bacterial and viral membranes. Thus, we obtained a novel AMP with an optimized, efficient heterologous expression system for potential therapeutic application against a wide range of life-threatening pathogens.
Hyper-Reflecting Foci in Multiple Sclerosis Retina Associate With Macrophage/Microglia-Derived Cytokines in Cerebrospinal Fluid
Authors: Puthenparampil Marco , Torresin Tommaso , Franciotta Silvia , Marin Annachiara , De Napoli Federica , Mauceri Valentina Annamaria , Miante Silvia , Pilotto Elisabetta , Midena Edoardo , Gallo Paolo
Published: May 2022

Background

Increasing evidence suggests that retinal hyper-reflecting foci (HRF) might be clusters of activated and proliferating microglia. Since microglia are widespread activated in multiple sclerosis (MS) brain, its evaluation in retina may help to understand and monitor MS-related pathology.

Aim

This study aims at investigating the association of HRF with cerebrospinal fluid (CSF) cytokines and MRI parameters in relapsing–remitting MS (RRMS).

Methods

Nineteen RRMS at clinical onset and 15 non-inflammatory neurological disorders (NIND) underwent brain 3T MRI and CSF examination. Optical coherence tomography (OCT) analysis, including HRF count, was performed on RRMS patients. Sixty-nine cytokines/chemokines were analyzed in the CSF by multiplex technology.

Results

In RRMS, HRF count in the ganglion cell layer (GCL) was associated with IL-1Ra, IL-9, IL-15, IFN-γ, and G-CSF. Moreover, in RRMS patients CSF concentrations of IL-1Ra and G-CSF associated with global cortical thickness. The HRF count in the inner nuclear layer (INL) correlated with IL-22, IL-34, IL-35, CXCL-2, CXCL-10, and CXCL-13, and multivariate analysis confirmed a strong association (r2: 0.47) with both CXCL-2 (β: -0.965, p = 0.0052) and CXCL-13 (β: 0.241, p = 0.018). This latter cytokine increased in RRMS with high HRF count compared with NIND and RRMS with low HRF count. Finally, the CXCL-13/CXCL-2 ratio strongly associated with HRF count (r: 0.8, p < 0.005) and cortical lesion volume (r: 0.5, p < 0.05).

Conclusions

The association of HRF with intrathecally produced monocyte/microglia-derived cytokines confirms their microglial origin and indicates they are worth further evaluating as markers of activated microglia.
Synergistic Interaction of Low Salinity Stress With Vibrio Infection Causes Mass Mortalities in the Oyster by Inducing Host Microflora Imbalance and Immune Dysregulation
Authors: Li Xin , Yang Ben , Shi Chenyu , Wang Hebing , Yu Ruihai , Li Qi , Liu Shikai
Published: May 2022

A sudden drop in salinity following extreme precipitation events usually causes mass mortality of oysters exposed to pathogens in ocean environment. While how low salinity stress interacts with pathogens to cause mass mortality remains obscure. In this study, we performed an experiment by low salinity stress and pathogen infection with Vibrio alginolyticus to investigate their synergistic effect on the mortality of the Pacific oyster toward understanding of the interaction among environment, host, and pathogen. We showed that low salinity stress did not significantly affect proliferation and virulence of V. alginolyticus, but significantly altered microbial composition and immune response of infected oysters. Microbial community profiling by 16S rRNA amplicon sequencing revealed disrupted homeostasis of digestive bacterial microbiota with the abundance of several pathogenic bacteria being increased, which may affect the pathogenesis in infected oysters. Transcriptome profiling of infected oysters revealed that a large number of genes associated with apoptosis and inflammation were significantly upregulated under low salinity, suggesting that low salinity stress may have triggered immune dysregulation in infected oysters. Our results suggest that host-pathogen interactions are strongly affected by low salinity stress, which is of great significance for assessing future environmental risk of pathogenic diseases, decoding the interaction among environment, host genetics and commensal microbes, and disease surveillance in the oyster.
The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis
Authors: Cutolo Maurizio , Campitiello Rosanna , Gotelli Emanuele , Soldano Stefano
Published: May 2022

Innate and adaptive immunity represent a harmonic counterbalanced system involved in the induction, progression, and possibly resolution of the inflammatory reaction that characterize autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis (RA). Although the immunopathophysiological mechanisms of the ARDs are not fully clarified, they are often associated with an inappropriate macrophage/T-cell interaction, where classical (M1) or alternative (M2) macrophage activation may influence the occurrence of T-helper (Th)1 or Th2 responses. In RA patients, M1/Th1 activation occurs in an inflammatory environment dominated by Toll-like receptor (TLR) and interferon (IFN) signaling, and it promotes a massive production of pro-inflammatory cytokines [i.e., tumor necrosis factor-α (TNFα), interleukin (IL)-1, IL-12, IL-18, and IFNγ], chemotactic factors, and matrix metalloproteinases resulting in osteoclastogenesis, erosion, and progressive joint destruction. On the other hand, the activation of M2/Th2 response determines the release of growth factors and cytokines [i.e., IL-4, IL-10, IL-13, and transforming growth factor (TGF)-β] involved in the anti-inflammatory process leading to the clinical remission of RA. Several subtypes of macrophages have been described. Five polarization states from M1 to M2 have been confirmed in in vitro studies analyzing morphological characteristics, gene expression of phenotype markers (CD80, CD86, TLR2, TLR4, or CD206, CD204, CD163, MerTK), and functional aspect, including the production of reactive oxygen species (ROS). An M1 and M2 macrophage imbalance may induce pathological consequences and contribute to several diseases, such as asthma or osteoclastogenesis in RA patients. In addition, the macrophage dynamic polarization from M1 to M2 includes the presence of intermediate polarity stages distinguished by the expression of specific surface markers and the production/release of distinct molecules (i.e., nitric oxide, cytokines), which characterize their morphological and functional state. This suggests a “continuum” of macrophage activation states playing an important role during inflammation and its resolution. This review discusses the importance of the delicate M1/M2 imbalance in the different phases of the inflammatory process together with the identification of specific pathways, cytokines, and chemokines involved, and its clinical outcomes in RA. The analysis of these aspects could shed a light on the abnormal inflammatory activation, leading to novel therapeutical approaches which may contribute to restore the M1/M2 balance.