bluuebunny/crossref_metadata_2025 huggingface dataset:
De novo full length transcriptome analysis and gene expression profiling to identify genes involved in phenylethanol glycosides biosynthesis in Cistanche tubulosa
Authors: Hou Lei , Li Guanghui , Chen Qingliang , Zhao JinJin , Pan Jiaowen , Lin Ruxia , Zhu Xiujin , Wang Pengfei , Wang Xingjun
Published: October 2022

Background

The dried stem of Cistanche, is a famous Chinese traditional medicine. The main active pharmacodynamic components are phenylethanol glycosides (PhGs). Cistanche tubulosa produces higher level of PhGs in its stems than that of Cistanche deserticola. However, the key genes in the PhGs biosynthesis pathway is not clear in C. tubulosa.

Results

In this study, we performed the full-length transcriptome sequencing and gene expression profiling of C. tubulosa using PacBio combined with BGISEQ-500 RNA-seq technology. Totally, 237,772 unique transcripts were obtained, ranging from 199 bp to 31,857 bp. Among the unique transcripts, 188,135 (79.12%) transcripts were annotated. Interestingly, 1080 transcripts were annotated as 22 enzymes related to PhGs biosynthesis. We measured the content of echinacoside, acteoside and total PhGs at two development stages, and found that the content of PhGs was 46.74% of dry matter in young fleshy stem (YS1) and then decreased to 31.22% at the harvest stage (HS2). To compare with YS1, 13,631 genes were up-regulated, and 15,521 genes were down regulated in HS2. Many differentially expressed genes (DEGs) were identified to be involved in phenylpropanoid biosynthesis pathway, phenylalanine metabolism pathway, and tyrosine metabolism pathway.

Conclusions

This is the first report of transcriptome study of C. tubulosa which provided the foundation for understanding of PhGs biosynthesis. Based on these results, we proposed a potential model for PhGs biosynthesis in C. tubulosa.
Occurrence of waterborne pathogens and antibiotic resistance in water supply systems in a small town in Mozambique
Authors: Taviani Elisa , van den Berg Harold , Nhassengo Fernando , Nguluve Eugenia , Paulo Jussa , Pedro Olivia , Ferrero Giuliana
Published: October 2022

Background

. Microbiological quality of drinking water supplied in Moamba, a small town in southern Mozambique, was assessed by collecting and analyzing 91 water sample from 5 sampling sites: raw or inlet water, treated water and 3 household taps along the water distribution system. The presence of Escherichia coli as indicator fecal contamination, three bacterial pathogens, Vibrio cholerae, Salmonella and Campylobacter spp., and Cefotaximee resistant E. coli as antibiotic resistance determinant, was assessed.

Results

. The results showed fecal contamination in all types of water samples: E. coli was found in 100% of inlet water samples, in 21% of treated water samples, and in 22% of tap water samples. No Salmonella spp. was detected during the study. The presence of V. cholerae was detected in 42% of all water samples tested: 100% of inlet water samples, in 16% of treated water samples, and in 23% household tap water samples. All V. cholerae confirmed isolates where genotyped by PCR as non-O1/non-O139; however, 9 isolates showed the presence of the genes encoding for cholera toxin. The presence of Campylobacter spp. was detected in 36% of the water samples tested: in 95% of inlet water samples, in 10% of treated water samples and in 23% household tap water samples. Cefotaxime resistant E. coli was detected in 63% of inlet water, 16% of treated water, and in 9% of tap water samples, these isolates were also resistant to multiple other antibiotics: ampicillin, streptomycin, tetracycline chloramphenicol. All 70 V. cholerae non-O1/non-O139 confirmed isolated were resistant to ampicillin, 51% to streptomycin, 13% to gentamycin, and 1 isolate was resistant to tetracycline; 13% showed a multi-drug resistant profile, being resistant to at least three antibiotics.

Conclusion

. The presence of fecal contamination and pathogens in the water treatment system and household taps in Moamba indicates a health risk for the population. This burden increases by the presence of bacterial pathogens showing multidrug resistance.
Comparative transcriptomic responses of European and Japanese larches to infection by Phytophthora ramorum
Authors: Dun Heather F. , Hung Tin Hang , Green Sarah , MacKay John J.
Published: October 2022

Background and objectives

Phytophthora ramorumseverely affects both European larch (EL) and Japanese larch (JL) trees as indicated by high levels of mortality particularly in the UK. Field observations suggested that EL is less severely affected and so may be less susceptible toP. ramorumthan JL; however, controlled inoculations have produced inconsistent or non-statistically significant differences. The present study aimed to compare RNA transcript accumulation profiles in EL and JL in response to inoculation withP. ramorumto improve our understanding of their defence responses.

Methodology

RNA-sequencing was carried out on bark tissues following the inoculation withP. ramorumof potted saplings in both EL and JL carried out under controlled environment conditions, with sampling at 1, 3, 10, and 25 days post inoculation in infected and control plants.

Results

All of the inoculated trees rapidly developed lesions but no statistically significant differences were found in lesion lengths between EL and JL. RNA-Sequencing comparing control and inoculate saplings identified key differences in differentially expressed genes (DEGs) between the two larch species. European larch had rapid induction of defence genes within 24 hours of infection followed by sustained expression until 25 days after inoculation. Results in JL were more varied; upregulation was stronger but more transient and represented fewer defence pathways. Gene enrichment analyses highlighted differences in jasmonate signalling and regulation including NPR1 upregulation in EL only, and specific aspects of secondary metabolism. Some DEGs were represented by multiple responsive copies including lipoxygenase, chalcone synthase and nucleotide-binding, leucine-rich-repeat genes.

Conclusion

The variations between EL and JL in responsive DEGs of interest as potentially related to differences seen in the field and should be considered in the selection of trees for planting and future breeding.
Joint analysis of PK and immunogenicity outcomes using factorization model − a powerful approach for PK similarity study
Authors: Haliduola Halimu N. , Berti Fausto , Stroissnig Heimo , Guenzi Eric , Otto Hendrik , Sattar Abid , Mansmann Ulrich
Published: October 2022

Biological products, whether they are innovator products or biosimilars, can incite an immunogenic response ensuing in the development of anti-drug antibodies (ADA). The presence of ADA’s often affects the drug clearance, resulting in an increase in the variability of pharmacokinetic (PK) analysis and challenges in the design and analysis of PK similarity studies. Immunogenic response is a complex process which may be manifested by product and non-product-related factors. Potential imbalances in non-product-related factors between treatment groups may lead to differences in antibodies formation and thus in PK outcome. The current standard statistical approaches dismiss any associations between immunogenicity and PK outcomes. However, we consider PK and immunogenicity as the two correlated outcomes of the study treatment. In this research, we propose a factorization model for the simultaneous analysis of PK parameters (normal variable after taking log-transformation) and immunogenic response subgroup (binary variable). The central principle of the factorization model is to describe the likelihood function as the product of the marginal distribution of one outcome and the conditional distribution of the second outcome given the previous one. Factorization model captures the additional information contained in the correlation between the outcomes, it is more efficient than models that ignore potential dependencies between the outcomes. In our context, factorization model accounts for variability in PK data by considering the influence of immunogenicity. Based on our simulation studies, the factorization model provides more accurate and efficient estimates of the treatment effect in the PK data by taking into account the impact of immunogenicity. These findings are supported by two PK similarity clinical studies with a highly immunogenic biologic.
Burden, clinical presentation and risk factors of advanced HIV disease in pregnant Mozambican women
Authors: Nhampossa Tacilta , González Raquel , Nhacolo Arsenio , Garcia-Otero Laura , Quintó Llorenç , Mazuze Maura , Mendes Anete , Casellas Aina , Bambo Gizela , Couto Aleny , Sevene Esperança , Munguambe Khátia , Menendez Clara
Published: October 2022

Background

Information on the frequency and clinical features of advanced HIV disease (AHD) in pregnancy and its effects on maternal and perinatal outcomes is limited. The objective of this study was to describe the prevalence and clinical presentation of AHD in pregnancy, and to assess the impact of AHD in maternal and perinatal outcomes in Mozambican pregnant women.

Methods

This is a prospective and retrospective cohort study including HIV-infected pregnant women who attended the antenatal care (ANC) clinic at the Manhiça District Hospital between 2015 and 2020. Women were followed up for 36 months. Levels of CD4 + cell count were determined to assess AHD immune-suppressive changes. Risk factors for AHD were analyzed and the immune-suppressive changes over time and the effect of AHD on pregnancy outcomes were assessed.

Results

A total of 2458 HIV-infected pregnant women were enrolled. The prevalence of AHD at first ANC visit was 14.2% (349/2458). Among women with AHD at enrolment, 76.2% (260/341) were on antiretroviral therapy (ART). The proportion of women with AHD increased with age reaching 20.5% in those older than 35 years of age (p < 0.001). Tuberculosis was the only opportunistic infection diagnosed in women with AHD [4.9% (17/349)]. There was a trend for increased CD4 + cell count in women without AHD during the follow up period; however, in women with AHD the CD4 + cell count remained below 200 cells/mm3 (p < 0.001). Forty-two out of 2458 (1.7%) of the women were severely immunosuppressed (CD4 + cell count < 50 cells/mm3). No significant differences were detected between women with and without AHD in the frequency of maternal mortality, preterm birth, low birth weight and neonatal HIV infection.

Conclusions

After more than two decades of roll out of ART in Mozambique, over 14% and nearly 2% of HIV-infected pregnant women present at first ANC clinic visit with AHD and severe immunosuppression, respectively. Prompt HIV diagnosis in women of childbearing age, effective linkage to HIV care with an optimal ART regimen and close monitoring after ART initiation may contribute to reduce this burden and improve maternal and child survival.
Psychometric properties of the Last-7-Day Sedentary Time Questionnaire (SIT-Q-7d): Testing the validity and reliability among general population
Authors: Bakhtari Aghdam Fatemeh , Aziz-Zadeh Sepideh , Musavi Saeed , Abbasalizad-Farhangi Mahdieh
Published: October 2022

Backgrounds

Sedentary behavior (SB) is an independent risk factor causing chronic diseases. Previous studies compared sitting time mostly with physical activity. The present study aimed to evaluate the validity and reliability of the Last-7-Day Sedentary Time Questionnaire (SIT-Q-7d) in Iran. Moreover, SB was assessed among the study participants.

Methods

The current validity study was conducted among 290 subjects (51.7% males vs. 48.3% females) with a mean age of 34.81 ± 9.63 years in Poldasht, Iran. Sampling was done using simple random sampling and the data were collected using the SIT-Q-7d. To confirm the validity of the questionnaire, forward–backward translation method, content validity, and construct validity were used. Furthermore, temporal stability was calculated by the test–retest method and internal consistency coefficient (ICC).

Results

Our results confirmed the content validity of the questionnaire (content validity score: 0.90 and content validity index: 0.80). Using exploratory factor analysis (EFA), seven factors of SB were identified as follows: eating while sitting down, doing domestic affairs, screen time, leisure time, studying books, watching TV, and attending family gatherings. The reliability of the questionnaire was confirmed using Cronbach’s alpha (α = 0.7). In addition, temporal stability was confirmed by test–retest method and ICC was 0.9 (95% CI: 83–97).

Conclusion

Our results confirmed that the Persian version of SIT-Q-7d is a reliable and valid tool for assessing SB.
Surgical outcomes between posterior decompression alone and posterior decompression with fusion surgery among patients with Meyerding grade 2 degenerative spondylolisthesis: a multicenter cohort study
Authors: Tozawa Keiichiro , Matsubayashi Yoshitaka , Kato So , Doi Toru , Taniguchi Yuki , Kumanomido Yudai , Higashikawa Akiro , Yosihida Yuichi , Kawamura Naohiro , Sasaki Katsuyuki , Azuma Seiichi , Yu Jim , Hara Nobuhiro , Iizuka Masaaki , Ono Takashi , Fukushima Masayoshi , Takeshita Yujiro , Tanaka Sakae , Oshima Yasushi
Published: October 2022

Background

Whether lumbar decompression with fusion surgery is effective against Meyerding grade 2 degenerative spondylolisthesis (DS) is unknown. Therefore, the current study aimed to compare the surgical outcomes between posterior decompression alone and posterior decompression with fusion surgery among patients with grade 2 DS with central canal stenosis.

Methods

This retrospective cohort study included prospectively registered patients (n = 3863) who underwent surgery for degenerative lumbar spinal canal stenosis at nine high-volume spine centers from April 2017 to July 2019. Patients with grade 2 DS and central canal stenosis were included in the analysis. Patients with radiculopathy, including foraminal stenosis, degenerative scoliosis, and concomitant anterior spinal fusion, and those with a previous history of lumbar surgery were excluded. The participants were divided into the decompression alone group (group D) and decompression with fusion surgery group (group F). Data about patient-reported outcomes, including Numeric Rating Scale (low back pain, leg pain, leg numbness, and foot numbness), Oswestry Disability Index, EuroQol Five-Dimensional questionnaire, and 12-Item Short-Form Health Survey scores, were obtained preoperatively and 2 years postoperatively.

Results

In total, 2354 (61%) patients, including 42 (1.8%) with grade 2 DS (n = 18 in group D and n = 24 in group F), completed the 2-year follow-up. Group D had a higher proportion of female patients than group F. However, the two groups did not significantly differ in terms of other baseline demographic characteristics. Group D had a significantly shorter surgical time and lower volume of intraoperative blood loss than group F. Postoperative patient-reported outcomes did not significantly differ between the two groups, although the preoperative degree of low back pain was higher in group F than in group D. The slip degree of group D did not worsen during the follow-up period.

Conclusion

The surgical outcomes were similar regardless of the addition of fusion surgery among patients with grade 2 DS. Decompression alone was superior to decompression with fusion surgery as it was associated with a lower volume of intraoperative blood loss and shorter surgical time.
Novel scoring system combined with a virtual reality technique for the preoperative evaluation of the stone-free status after flexible ureteroscopy: the H.L.P.E.S. score
Authors: Gu Jianglin , Luo Shengjun , Jiang Li , Hu Daixing , Zhao Guozhi , Tang Wei
Published: October 2022

Objective

The original S.O.L.V.E. scoring system was modified using virtual reality technology, and a new H.L.P.E.S scoring system was constructed to improve the accuracy of predicting the stone-free rate after flexible ureteroscopy.

Methods

We retrospectively analyzed clinical and virtual reality data of 150 patients with renal calculi who underwent flexible ureteroscopy at the First Affiliated Hospital of Chongqing Medical University, Chongqing, China, from September 2019 to January 2022. Factors affecting the stone-free rate were evaluated in univariate and multiple logical regression analyses. Factors were divided by cut-off value under the receiver-operating characteristic curve and scored accordingly to a well-known international scoring system. Area under the curve predicted the stone-free rate. The accuracy and superiority of the stone-free rate after flexible ureterorenoscopy was compared between this scoring system and the S.O.L.V.E, R.I.R.S, T.O.HO, and RUSS scores.

Results

Multiple logistic regression showed that the stone surface area, renal pelvis volume, and length of the calyces funnel were correlated with stone-free rate (P < 0.01, P = 0.021, P = 0.019, respectively). The H.L.P.E.S. score included stone surface area (1–2 points), renal pelvis volume (1–2 points), length of calyces funnel (1–2 points), pelvic calyceal height (1–2 points), and essence of stone (1–2 points). The area under the receiver-operating characteristic curve of H.L.P.E.S. score was 0.927, which was higher than the S.O.L.V.E., R.I.R.S., T.O.HO, and RUSS scores.

Conclusion

H.L.P.E.S. scoring can effectively predict the stone-free rate after flexible ureteroscopy for renal calculi and is superior to other scoring systems.
Up-regulation of miR-133a-3p promotes ovary insulin resistance on granulosa cells of obese PCOS patients via inhibiting PI3K/AKT signaling
Authors: Yang Xiaoman , Wang Kehua , Lang Jiajia , Guo Danyang , Gao Haixia , Qiu Yue , Jin Xiaohan , Zhang Mingyue , Shi Jiaxiu , Ma QianQian , Ma Qian , Wen Zixi
Published: October 2022

Background

MicroRNAs are a type of non-coding single-stranded RNA, which is involved in the regulation of ovary insulin resistance (IR). This study aims to explore the underlying mechanisms of miR-133a-3p regulating ovary IR in obese polycystic ovary syndrome (PCOS).

Methods

Granulosa cells (GCs) were extracted from follicular fluids of PCOS patients (obese PCOS group and non-obese PCOS group) and healthy women (control group). The expression of miR-133a-3p in GCs was detected by qRT-PCR. The targets and pathways of miR-133a-3p were predicted by bioinformatics analyses. The protein levels of PI3K, p-AKT, GLUT4, p-GSK-3β, and p-FOXO1 were measured by Western blotting.

Results

MiR-133a-3p was highly expressed in GCs from PCOS patients, especially in obese PCOS patients. The protein levels of PI3K and p-AKT was downregulated in GCs from PCOS patients. There were 11 target genes of miR-133a-3p enriching in PI3K/AKT signaling pathway. miR-133a-3p mimic downregulated the expression of PI3K, p-AKT, and GLUT4, and upregulated the protein levels of p-GSK-3β and p-FOXO1. miR-133a-3p inhibitor presented the opposite effect of miR-133a-3p mimic.

Conclusion

MiR-133a-3p promotes ovary IR on GCs of obese PCOS patients via inhibiting PI3K/AKT signaling pathway. This study lays a foundation for further research on the mechanism of ovary IR in obese PCOS patients.
Investigating the role of health information technology in the control and management of Systemic Lupus Erythematosus (SLE): a systematic review
Authors: Moulaei Khadijeh , Rajaei Elham , Ahmadian Leila , Khajouei Reza
Published: October 2022

Background

Despite the use of health information technology (HIT) for controlling and managing lupus, its effectiveness has not been well studied. The objective of this study was to investigate the role of HIT in controlling and managing lupus.

Methods

We searched Scopus, PubMed, Web of Science, and Embase, using "self-management", "self-care" and "Systemic Lupus Erythematosus" keywords. Two researchers selected relevant papers and extracted data using a data collection form. Disagreements were resolved in consultation with the third and fourth researchers. After extraction, the data were analyzed.

Results

Totally, 23 papers met the inclusion criteria. About 75% of the studies used web and telephone-based technologies. Most services provided with health technologies were ‘Training’ and ‘consulting’. The ‘lifestyle" and ‘Consultation and education’ axes were the most widely used HIT services to control and manage lupus. While, ‘Better management and control of the disease’, ‘Increasing knowledge and awareness of people about lupus’ and ‘Improving behaviors and attitudes toward self-management and self-care’ were also the most important outcomes. ‘Collectiing patient data and information’, 'Providing education and consultation services to patients', 'Measuring patient-reported outcomes', and 'Increasing patients' knowledge and awareness of their disease' were the most important advantages of various technologies. 'Slow internet speed' and 'Challenges and problems related to appearance and usability' and 'Patient concerns about privacy and misuse of their data' were three disadvantages of technologies.

Conclusion

The findings showed that HIT can improve the management and control of lupus and facilitate self-efficacy, self-care, and self-management in patients. The axes and data elements identified in this study can be the basis for developing and implementing efficient HIT-based systems to improve, control, and manage lupus.
Workload and quality of nursing care: the mediating role of implicit rationing of nursing care, job satisfaction and emotional exhaustion by using structural equations modeling approach
Authors: Maghsoud Fatemeh , Rezaei Mahboubeh , Asgarian Fatemeh Sadat , Rassouli Maryam
Published: October 2022

Background

Nursing workload and its effects on the quality of nursing care is a major concern for nurse managers. Factors which mediate the relationship between workload and the quality of nursing care have not been extensively studied. This study aimed to investigate the mediating role of implicit rationing of nursing care, job satisfaction and emotional exhaustion in the relationship between workload and quality of nursing care.

Methods

In this cross-sectional study, 311 nurses from four different hospitals in center of Iran were selected by convenience sampling method. Six self-reported questionnaires were completed by the nurses. The data were analyzed by SPSS version 16. Structural equation modeling was used to determine the relationships between the components using Stata 14 software.

Results

Except direct and mutual relationship between workload and quality of nursing care (P ≥ 0.05), the relationship between other variables was statistically significant (P < 0.05). The hypothesized model fitted the empirical data and confirmed the mediating role of implicit rationing of nursing care, job satisfaction and emotional exhaustion in the relationship between workload and the quality of nursing care (TLI, CFI > 0.9 and RMSEA < 0.08 and χ2/df < 3).

Conclusion

Workload affects the quality of the provided nursing care by affecting implicit rationing of nursing care, job satisfaction and emotional exhaustion. Nurse managers need to acknowledge the importance of quality of nursing care and its related factors. Regular supervision of these factors and provision of best related strategies, will ultimately lead to improve the quality of nursing care.
Healthcare resource utilization and costs among patients with heart failure with preserved, mildly reduced, and reduced ejection fraction in Spain
Authors: Escobar Carlos , Palacios Beatriz , Varela Luis , Gutiérrez Martín , Duong Mai , Chen Hungta , Justo Nahila , Cid-Ruzafa Javier , Hernández Ignacio , Hunt Phillip R. , Delgado Juan F.
Published: October 2022

Aims

To describe healthcare resource utilization (HCRU) of patients with heart failure with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF) in Spain. 

Methods

Adults with ≥ 1 HF diagnosis and ≥ 1 year of continuous enrolment before the corresponding index date (1/January/2016) were identified through the BIG-PAC database. Rate per 100 person-years of all-cause and HF-related HCRU during the year after the index date were estimated using bootstrapping with replacement.

Results

Twenty-one thousand two hundred ninety-seven patients were included, of whom 48.5% had HFrEF, 38.6% HFpEF and 4.2% HFmrEF, with the rest being of unknown EF. Mean age was 78.8 ± 11.8 years, 53.0% were men and 83.0% were in NYHA functional class II/III. At index, 67.3% of patients were taking renin angiotensin system inhibitors, 61.2% beta blockers, 23.4% aldosterone antagonists and 5.2% SGLT2 inhibitors. Rates of HF-related outpatient visits and hospitalization were 968.8 and 51.6 per 100 person-years, respectively. Overall, 31.23% of patients were hospitalized, mainly because of HF (87.88% of total hospitalizations); HF hospitalization length 21.06 ± 17.49 days (median 16; 25th, 75th percentile 9–27). HF hospitalizations were the main cost component: inpatient 73.64%, pharmacy 9.67%, outpatient 9.43%, and indirect cost 7.25%. Rates of all-cause and HF-related HCRU and healthcare cost were substantial across all HF subgroups, being higher among HFrEF compared to HFmrEF and HFpEF patients.

Conclusions

HCRU and cost associated with HF are high in Spain, HF hospitalizations being the main determinant. Medication cost represented only a small proportion of total costs, suggesting that an optimization of HF therapy may reduce HF burden.
Chromosome-level assemblies from diverse clades reveal limited structural and gene content variation in the genome of Candida glabrata
Authors: Marcet-Houben Marina , Alvarado María , Ksiezopolska Ewa , Saus Ester , de Groot Piet W. J. , Gabaldón Toni
Published: October 2022

Background

Candida glabrata is an opportunistic yeast pathogen thought to have a large genetic and phenotypic diversity and a highly plastic genome. However, the lack of chromosome-level genome assemblies representing this diversity limits our ability to accurately establish how chromosomal structure and gene content vary across strains.

Results

Here, we expanded publicly available assemblies by using long-read sequencing technologies in twelve diverse strains, obtaining a final set of twenty-one chromosome-level genomes spanning the known C. glabrata diversity. Using comparative approaches, we inferred variation in chromosome structure and determined the pan-genome, including an analysis of the adhesin gene repertoire. Our analysis uncovered four new adhesin orthogroups and inferred a rich ancestral adhesion repertoire, which was subsequently shaped through a still ongoing process of gene loss, gene duplication, and gene conversion.

Conclusions

C. glabrata has a largely stable pan-genome except for a highly variable subset of genes encoding cell wall-associated functions. Adhesin repertoire was established for each strain and showed variability among clades.
Dietary-derived vitamin B12 protects Caenorhabditis elegans from thiol-reducing agents
Authors: Winter Alan D. , Tjahjono Elissa , Beltrán Leonardo J. , Johnstone Iain L. , Bulleid Neil J. , Page Antony P.
Published: October 2022

Background

One-carbon metabolism, which includes the folate and methionine cycles, involves the transfer of methyl groups which are then utilised as a part of multiple physiological processes including redox defence. During the methionine cycle, the vitamin B12-dependent enzyme methionine synthetase converts homocysteine to methionine. The enzyme S-adenosylmethionine (SAM) synthetase then uses methionine in the production of the reactive methyl carrier SAM. SAM-binding methyltransferases then utilise SAM as a cofactor to methylate proteins, small molecules, lipids, and nucleic acids.

Results

We describe a novel SAM methyltransferase, RIPS-1, which was the single gene identified from forward genetic screens in Caenorhabditis elegans looking for resistance to lethal concentrations of the thiol-reducing agent dithiothreitol (DTT). As well as RIPS-1 mutation, we show that in wild-type worms, DTT toxicity can be overcome by modulating vitamin B12 levels, either by using growth media and/or bacterial food that provide higher levels of vitamin B12 or by vitamin B12 supplementation. We show that active methionine synthetase is required for vitamin B12-mediated DTT resistance in wild types but is not required for resistance resulting from RIPS-1 mutation and that susceptibility to DTT is partially suppressed by methionine supplementation. A targeted RNAi modifier screen identified the mitochondrial enzyme methylmalonyl-CoA epimerase as a strong genetic enhancer of DTT resistance in a RIPS-1 mutant. We show that RIPS-1 is expressed in the intestinal and hypodermal tissues of the nematode and that treating with DTT, β-mercaptoethanol, or hydrogen sulfide induces RIPS-1 expression. We demonstrate that RIPS-1 expression is controlled by the hypoxia-inducible factor pathway and that homologues of RIPS-1 are found in a small subset of eukaryotes and bacteria, many of which can adapt to fluctuations in environmental oxygen levels.

Conclusions

This work highlights the central importance of dietary vitamin B12 in normal metabolic processes in C. elegans, defines a new role for this vitamin in countering reductive stress, and identifies RIPS-1 as a novel methyltransferase in the methionine cycle.
Genome-wide association mapping reveals genes underlying population-level metabolome diversity in a fungal crop pathogen
Authors: Singh Nikhil Kumar , Tralamazza Sabina Moser , Abraham Leen Nanchira , Glauser Gaétan , Croll Daniel
Published: October 2022

Background

Fungi produce a wide range of specialized metabolites (SMs) involved in biotic interactions. Pathways for the production of SMs are often encoded in clusters of tightly arranged genes identified as biosynthetic gene clusters. Such gene clusters can undergo horizontal gene transfers between species and rapid evolutionary change within species. The acquisition, rearrangement, and deletion of gene clusters can generate significant metabolome diversity. However, the genetic basis underlying variation in SM production remains poorly understood.

Results

Here, we analyzed the metabolite production of a large population of the fungal pathogen of wheat, Zymoseptoria tritici. The pathogen causes major yield losses and shows variation in gene clusters. We performed untargeted ultra-high performance liquid chromatography-high resolution mass spectrometry to profile the metabolite diversity among 102 isolates of the same species. We found substantial variation in the abundance of the detected metabolites among isolates. Integrating whole-genome sequencing data, we performed metabolite genome-wide association mapping to identify loci underlying variation in metabolite production (i.e., metabolite-GWAS). We found that significantly associated SNPs reside mostly in coding and gene regulatory regions. Associated genes encode mainly transport and catalytic activities. The metabolite-GWAS identified also a polymorphism in the 3′UTR region of a virulence gene related to metabolite production and showing expression variation.

Conclusions

Taken together, our study provides a significant resource to unravel polymorphism underlying metabolome diversity within a species. Integrating metabolome screens should be feasible for a range of different plant pathogens and help prioritize molecular studies.
Dissection of a sensorimotor circuit underlying pathogen aversion in C. elegans
Authors: Filipowicz Adam , Lalsiamthara Jonathan , Aballay Alejandro
Published: October 2022

Background

Altering animal behavior to reduce pathogen exposure is a key line of defense against pathogen attack. In Caenorhabditis elegans, alterations in intestinal physiology caused by pathogen colonization and sensation of microbial metabolites may lead to activation of pathogen aversive behaviors ranging from aversive reflexes to learned avoidance. However, the neural circuitry between chemosensory neurons that sense pathogenic bacterial cues and the motor neurons responsible for avoidance-associated locomotion remains unknown.

Results

Using C. elegans, we found that backward locomotion was a component of learned pathogen avoidance, as animals pre-exposed to Pseudomonas aeruginosa or Enterococcus faecalis showed reflexive aversion to drops of the bacteria driven by chemosensory neurons, including the olfactory AWB neurons. This response also involved intestinal distention and, for E. faecalis, required expression of TRPM channels in the intestine and excretory system. Additionally, we uncovered a circuit composed of olfactory neurons, interneurons, and motor neurons that controls the backward locomotion crucial for learned reflexive aversion to pathogenic bacteria, learned avoidance, and the repulsive odor 2-nonanone.

Conclusions

Using whole-brain simulation and functional assays, we uncovered a novel sensorimotor circuit governing learned reflexive aversion. The discovery of a complete sensorimotor circuit for reflexive aversion demonstrates the utility of using the C. elegans connectome and computational modeling in uncovering new neuronal regulators of behavior.
Gene loss, pseudogenization, and independent genome reduction in non-photosynthetic species of Cryptomonas (Cryptophyceae) revealed by comparative nucleomorph genomics
Authors: Kim Jong Im , Tanifuji Goro , Jeong Minseok , Shin Woongghi , Archibald John M.
Published: October 2022

Background

Cryptophytes are ecologically important algae of interest to evolutionary cell biologists because of the convoluted history of their plastids and nucleomorphs, which are derived from red algal secondary endosymbionts. To better understand the evolution of the cryptophyte nucleomorph, we sequenced nucleomorph genomes from two photosynthetic and two non-photosynthetic species in the genus Cryptomonas. We performed a comparative analysis of these four genomes and the previously published genome of the non-photosynthetic species Cryptomonas paramecium CCAP977/2a.

Results

All five nucleomorph genomes are similar in terms of their general architecture, gene content, and gene order and, in the non-photosynthetic strains, loss of photosynthesis-related genes. Interestingly, in terms of size and coding capacity, the nucleomorph genome of the non-photosynthetic species Cryptomonas sp. CCAC1634B is much more similar to that of the photosynthetic C. curvata species than to the non-photosynthetic species C. paramecium.

Conclusions

Our results reveal fine-scale nucleomorph genome variation between distantly related congeneric taxa containing photosynthetic and non-photosynthetic species, including recent pseudogene formation, and provide a first glimpse into the possible impacts of the loss of photosynthesis on nucleomorph genome coding capacity and structure in independently evolved colorless strains.
Identifying optimal vaccination scenarios to reduce varicella zoster virus transmission and reactivation
Authors: Bakker Kevin M , Eisenberg Marisa C , Woods Robert J , Martinez Micaela E
Published: October 2022

Background

Varicella zoster virus (VZV) is one of the eight known human herpesviruses. Initial VZV infection results in chickenpox, while viral reactivation following a period of latency manifests as shingles. Separate vaccines exist to protect against both initial infection and subsequent reactivation. Controversy regarding chickenpox vaccination is contentious with most countries not including the vaccine in their childhood immunization schedule due to the hypothesized negative impact on immune-boosting, where VZV reactivation is suppressed through exogenous boosting of VZV antibodies from exposure to natural chickenpox infections.

Methods

Population-level chickenpox and shingles notifications from Thailand, a country that does not vaccinate against either disease, were previously fitted with mathematical models to estimate rates of VZV transmission and reactivation. Here, multiple chickenpox and shingles vaccination scenarios were simulated and compared to a model lacking any vaccination to analyze the long-term impacts of VZV vaccination.

Results

As expected, simulations suggested that an introduction of the chickenpox vaccine, at any coverage level, would reduce chickenpox incidence. However, chickenpox vaccine coverage levels above 35% would increase shingles incidence under realistic estimates of shingles coverage with the current length of protective immunity from the vaccine. A trade-off between chickenpox and shingles vaccination coverage was discovered, where mid-level chickenpox coverage levels were identified as the optimal target to minimize total zoster burden. Only in scenarios where shingles vaccine provided lifelong immunity or coverage exceeded current levels could large reductions in both chickenpox and shingles be achieved.

Conclusions

The complicated nature of VZV makes it impossible to select a single vaccination scenario as universal policy. Strategies focused on reducing both chickenpox and shingles incidence, but prioritizing the latter should maximize efforts towards shingles vaccination, while slowly incorporating chickenpox vaccination. Alternatively, countries may wish to minimize VZV complications of both chickenpox and shingles, which would lead to maximizing vaccine coverage levels across both diseases. Balancing the consequences of vaccination to overall health impacts, including understanding the impact of an altered mean age of infection for both chickenpox and shingles, would need to be considered prior to any vaccine introduction.
Identification of core genes and pathways between geriatric multimorbidity and renal insufficiency: potential therapeutic agents discovered using bioinformatics analysis
Authors: Zhang Lingyun , Cai Jiasheng , Xiao Jing , Ye Zhibin
Published: October 2022

Background

Geriatric people are prone to suffer from multiple chronic diseases, which can directly or indirectly affect renal function. Through bioinformatics analysis, this study aimed to identify key genes and pathways associated with renal insufficiency in patients with geriatric multimorbidity and explore potential drugs against renal insufficiency.

Methods

The text mining tool Pubmed2Ensembl was used to detect genes associated with the keywords including "Geriatric", "Multimorbidity" and "Renal insufficiency". The GeneCodis program was used to specify Gene Ontology (GO) biological process terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Protein–protein interaction (PPI) networks were constructed using STRING and visualized in Cytoscape. Module analysis was performed using CytoHubba and Molecular Complex Detection (MCODE) plugins. GO and KEGG analysis of gene modules was performed using the Database for Annotation, Visualization and Integrated Discover (DAVID) platform database. Genes clustered in salient modules were selected as core genes. Then, the functions and pathways of core genes were visualized using ClueGO and CluePedia. Finally, the drug-gene interaction database was used to explore drug-gene interactions of the core genes to identify drug candidates for renal insufficiency in patients with geriatric multimorbidity.

Results

Through text mining, 351 genes associated with "Geriatric", "Multimorbidity" and "Renal insufficiency" were identified. A PPI network consisting of 216 nodes and 1087 edges was constructed and CytoHubba was used to sequence the genes. Five gene modules were obtained by MCODE analysis. The 26 genes clustered in module1 were selected as core candidate genes primarily associated with renal insufficiency in patients with geriatric multimorbidity. The HIF-1, PI3K-Akt, MAPK, Rap1, and FoxO signaling pathways were enriched. We found that 21 of the 26 selected genes could be targeted by 34 existing drugs.

Conclusion

This study indicated thatCST3,SERPINA1,FN1,PF4,IGF1,KNG1,IL6,VEGFA,ALB,TIMP1,TGFB1,HGF,SERPINE1,APOA1,APOB,FGF23,EGF,APOE,VWF,TF,CP,GAS6,APP,IGFBP3,P4HB,andSPP1were key genes potentially involved with renal insufficiency in patients with geriatric multimorbidity. In addition, 34 drugs were identified as potential agents for the treatment and management of renal insufficiency.
Real-world characteristics, modern antidiabetic treatment patterns, and comorbidities of patients with type 2 diabetes in central and Eastern Europe: retrospective cross-sectional and longitudinal evaluations in the CORDIALLY® study
Authors: Prázný Martin , Suplotova Lyudmila , Gumprecht Janusz , Kamenov Zdravko , Fülöp Tibor , Medvedchikov Alexey , Rosenzweig Doron , Aleksandric Milos
Published: October 2022

Background

Guidelines from 2016 onwards recommend early use of SGLT2i or GLP-1 RA for patients with type 2 diabetes (T2D) and cardiovascular disease (CVD), to reduce CV events and mortality. Many eligible patients are not treated accordingly, although data are lacking for Central and Eastern Europe (CEE).

Methods

The CORDIALLY non-interventional study evaluated the real-world characteristics, modern antidiabetic treatment patterns, and the prevalence of CVD and chronic kidney disease (CKD) in adults with T2D at nonhospital-based practices in CEE. Data were retrospectively collated by medical chart review for patients initiating empagliflozin, another SGLT2i, DPP4i, or GLP-1 RA in autumn 2018. All data were analysed cross-sectionally, except for discontinuations assessed 1 year ± 2 months after initiation.

Results

Patients (N = 4055) were enrolled by diabetologists (56.7%), endocrinologists (40.7%), or cardiologists (2.5%). Empagliflozin (48.5%) was the most prescribed medication among SGLT2i, DPP4i, and GLP-1 RA; > 3 times more patients were prescribed empagliflozin than other SGLT2i (10 times more by cardiologists). Overall, 36.6% of patients had diagnosed CVD. Despite guidelines recommending SGLT2i or GLP-1 RA, 26.8% of patients with CVD received DPP4i. Patients initiating DPP4i were older (mean 66.4 years) than with SGLT2i (62.4 years) or GLP-1 RA (58.3 years). CKD prevalence differed by physician assessment (14.5%) or based on eGFR and UACR (27.9%). Many patients with CKD (≥ 41%) received DPP4i, despite guidelines recommending SGLT2is owing to their renal benefits. 1 year ± 2-months after initiation, 10.0% (7.9–12.3%) of patients had discontinued study medication: 23.7–45.0% due to ‘financial burden of co-payment’, 0–1.9% due to adverse events (no patients discontinued DPP4i due to adverse events). Treatment guidelines were ‘highly relevant’ for a greater proportion of cardiologists (79.4%) and endocrinologists (72.9%) than diabetologists (56.9%), and ≤ 20% of physicians consulted other physicians when choosing and discontinuing treatments.

Conclusions

In CORDIALLY, significant proportions of patients with T2D and CVD/CKD who initiated modern antidiabetic medication in CEE in autumn 2018 were not treated with cardioprotective T2D medications. Use of DPP4i instead of SGLT2i or GLP-1 RA may be related to lack of affordable access, the perceived safety of these medications, lack of adherence to the latest treatment guidelines, and lack of collaboration between physicians. Thus, many patients with T2D and comorbidities may develop preventable complications or die prematurely.

Trial registration NCT03807440.
The journey of CAR-T therapy in hematological malignancies
Authors: Lu Junru , Jiang Guan
Published: October 2022

Chimeric antigen receptor T (CAR-T) cells therapy has revolutionized the treatment paradigms for hematological malignancies, with multi-line therapy-refractory patients achieving durable complete remissions (CR) and relatively high objective response rate (ORR). So far, many CAR-T products, such as Kymriah, Yescarta and Tecartus, have been developed and got the unprecedented results. However, some patients may relapse afterwards, driving intense investigations into promoting the development of novel strategies to overcome resistance and mechanisms of relapse. Notable technical progress, such as nanobodies and CRISPR-Case9, has also taken place to ensure CAR-T cell therapy fully satisfies its medical potential. In this review, we outline the basic principles for the development and manufacturing processes of CAR-T cell therapy, summarize the similarities and differences in efficacy of different products as well as their corresponding clinical results, and discuss CAR-T immunotherapy combined with other clinical effects of drug therapy.
Mediation analysis of erythrocyte lipophilic index on the association between BMI and risk of oral cancer
Authors: Fan Yi , Chen Qing , Wang Yaping , Wang Jing , Li Yanni , Wang Sijie , Weng Yanfeng , Yang Qiujiao , Chen Chen , Lin Lisong , Qiu Yu , Chen Fa , Wang Jing , He Baochang , Liu Fengqiong
Published: October 2022

Aims

To explore the relationship between the fatty acid lipophilic index (LI) of the erythrocyte membrane and oral cancer risk, as well as to evaluate the possibility of LI acting as a mediator of the association between body mass index (BMI) and oral cancer.

Method

Twenty-three fatty acids (FAs) of the erythrocyte membrane were measured using gas chromatography in 380 patients with oral cancer and 387 control subjects. The LI was calculated based on the FA proportion and FA melting points. The association of BMI and erythrocyte LI with oral cancer risk was analysed using logistic regression. The mediation effect of LI on the association between BMI and oral cancer risk was evaluated using mediation analysis.

Results

Among the control group, 46.0% were overweight or obese, which was significantly higher than that of oral cancer patients (29.5%). Significant differences in erythrocyte membrane saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) were observed between the patient and control groups. The proportion of C18:1 n-9 from the MUFA family increased in oral cancer patients (12.67%) compared with controls (12.21%). While the total proportion of n-3 PUFAs decreased in oral cancer patients compared with controls, with C20:5 n-3 decreasing from 0.66 to 0.47%, and C22:6 n-3 decreasing from 5.82 to 4.86%. The LI was lower in the control participants (M = 27.6, IQR: 27.3–27.9) than in the oral cancer patients (M = 28.2, IQR: 27.9–28.5). BMI was inversely associated with oral cancer risk with a fully adjustedORof 0.59 (95%CI: 0.43–0.83), while LI was positively associated with oral cancer risk with a fully adjustedORof 1.99 (95%CI:1.36–2.94). LI explained 7% of the variance in the relationship between BMI and oral cancer risk.

Conclusions

The distribution of the FA profile in erythrocyte membranes differed between the oral cancer patients and the control group. The LI derived from the profile of FAs was positively associated with the risk of oral cancer, and the associations between BMI and oral cancer risk can be explained, at least in part, by LI.