bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting the gut-lung axis by synbiotic feeding to infants in a randomized controlled trial
Authors: Sjödin Kotryna Simonyté , Sjödin Andreas , Ruszczyński Marek , Kristensen Mette Bach , Hernell Olle , Szajewska Hania , West Christina E.
Published: February 2023

Background

Formula-fed infants are at increased risk of infections. Due to the cross-talk between the mucosal systems of the gastrointestinal and respiratory tracts, adding synbiotics (prebiotics and probiotics) to infant formula may prevent infections even at distant sites. Infants that were born full term and weaned from breast milk were randomized to prebiotic formula (fructo- and galactooligosaccharides) or the same prebiotic formula with Lactobacillus paracasei ssp. paracasei F19 (synbiotics) from 1 to 6 months of age. The objective was to examine the synbiotic effects on gut microbiota development.

Results

Fecal samples collected at ages 1, 4, 6, and 12 months were analyzed using 16S rRNA gene sequencing and a combination of untargeted gas chromatography-mass spectrometry/liquid chromatography-mass spectrometry. These analyses revealed that the synbiotic group had a lower abundance of Klebsiella, a higher abundance of Bifidobacterium breve compared to the prebiotic group, and increases in the anti-microbial metabolite d-3-phenyllactic acid. We also analyzed the fecal metagenome and antibiotic resistome in the 11 infants that had been diagnosed with lower respiratory tract infection (cases) and 11 matched controls using deep metagenomic sequencing. Cases with lower respiratory tract infection had a higher abundance of Klebsiella species and antimicrobial resistance genes related to Klebsiella pneumoniae, compared to controls. The results obtained using 16S rRNA gene amplicon and metagenomic sequencing were confirmed in silico by successful recovery of the metagenome-assembled genomes of the bacteria of interest.

Conclusions

This study demonstrates the additional benefit of feeding specific synbiotics to formula-fed infants over prebiotics only. Synbiotic feeding led to the underrepresentation of Klebsiella, enrichment of bifidobacteria, and increases in microbial degradation metabolites implicated in immune signaling and in the gut-lung and gut-skin axes. Our findings support future clinical evaluation of synbiotic formula in the prevention of infections and associated antibiotic treatment as a primary outcome when breastfeeding is not feasible.

Trial registration

ClinicalTrials.gov NCT01625273. Retrospectively registered on 21 June 2012.
Osteosarcoma transcriptome data exploration reveals STC2 as a novel risk indicator in disease progression
Authors: Wang Ziyue , Zeng Zixin , Gao Feng , Gui Ziwei , Du Juan , Shen Ningning , Shang Yangwei , Yang Zhiqing , Shang Lifang , Wei Rong , Ma Wenxia , Wang Chen
Published: February 2023

Background

Osteosarcoma has been the most common primary bone malignant tumor in children and adolescents. Despite the considerable improvement in the understanding of genetic events attributing to the rapid development of molecular pathology, the current information is still lacking, partly due to the comprehensive and highly heterogeneous nature of osteosarcoma. The study is to identify more potential responsible genes during the development of osteosarcoma, thus identifying promising gene indicators and aiding more precise interpretation of the disease.

Methods

Firstly, from GEO database, osteosarcoma transcriptome microarrays were used to screen the differential expression genes (DEGS) in cancer comparing to normal bone samples, followed by GO/KEGG interpretation, risk score assessment and survival analysis of the genes, for the purpose of selecting a credible key gene. Further, the basic physicochemical properties, predicted cellular location, gene expression in human cancers, the association with clinical pathological features and potential signaling pathways involved in the key gene’s regulation on osteosarcoma development were in succession explored.

Results

Based on the selected GEO osteosarcoma expression profiles, we identified the differential expression genes in osteosarcoma versus normal bone samples, and the genes were classified into four groups based on the difference level, further genes interpretation indicated that the high differently level (> 8 fold) genes were mainly located extracellular and related to matrix structural constituent regulation. Meanwhile, module function analysis of the 67 high differential level (> 8 fold) DEGS revealed a 22-gene containing extracellular matrix regulation associated hub gene cluster. Further survival analysis of the 22 genes revealed that STC2 was an independent prognosis indicator in osteosarcoma. Moreover, after validating the differential expression of STC2 in cancer vs. normal tissues using local hospital osteosarcoma samples by IHC and qRT-PCR experiment, the gene’s physicochemical property revealed STC2 as a cellular stable and hydrophilic protein, and the gene’s association with osteosarcoma clinical pathological parameters, expression in pan-cancers and the probable biological functions and signaling pathways it involved were explored.

Conclusion

Using multiple bioinformatic analysis and local hospital samples validation, we revealed the gain of expression of STC2 in osteosarcoma, which associated statistical significantly with patients survival, and the gene’s clinical features and potential biological functions were also explored. Although the results shall provide inspiring insights into further understanding of the disease, further experiments and detailed rigorous clinical trials are needed to reveal its potential drug-target role in clinical medical use.
A novel DNA damage repair gene-related prognostic model for evaluating the prognosis and tumor microenvironment infiltration of esophageal squamous cell carcinoma
Authors: Guo Dong , Zhang Xueyuan , Du Xingyu , Yao Weinan , Shen Wenbin , Zhu Shuchai
Published: February 2023

Background

This study aimed to investigate the potential prognostic value of DNA damage repair genes (DDRGs) in esophageal squamous cell carcinoma (ESCC) and their relationship with immune-related characteristics.

Methods

We analyzed DDRGs of the Gene Expression Omnibus database (GSE53625). Subsequently, the GSE53625 cohort was used to construct a prognostic model based on least absolute shrinkage and selection operator regression, and Cox regression analysis was used to construct a nomogram. The immunological analysis algorithms explored the differences between the potential mechanism, tumor immune activity, and immunosuppressive genes in the high- and low-risk groups. Of the prognosis model-related DDRGs, we selected PPP2R2A for further investigation. Functional experiments were conducted to evaluate the effect on ESCC cells in vitro.

Results

A 5-DDRG (ERCC5, POLK, PPP2R2A, TNP1 and ZNF350) prediction signature was established for ESCC, stratifying patients into two risk groups. Multivariate Cox regression analysis showed that the 5-DDRG signature was an independent predictor of overall survival. Immune cells such as CD4 T cells and monocytes displayed lower infiltration levels in the high-risk group. Additionally, the immune, ESTIMATE, and stromal scores in the high-risk group were all considerably higher than those in the low-risk group. Functionally, knockdown of PPP2R2A significantly suppressed cell proliferation, migration and invasion in two ESCC cell lines (ECA109 and TE1).

Conclusion

The clustered subtypes and prognostic model of DDRGs could effectively predict the prognosis and immune activity of ESCC patients.
The interplay of inflammation, exosomes and Ca2+ dynamics in diabetic cardiomyopathy
Authors: Sanganalmath Santosh K , Dubey Shubham , Veeranki Sudhakar , Narisetty Keerthy , Krishnamurthy Prasanna
Published: February 2023

Diabetes mellitus is one of the prime risk factors for cardiovascular complications and is linked with high morbidity and mortality. Diabetic cardiomyopathy (DCM) often manifests as reduced cardiac contractility, myocardial fibrosis, diastolic dysfunction, and chronic heart failure. Inflammation, changes in calcium (Ca2+) handling and cardiomyocyte loss are often implicated in the development and progression of DCM. Although the existence of DCM was established nearly four decades ago, the exact mechanisms underlying this disease pathophysiology is constantly evolving. Furthermore, the complex pathophysiology of DCM is linked with exosomes, which has recently shown to facilitate intercellular (cell-to-cell) communication through biomolecules such as micro RNA (miRNA), proteins, enzymes, cell surface receptors, growth factors, cytokines, and lipids. Inflammatory response and Ca2+ signaling are interrelated and DCM  has been known to adversely affect many of these signaling molecules either qualitatively and/or quantitatively. In this literature review, we have demonstrated that Ca2+ regulators are tightly controlled at different molecular and cellular levels during various biological processes in the heart. Inflammatory mediators, miRNA and exosomes are shown to interact with these regulators, however how these mediators are linked to Ca2+ handling during DCM pathogenesis remains elusive. Thus, further investigations are needed to understand the mechanisms to restore cardiac Ca2+ homeostasis and function, and to serve as potential therapeutic targets in the treatment of DCM.
MMP2 is a immunotherapy related biomarker and correlated with cancer-associated fibroblasts infiltrate in melanoma
Authors: Peng Kunwei , Zhang Yanyan , Liu Deyi , Chen Jingqi
Published: February 2023

Background

Mounting evidence supports that matrix metalloproteinase (MMPs) are highly associated with tumor progression and that targeting MMPs may overcome the barrier of immune suppression. Among these, whether MMP2 functions as an immunosuppressive role in melanoma, remains unclear.

Methods

The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) databases were used to assess the prognosis of MMP2 in melanoma, after which Tumor immune estimation resource (TIMER) was used to explore the relationship between MMP2 expression and cancer associated fibroblasts (CAFs) infiltration. Finally, we evaluated the efficacy of MMP2 inhibitor on CAFs infiltration and immunotherapy using a mouse melanoma model.

Results

In general, the expression of MMP2, MMP13, MMP16, MMP17 and MMP25 were significantly associated with skin cutaneous melanoma (SKCM) patients prognosis, among which MMP2 low expression benefited patients the most. Especially, the overall survival (OS) of BRAF mutation patients with high MMP2 expression was significantly lower than the MMP2 low expression group, but there was no significant difference in BRAF wild-type patients. KEGG and GO enrichment analysis indicated that MMP2 related genes were mostly associated with extracellular structure organization, collagen-containing extracellular matrix and extracellular matrix structural constituent. Furthermore, in almost all cancers, MMP2 expression was positively correlated with CAFs infiltration. MMP2 inhibitor works synergistically with PD-1 antibody and induces tumor regression in a mouse melanoma model, which is dependent on decreased CAFs infiltration.

Conclusions

This suggests that MMP2 plays a vital role in the regulation of CAFs infiltration, potentially participating in immunotherapy response, and thus representing a valuable target of immunotherapy in melanoma.
Metabolic responses in blood-stage malaria parasites associated with increased and decreased sensitivity to PfATP4 inhibitors
Authors: Tewari Shivendra G. , Elahi Rubayet , Kwan Bobby , Rajaram Krithika , Bhatnagar Suyash , Reifman Jaques , Prigge Sean T. , Vaidya Akhil B. , Wallqvist Anders
Published: February 2023

Background

Spiroindolone and pyrazoleamide antimalarial compounds target Plasmodium falciparum P-type ATPase (PfATP4) and induce disruption of intracellular Na+ homeostasis. Recently, a PfATP4 mutation was discovered that confers resistance to a pyrazoleamide while increasing sensitivity to a spiroindolone. Transcriptomic and metabolic adaptations that underlie this seemingly contradictory response of P. falciparum to sublethal concentrations of each compound were examined to understand the different cellular accommodation to PfATP4 disruptions.

Methods

A genetically engineered P. falciparum Dd2 strain (Dd2A211V) carrying an Ala211Val (A211V) mutation in PfATP4 was used to identify metabolic adaptations associated with the mutation that results in decreased sensitivity to PA21A092 (a pyrazoleamide) and increased sensitivity to KAE609 (a spiroindolone). First, sublethal doses of PA21A092 and KAE609 causing substantial reduction (30–70%) in Dd2A211V parasite replication were identified. Then, at this sublethal dose of PA21A092 (or KAE609), metabolomic and transcriptomic data were collected during the first intraerythrocytic developmental cycle. Finally, the time-resolved data were integrated with a whole-genome metabolic network model of P. falciparum to characterize antimalarial-induced physiological adaptations.

Results

Sublethal treatment with PA21A092 caused significant (p < 0.001) alterations in the abundances of 91 Plasmodium gene transcripts, whereas only 21 transcripts were significantly altered due to sublethal treatment with KAE609. In the metabolomic data, a substantial alteration (≥ fourfold) in the abundances of carbohydrate metabolites in the presence of either compound was found. The estimated rates of macromolecule syntheses between the two antimalarial-treated conditions were also comparable, except for the rate of lipid synthesis. A closer examination of parasite metabolism in the presence of either compound indicated statistically significant differences in enzymatic activities associated with synthesis of phosphatidylcholine, phosphatidylserine, and phosphatidylinositol.

Conclusion

The results of this study suggest that malaria parasites activate protein kinases via phospholipid-dependent signalling in response to the ionic perturbation induced by the Na+ homeostasis disruptor PA21A092. Therefore, targeted disruption of phospholipid signalling in PA21A092-resistant parasites could be a means to block the emergence of resistance to PA21A092.
Fusion plasmid enhanced the endemic extensively drug resistant Klebsiella pneumoniae clone ST147 harbored blaOXA-48 to acquire the hypervirulence and cause fatal infection
Authors: Liu Chao , Du Pengcheng , Yang Ping , Lu Ming , Shen Ning
Published: February 2023

Background

Klebsiella Pneumoniae (Kp) sequence type (ST) 147 has emerged globally and spread rapidly, particularly the extensively drug resistant (XDR) isolates. However, the infections caused by this subtype is rare reported in China for now. The clinical, microbiological and genomic characteristics are unclear.

Methods

A systemic retrospective study was conducted in a Chinese tertiary hospital. Clinical information of the infection cases was collected, and whole-genome sequencing and phenotypic experiments were performed on the ST147 isolates. The resistance and virulence genes were identified, and the plasmids harboring these genes were further studied.

Results

Six ST147 isolates from six patients among 720 available clincial Kp isolates were detected. Notably, two isolates, PEKP4035 and PEKP4265, represented both XDR and hypervirulence by acquiring blaOXA-48, blaCTX-M-15 and key virulence genes, iucA + rmpA2, representing no fitness cost and resulting fatal infection. Four of the six ST147 isolates presented with more nucleotide differences, whereas the PEKP4035 and PEKP4265 both isolated from the intensive care unit possessed 20 single nucleotide polymorphisms among one year, indicating the prolonged survive and transmission. Interestingly, the two isolates harbored the same fused plasmid composed of sul2 and iucA + rmpA2, which might be generated by recombination of a plasmid like KpvST101_OXA-48 with the pLVPK plasmid via IS26. Besides, two ~ 70 kb plasmids conferring multiple-drug resistance were also identified among the two isolates, which presented resistance genes including blaOXA-48, blaCTX-M-16, strA and strB. Interestingly, we reported that blaCTX-M-15, a common resistance gene within ST147, has successfully transferred into the chromosome by ISEcp1.

Conclusions

XDR hypervirulent ST147 Kp is emerging, suggesting enhanced surveillance is essential.
Comparison of in vitro activities of newer triazoles and classic antifungal agents against dermatophyte species isolated from Iranian University Hospitals: a multi-central study
Authors: Badiee Parisa , Shokohi Tahereh , Hashemi Jamal , Mohammadi Rasoul , Najafzadeh Mohammad Javad , Amin Shahidi Maneli , Ghasemi Fatemeh , Jafarian Hadis
Published: February 2023

Background

Dermatophytes have the ability to invade the keratin layer of humans and cause infections. The aims of this study were the accurate identification of dermatophytes by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism method and sequencing and comparison between the in vitro activities of newer and established antifungal agents against them.

Methods

Clinical specimens of patients from five Iranian university laboratories were entered in this study. Samples were cultured on sabouraud dextrose agar medium. For molecular identification, extracted DNAs were amplified by the universal fungal primers ITS1 and ITS4, and digested with MvaI enzymes. The antifungal susceptibility test for each isolate to terbinafine, griseofulvin, caspofungin, fluconazole, itraconazole, luliconazole, and isavuconazole was performed, according to the microdilution CLSI M38-A2 and CLSI M61 standard methods.

Results

Two hundred and seven fungi species similar to dermatophytes were isolated of which 198 (95.6%) were dermatophytes by molecular assay. The most commonly isolated were Trichophyton mentagrophytes (76/198), followed by Trichophyton interdigitale (57/198), Trichophyton rubrum (34/198), Trichophyton tonsurans (12/198), Microsporum canis (10/198), Trichophyton simii (3/198), Epidermophyton floccosum (3/198), Trichophyton violaceum (2/198), and Trichophyton benhamiae (1/198). The GM MIC and MIC90 values for all the isolates were as follows: terbinafine (0.091 and 1 μg/ml), griseofulvin (1.01 and 4 μg/ml), caspofungin (0.06 and 4 μg/ml), fluconazole (16.52 and 32 μg/ml), itraconazole (0.861 and 8 μg/ml), isavuconazole (0.074 and 2 μg/ml), and luliconazole (0.018 and 0.25 μg/ml).

Conclusion

Trichophyton mentagrophytes, Trichophyton interdigitale, and Trichophyton rubrum were the most common fungal species isolated from the patients. luliconazole, terbinafine, and isavuconazole in vitro were revealed to be the most effective antifungal agents against all dermatophyte isolates.
Genetic determinants of macrolide and tetracycline resistance in penicillin non-susceptible Streptococcus pneumoniae isolates from people living with HIV in Dar es Salaam, Tanzania
Authors: Manyahi Joel , Moyo Sabrina J. , Langeland Nina , Blomberg Bjørn
Published: February 2023

Background

Over one million yearly deaths are attributable to Streptococcus pneumoniae and people living with HIV are particularly vulnerable. Emerging penicillin non-susceptible Streptococcus pneumoniae (PNSP) challenges therapy of pneumococcal disease. The aim of this study was to determine the mechanisms of antibiotic resistance among PNSP isolates by next generation sequencing.

Methods

We assessed 26 PNSP isolates obtained from the nasopharynx from 537 healthy human immunodeficiency virus (HIV) infected adults in Dar es Salaam, Tanzania, participating in the randomized clinical trial CoTrimResist (ClinicalTrials.gov identifier: NCT03087890, registered on 23rd March, 2017). Next generation whole genome sequencing on the Illumina platform was used to identify mechanisms of resistance to antibiotics among PNSP.

Results

Fifty percent (13/26) of PNSP were resistant to erythromycin, of these 54% (7/13) and 46% (6/13) had MLSB phenotype and M phenotype respectively. All erythromycin resistant PNSP carried macrolide resistance genes; six isolates had mef(A)-msr(D), five isolates had both erm(B) and mef(A)-msr(D) while two isolates carried erm(B) alone. Isolates harboring the erm(B) gene had increased MIC (> 256 µg/mL) towards macrolides, compared to isolates without erm(B) gene (MIC 4-12 µg/mL) p < 0.001. Using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines, the prevalence of azithromycin resistance was overestimated compared to genetic correlates. Tetracycline resistance was detected in 13/26 (50%) of PNSP and all the 13 isolates harbored the tet(M) gene. All isolates carrying the tet(M) gene and 11/13 isolates with macrolide resistance genes were associated with the mobile genetic element Tn6009 transposon family. Of 26 PNSP isolates, serotype 3 was the most common (6/26), and sequence type ST271 accounted for 15% (4/26). Serotypes 3 and 19 displayed high-level macrolide resistance and frequently carried both macrolide and tetracycline resistance genes.

Conclusion

The erm(B) and mef(A)-msr(D) were common genes conferring resistance to MLSB in PNSP. Resistance to tetracycline was conferred by the tet(M) gene. Resistance genes were associated with the Tn6009 transposon.
Parental stress and physical violence against children during the second year of the COVID-19 pandemic: results of a population-based survey in Germany
Authors: Geprägs Alina , Bürgin David , Fegert Jörg M. , Brähler Elmar , Clemens Vera
Published: February 2023

Background

Parents and caregivers belonged to those with the highest burdens during the COVID-pandemic. Considering the close link between parental stress and child maltreatment, identifying families with high parental stress is of utmost importance to prevent violence against children. Within this study, we thus aimed to investigate the interplay of parental stress, changes in parental stress, and physical violence against children during the second year of the COVID-pandemic on an exploratory level.

Methods

We conducted a cross-sectional, observational study in Germany from July to October 2021. By using different sampling steps, a representative probability sample of the German population was generated. A subsample of these participants with children under the age of 18 was included for analysis within this study (N = 453, 60.3% females, Mage = 40.08; SD = 8.53).

Results

Higher parental stress levels were associated with more physical violence against children, higher levels of own experiences of child maltreatment, and mental health symptoms. An increase in parental stress during the pandemic was associated with female sex, the use of physical violence against children, and parental experience of child maltreatment. Parents who have ever used physical violence against their children have been characterized by higher parental stress levels, a stronger increase in parental stress during the pandemic, own experience of child maltreatment, mental health symptoms and sociodemographic characteristics. Higher parental stress levels, a stronger increase of parental stress during the pandemic, having pre-existing psychiatric disorders, and parental experience of child maltreatment predicted an increased use of physical violence against children during the pandemic.

Conclusions

Our results underscore the importance of parental stress for the risk of physical violence against children, more so in times of overall increased stress due to the pandemic and underline the need for low threshold support for families at risk in times of crises.
The gut microbiota and metabolite profiles are altered in patients with spinal cord injury
Authors: Kong Ganggang , Zhang Wenwu , Zhang Siyun , Chen Jiewen , He kejun , Zhang Changming , Yuan Xi , Xie Baoshu
Published: February 2023

Background

Metabolites secreted by the gut microbiota may play an essential role in microbiota–gut–central nervous system crosstalk. In this study, we explored the changes occurring in the gut microbiota and their metabolites in patients with spinal cord injury (SCI) and analyzed the correlations among them.

Methods

The structure and composition of the gut microbiota derived from fecal samples collected from patients with SCI (n = 11) and matched control individuals (n = 10) were evaluated using 16S rRNA gene sequencing. Additionally, an untargeted metabolomics approach was used to compare the serum metabolite profiles of both groups. Meanwhile, the association among serum metabolites, the gut microbiota, and clinical parameters (including injury duration and neurological grade) was also analyzed. Finally, metabolites with the potential for use in the treatment of SCI were identified based on the differential metabolite abundance analysis.

Results

The composition of the gut microbiota was different between patients with SCI and healthy controls. At the genus level, compared with the control group, the abundance of UBA1819, Anaerostignum, Eggerthella, and Enterococcus was significantly increased in the SCI group, whereas that of Faecalibacterium, Blautia, Escherichia–Shigella, Agathobacter, Collinsella, Dorea, Ruminococcus, Fusicatenibacter, and Eubacterium was decreased. Forty-one named metabolites displayed significant differential abundance between SCI patients and healthy controls, including 18 that were upregulated and 23 that were downregulated. Correlation analysis further indicated that the variation in gut microbiota abundance was associated with changes in serum metabolite levels, suggesting that gut dysbiosis is an important cause of metabolic disorders in SCI. Finally, gut dysbiosis and serum metabolite dysregulation was found to be associated with injury duration and severity of motor dysfunction after SCI.

Conclusions

We present a comprehensive landscape of the gut microbiota and metabolite profiles in patients with SCI and provide evidence that their interaction plays a role in the pathogenesis of SCI. Furthermore, our findings suggested that uridine, hypoxanthine, PC(18:2/0:0), and kojic acid may be important therapeutic targets for the treatment of this condition.
Diagnostic accuracy of a three-protein signature in women with suspicious breast lesions: a multicenter prospective trial
Authors: Lee Eun-Shin , Kim Yumi , Shin Hee-Chul , Hwang Ki-Tae , Min Junwon , Kim Min Kyoon , Ahn SooKyung , Jung So-Youn , Shin Hyukjai , Chung MinSung , Yoo Tae-Kyung , Jung Seungpil , Woo Sang Uk , Kim Ju-Yeon , Noh Dong-Young , Moon Hyeong-Gon
Published: February 2023

Background

Mammography screening has been proven to detect breast cancer at an early stage and reduce mortality; however, it has low accuracy in young women or women with dense breasts. Blood-based diagnostic tools may overcome the limitations of mammography. This study assessed the diagnostic performance of a three-protein signature in patients with suspicious breast lesions.

Findings

This trial (MAST; KCT0004847) was a prospective multicenter observational trial. Three-protein signature values were obtained using serum and plasma from women with suspicious lesions for breast malignancy before tumor biopsy. Additionally, blood samples from women who underwent clear or benign mammography were collected for the assays. Among 642 participants, the sensitivity, specificity, and overall accuracy values of the three-protein signature were 74.4%, 66.9%, and 70.6%, respectively, and the concordance index was 0.698 (95% CI 0.656, 0.739). The diagnostic performance was not affected by the demographic features, clinicopathologic characteristics, and co-morbidities of the participants.

Conclusions

The present trial showed an accuracy of 70.6% for the three-protein signature. Considering the value of blood-based biomarkers for the early detection of breast malignancies, further evaluation of this proteomic assay is warranted in larger, population-level trials.

This Multi-protein Assessment using Serum to deTermine breast lesion malignancy (MAST) was registered at the Clinical Research Information Service of Korea with the identification number of KCT0004847 (https://cris.nih.go.kr).
siVAE: interpretable deep generative models for single-cell transcriptomes
Authors: Choi Yongin , Li Ruoxin , Quon Gerald
Published: February 2023

Neural networks such as variational autoencoders (VAE) perform dimensionality reduction for the visualization and analysis of genomic data, but are limited in their interpretability: it is unknown which data features are represented by each embedding dimension. We present siVAE, a VAE that is interpretable by design, thereby enhancing downstream analysis tasks. Through interpretation, siVAE also identifies gene modules and hubs without explicit gene network inference. We use siVAE to identify gene modules whose connectivity is associated with diverse phenotypes such as iPSC neuronal differentiation efficiency and dementia, showcasing the wide applicability of interpretable generative models for genomic data analysis.
Effect of vitamin D supplementation versus placebo on recovery delay among COVID-19 Tunisian patients: a randomized-controlled clinical trial
Authors: Abroug Hela , Maatouk Amani , Bennasrallah Cyrine , Dhouib Wafa , Ben Fredj Manel , Zemni Imen , Kacem Meriem , Mhalla Salma , Nouira Sarra , Ben Belgacem Manel , Nasri Aymen , Klii Rim , Loussaief Chawki , Ben Alya Nissaf , Bouanene Ines , Belguith Sriha Asma
Published: February 2023

Introduction

The present study aimed to determine the impact of vitamin D supplementation (VDs) on recovery delay among COVID-19 patients.

Methods

We performed a randomized controlled clinical trial at the national COVID-19 containment center in Monastir (Tunisia), from May to August 2020. Simple randomization was done in a 1:1 allocation ratio. We included patients aged more than 18 years who had confirmed reverse transcription-polymerase chain reaction (RT-PCR) and who remained positive on the 14th day. The intervention group received VDs (200,000 IU/1 ml of cholecalciferol); the control group received a placebo treatment (physiological saline (1 ml)). We measured the recovery delay and the cycle threshold (Ct) values in RT-PCR for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The log-rank test and hazard ratios (HR) were calculated.

Results

A total of 117 patients were enrolled. The mean age was 42.7 years (SD 14). Males represented 55.6%. The median duration of viral RNA conversion was 37 days (95% confidence interval (CI): 29–45.50) in the intervention group and 28 days (95% CI: 23–39) in the placebo group (p=0.010). HR was 1.58 (95% CI: 1.09–2.29, p=0.015). Ct values revealed a stable trend over time in both groups.

Conclusion

VDs was not associated with a shortened recovery delay when given to patients for whom the RT-PCR remained positive on the 14th day.

Trial registration

This study was approved by the Human Subjects Protection Tunisia center (TN2020-NAT-INS-40) on April 28, 2020, and by ClinicalTrial.gov on May 12, 2021 with approval number ClinicalTrials.gov ID: NCT04883203.
Effectiveness of four deconstructive meditative practices on well-being and self-deconstruction: study protocol for an exploratory randomized controlled trial
Authors: García-Campayo Javier , Hijar-Aguinaga Rinchen , López-Del-Hoyo Yolanda , Magallón-Botaya Rosa , Fernández-Martínez Selene , Barceló-Soler Alberto , Soler-Ribaudi Joaquim , Montero-Marin Jesus
Published: February 2023

Introduction

The efficacy of interventions based on mindfulness and compassion has been demonstrated in both clinical and general population, and in different social contexts. These interventions include so-called attentional and constructive meditation practices, respectively. However, there is a third group, known as deconstructive meditation practices, which has not been scientifically studied. Deconstructive practices aim to undo maladaptive cognitive patterns and generate knowledge about internal models of oneself, others and the world. Although there are theoretical and philosophical studies on the origin of addiction to the self or on the mechanisms of action associated with the deconstruction of the self, there are no randomized controlled trials evaluating these techniques in either a healthy population or clinical samples. This study aims to evaluate the effect of three deconstructive techniques by comparing them to mindfulness in the general population.

Methods and analysis

A randomized controlled clinical trial will be conducted with about 240 participants allocated to four groups: (a) mindful breathing, (b) prostrations, according to Tibetan Buddhist tradition; (c) the Koan Mu, according to Zen Buddhist tradition; and (d) the mirror exercise, according to Toltec tradition. The primary outcome will be the qualities of the non-dual experience and spiritual awakening, measured by the Nondual Embodiment Thematic Inventory, assessed at pre- and post-treatment and at 3- and 6-month follow-ups. Other outcomes will be mindfulness, happiness, compassion, affectivity and altered state of consciousness. Quantitative data will be compared using mixed-effects linear regression models, and qualitative data will be analysed through thematic analysis and using the constant comparative method from grounded theory.

Ethics and dissemination

Approval was obtained from the Research Ethics Committee of Aragon, Spain. The results will be submitted to peer-reviewed specialized journals, and brief reports will be sent to participants on request.

Trial registration

ClinicalTrials.gov NCT05317754. Registered on August 2,2022.
Synthesis, DFT investigations, antioxidant, antibacterial activity and SAR-study of novel thiophene-2-carboxamide derivatives
Authors: Metwally Heba M. , Khalaf Norhan A. , Abdel-Latif Ehab , Ismail Mohamed A.
Published: February 2023

Synthetic strategy for the synthesis of thiophene 2-carboxamide derivatives substituted with hydroxyl, methyl and amino groups at position-3 was proposed. The strategy includes the cyclization of the precursor ethyl 2-arylazo-3-mercapto-3-(phenylamino)acrylate derivatives, 2-acetyl-2-arylazo-thioacetanilide derivatives and N-aryl-2-cyano-3-mercapto-3-(phenylamino)acrylamide derivatives with N-(4-acetylphenyl)-2-chloroacetamide in alcoholic sodium ethoxide. IR, 1H NMR, and mass spectroscopic analyses were used to characterize the synthesized derivatives. In addition, molecular, electronic properties of the synthesized products were studied by the density functional theory (DFT) where they exhibited close HOMO–LUMO energy gap (ΔEH-L) in which the amino derivatives 7a-c have the highest while the methyl derivatives 5a-c were the lowest. Using the ABTS method, the antioxidant properties of the produced compounds were evaluated, where amino thiophene-2-carboxamide 7a exhibit significant inhibition activity 62.0% compared to ascorbic acid The antibacterial activity against two pathogenic Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two of pathogenic Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) revealed that 7b records the highest activity index compared to ampicillin 83.3, 82.6, 64.0, 86.9%, respectively. Furthermore, the thiophene-2-carboxamide derivatives were docked with five different proteins with the use molecular docking tools and the results explained interactions between amino acid residue of enzyme and compounds. Compounds 3b and 3c showed the highest binding score with 2AS1 protein.

Graphical Abstract
Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder
Authors: Cardo Lucia F. , de la Fuente Daniel C. , Li Meng
Published: February 2023

Background

Disruptions of SETBP1 (SET binding protein 1) on 18q12.3 by heterozygous gene deletion or loss-of-function variants cause SETBP1 disorder. Clinical features are frequently associated with moderate to severe intellectual disability, autistic traits and speech and motor delays. Despite the association of SETBP1 with neurodevelopmental disorders, little is known about its role in brain development.

Methods

Using CRISPR/Cas9 genome editing technology, we generated a SETBP1 deletion model in human embryonic stem cells (hESCs) and examined the effects of SETBP1-deficiency in neural progenitors (NPCs) and neurons derived from these stem cells using a battery of cellular assays, genome-wide transcriptomic profiling and drug-based phenotypic rescue.

Results

Neural induction occurred efficiently in all SETBP1 deletion models as indicated by uniform transition into neural rosettes. However, SETBP1-deficient NPCs exhibited an extended proliferative window and a decrease in neurogenesis coupled with a deficiency in their ability to acquire ventral forebrain fate. Genome-wide transcriptome profiling and protein biochemical analysis revealed enhanced activation of Wnt/β-catenin signaling in SETBP1 deleted cells. Crucially, treatment of the SETBP1-deficient NPCs with a small molecule Wnt inhibitor XAV939 restored hyper canonical β-catenin activity and restored both cortical and MGE neuronal differentiation.

Limitations

The current study is based on analysis of isogenic hESC lines with genome-edited SETBP1 deletion and further studies would benefit from the use of patient-derived iPSC lines that may harbor additional genetic risk that aggravate brain pathology of SETBP1 disorder.

Conclusions

We identified an important role for SETBP1 in controlling forebrain progenitor expansion and neurogenic differentiation. Our study establishes a novel regulatory link between SETBP1 and Wnt/β-catenin signaling during human cortical neurogenesis and provides mechanistic insights into structural abnormalities and potential therapeutic avenues for SETBP1 disorder.
Single cell and lineage tracing studies reveal the impact of CD34+ cells on myocardial fibrosis during heart failure
Authors: Du Luping , Sun Xiaotong , Gong Hui , Wang Ting , Jiang Liujun , Huang Chengchen , Xu Xiaodong , Li Zhoubin , Xu Hongfei , Ma Liang , Li Weidong , Chen Ting , Xu Qingbo
Published: February 2023

Background

CD34+ cells have been used to treat the patients with heart failure, but the outcome is variable. It is of great significance to scrutinize the fate and the mechanism of CD34+ cell differentiation in vivo during heart failure and explore its intervention strategy.

Methods

We performed single-cell RNA sequencing (scRNA-seq) of the total non-cardiomyocytes and enriched Cd34-tdTomato+ lineage cells in the murine (male Cd34-CreERT2; Rosa26-tdTomato mice) pressure overload model (transverse aortic constriction, TAC), and total non-cardiomyocytes from human adult hearts. Then, in order to determine the origin of CD34+ cell that plays a role in myocardial fibrosis, bone marrow transplantation model was performed. Furthermore, to further clarify the role of CD34 + cells in myocardial remodeling in response to TAC injury, we generated Cd34-CreERT2; Rosa26-eGFP-DTA (Cre/DTA) mice.

Results

By analyzing the transcriptomes of 59,505 single cells from the mouse heart and 22,537 single cells from the human heart, we illustrated the dynamics of cell landscape during the progression of heart hypertrophy, including CD34+ cells, fibroblasts, endothelial and immune cells. By combining genetic lineage tracing and bone marrow transplantation models, we demonstrated that non-bone-marrow-derived CD34+ cells give rise to fibroblasts and endothelial cells, while bone-marrow-derived CD34+ cell turned into immune cells only in response to pressure overload. Interestingly, partial depletion of CD34+ cells alleviated the severity of myocardial fibrosis with a significant improvement of cardiac function in Cd34-CreERT2; Rosa26-eGFP-DTA model. Similar changes of non-cardiomyocyte composition and cellular heterogeneity of heart failure were also observed in human patient with heart failure. Furthermore, immunostaining showed a double labeling of CD34 and fibroblast markers in human heart tissue. Mechanistically, our single-cell pseudotime analysis of scRNA-seq data and in vitro cell culture study revealed that Wnt-β-catenin and TGFβ1/Smad pathways are critical in regulating CD34+ cell differentiation toward fibroblasts.

Conclusions

Our study provides a cellular landscape of CD34+ cell-derived cells in the hypertrophy heart of human and animal models, indicating that non-bone-marrow-derived CD34+ cells differentiating into fibroblasts largely account for cardiac fibrosis. These findings may provide novel insights for the pathogenesis of cardiac fibrosis and have further potential therapeutic implications for the heart failure.
Estimating the impact of stimulant use on initiation of buprenorphine and extended-release naltrexone in two clinical trials and real-world populations
Authors: Cook R. R. , Foot C. , Arah O. A. , Humphreys K. , Rudolph K. E. , Luo S. X. , Tsui J. I. , Levander X. A. , Korthuis P. T.
Published: February 2023

Background

Co-use of stimulants and opioids is rapidly increasing. Randomized clinical trials (RCTs) have established the efficacy of medications for opioid use disorder (MOUD), but stimulant use may decrease the likelihood of initiating MOUD treatment. Furthermore, trial participants may not represent “real-world” populations who would benefit from treatment.

Methods

We conducted a two-stage analysis. First, associations between stimulant use (time-varying urine drug screens for cocaine, methamphetamine, or amphetamines) and initiation of buprenorphine or extended-release naltrexone (XR-NTX) were estimated across two RCTs (CTN-0051 X:BOT and CTN-0067 CHOICES) using adjusted Cox regression models. Second, results were generalized to three target populations who would benefit from MOUD: Housed adults identifying the need for OUD treatment, as characterized by the National Survey on Drug Use and Health (NSDUH); adults entering OUD treatment, as characterized by Treatment Episodes Dataset (TEDS); and adults living in rural regions of the U.S. with high rates of injection drug use, as characterized by the Rural Opioids Initiative (ROI). Generalizability analyses adjusted for differences in demographic characteristics, substance use, housing status, and depression between RCT and target populations using inverse probability of selection weighting.

Results

Analyses included 673 clinical trial participants, 139 NSDUH respondents (weighted to represent 661,650 people), 71,751 TEDS treatment episodes, and 1,933 ROI participants. The majority were aged 30–49 years, male, and non-Hispanic White. In RCTs, stimulant use reduced the likelihood of MOUD initiation by 32% (adjusted HR [aHR] = 0.68, 95% CI 0.49–0.94, p = 0.019). Stimulant use associations were slightly attenuated and non-significant among housed adults needing treatment (25% reduction, aHR = 0.75, 0.48–1.18, p = 0.215) and adults entering OUD treatment (28% reduction, aHR = 0.72, 0.51–1.01, p = 0.061). The association was more pronounced, but still non-significant among rural people injecting drugs (39% reduction, aHR = 0.61, 0.35–1.06, p = 0.081). Stimulant use had a larger negative impact on XR-NTX initiation compared to buprenorphine, especially in the rural population (76% reduction, aHR = 0.24, 0.08–0.69, p = 0.008).

Conclusions

Stimulant use is a barrier to buprenorphine or XR-NTX initiation in clinical trials and real-world populations that would benefit from OUD treatment. Interventions to address stimulant use among patients with OUD are urgently needed, especially among rural people injecting drugs, who already suffer from limited access to MOUD.
Study on anxiety and depression in elderly patients with malignant liver tumor undergoing hepatectomy
Authors: Xu Lining , Xu Yingying , Li Guiping , Yang Bo
Published: February 2023

Background

Patients with malignant tumors are more likely to have psychological problems due to their worries about their life expectancy. To understand the psychological status of elderly patients with malignant liver tumor undergoing hepatectomy better, the study was designed to investigate the current situation of anxiety and depression in elderly patients with malignant liver tumor undergoing hepatectomy and to analyze its related factors.

Methods

A total of 126 elderly patients with malignant liver tumor undergoing hepatectomy were selected as the research objects. The anxiety and depression of all subjects were evaluated by HADS (Hosptial Anxiety and Depression Scale). The correlation factors affecting the psychological state of elderly patients with malignant liver tumor undergoing hepatectomy were analyzed by linear regression method.

Results

The HADS-A score of elderly patients with malignant liver tumor undergoing hepatectomy was 8.79 ± 2.56, among which 37 patients were asymptomatic, 60 patients with suspicious symptoms, and 29 patients with definite symptoms. The HADS-D score was 8.40 ± 2.97, among which 61 patients were asymptomatic, 39 patients with suspicious symptoms, and 26 patients with definite symptoms. Multivariate analysis using linear regression method showed that FRAIL score, residence, and complication were significantly associated with anxiety and depression of elderly patients with malignant liver tumor undergoing hepatectomy.

Conclusions

Anxiety and depression in elderly patients with malignant liver tumor undergoing hepatectomy were obvious. FRAIL score, regional differences, and the complication were the risk factors for anxiety and depression in elderly patients with malignant liver tumor undergoing hepatectomy. Improving frailty, reducing regional differences, and preventing complications is beneficial to alleviate the adverse mood of elderly patients with malignant liver tumor undergoing hepatectomy.
Establishing a standard method for analysing case detection delay in leprosy using a Bayesian modelling approach
Authors: Hambridge Thomas , Coffeng Luc E. , de Vlas Sake J. , Richardus Jan Hendrik
Published: February 2023

Background

Leprosy is an infectious disease caused by Mycobacterium leprae and remains a source of preventable disability if left undetected. Case detection delay is an important epidemiological indicator for progress in interrupting transmission and preventing disability in a community. However, no standard method exists to effectively analyse and interpret this type of data. In this study, we aim to evaluate the characteristics of leprosy case detection delay data and select an appropriate model for the variability of detection delays based on the best fitting distribution type.

Methods

Two sets of leprosy case detection delay data were evaluated: a cohort of 181 patients from the post exposure prophylaxis for leprosy (PEP4LEP) study in high endemic districts of Ethiopia, Mozambique, and Tanzania; and self-reported delays from 87 individuals in 8 low endemic countries collected as part of a systematic literature review. Bayesian models were fit to each dataset to assess which probability distribution (log-normal, gamma or Weibull) best describes variation in observed case detection delays using leave-one-out cross-validation, and to estimate the effects of individual factors.

Results

For both datasets, detection delays were best described with a log-normal distribution combined with covariates age, sex and leprosy subtype [expected log predictive density (ELPD) for the joint model: −1123.9]. Patients with multibacillary (MB) leprosy experienced longer delays compared to paucibacillary (PB) leprosy, with a relative difference of 1.57 [95% Bayesian credible interval (BCI): 1.14–2.15]. Those in the PEP4LEP cohort had 1.51 (95% BCI: 1.08–2.13) times longer case detection delay compared to the self-reported patient delays in the systematic review.

Conclusions

The log-normal model presented here could be used to compare leprosy case detection delay datasets, including PEP4LEP where the primary outcome measure is reduction in case detection delay. We recommend the application of this modelling approach to test different probability distributions and covariate effects in studies with similar outcomes in the field of leprosy and other skin-NTDs.

Graphical Abstract