bluuebunny/crossref_metadata_2025 huggingface dataset:
Conserved regions in the vlhA protein from field strains Mycoplasma gallisepticum and Myc. synoviae isolated from chicken farms in Mexico.
Authors: Maya Linda , Gómez-Verduzco Gabriela , Trigo-Tavera Francisco J. , Moreno-Fierros Leticia , Rojas-Trejo Verónica , Miranda-Morales Rosa Elena
Published: December 2023

Avian mycoplasmosis caused by Mycoplasma synoviae and Myc. gallisepticum represents an economic impact disease because causes respiratory problems and egg deformation. Hemagglutinin (vlhA) is associated with pathogenicity in both species; it has a conserved region (MSPB) and a variable region (MSPA). It was analyzed both regions of the vlhA sequence in several field strains from central Mexico to determine a close cluster relationship. 124 deformed eggs from birds suspected of mycoplasmosis were processed, the birds (Hy-line and Bovans White lineages) of 9 farms were not immunized against mycoplasmosis and were typified 21 field strains by PCR mgc2 and 16S RNAr genes. The vlhA was investigated using AF035624.1 sequences, employing ATTC strains as positive controls. The study was a complementary with 20 samples more negatives for isolation; it was observed 2 amplifications in all field tested, 1er MSPB and 2nd MSPA, regions. Via bioanalysis, were determined also the relationship with other avian mycoplasma sequences reported in Gene Bank, beside were observed amplification in Acholepasma laidlawii PG8 and Escherichia coli showed relationships with the other strains. The lipoproteins are relevant in pathogenicity, survival and immune evasion, and conserved sequences can be used as targets in therapy and phylogenetic studies.
Tianweitania aestuarii sp. nov., isolated from a coastal dune, reclassification of Corticibacterium populi as Tianweitania populi comb. nov., and emended description of the genus Tianweitania
Authors: Song Ji Hyeon , Park Sooyeon , Lee Jung-Sook , Kim Wonyong , Yoon Jung-Hoon
Published: December 2023

A Gram-stain-negative, aerobic, non-flagellated and coccoid or ovoid bacterial strain, BSSL-BM11T, was isolated from sand of coastal dunes along the Yellow Sea of the Korean peninsula. Strain BSSL-BM11T grew optimally at 30 °C, at pH 7.0–8.0 and in the presence of 2.0–3.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences, the up-to-date bacterial core gene set and average amino acid identity (AAI) showed that strain BSSL-BM11T forms a cluster with the type strains of

Tianweitania sediminis

and

Corticibacterium populi

. Strain BSSL-BM11T showed 16S rRNA gene sequence similarities of 98.3 and 98.0 % to the type strains of

T. sediminis

and

C. populi

, respectively, and less than 96.4 % to the type strains of the other recognized species. The average nucleotide identity (ANI) and digital DNA–DNA hybridization (dDDH) values between strain BSSL-BM11T and the type strains of

T. sediminis

and

C. populi

were 77.0–84.8 % and 20.0–28.1 %, respectively. The 16S rRNA gene similarity, AAI, ANI and dDDH values between

T. sediminis

Z8T and

C. populi

KCTC 42249T were 98.0, 77.4, 76.7 and 20.1 %, respectively. The DNA G+C content of strain BSSL-BM11T from genomic sequence data was 61.3 mol%. Strain BSSL-BM11T contained Q-10 as the predominant ubiquinone and C18 : 1
 ω7c, C16 : 0 and cyclo C19 : 0
 ω8c as the major fatty acids. The major polar lipids of strain BSSL-BM11T were phosphatidylcholine, phosphatidylglycerol and phosphatidylethanolamine. Based on the polyphasic data, it is proposed that C, populi be reclassified as a member of the genus

Tianweitania

. Phenotypic and phylogenetic analyses revealed that strain BSSL-BM11T is separated from

T. sediminis

and

C. populi

. On the basis of the data presented here, strain BSSL-BM11T (=KACC 21634T=NBRC 114503T) is considered to represent a novel species of the genus

Tianweitania

, for which the name Tianweitania aestuarii sp. nov. is proposed.
Evaluation of a novel chromogenic screening method for detection of carbapenem-resistant Escherichia coli
Authors: Das Bhaskar Jyoti , Singha K. Melson , Wangkheimayum Jayalaxmi , Dhar Chanda Debadatta , Bhattacharjee Amitabha
Published: December 2023

Introduction. Early detection of carbapenem-resistant

Escherichia coli

(CREco), categorized as a critical priority pathogen by the World Health Organization (WHO), is crucial in optimizing therapeutic options and to thwart outbreaks in clinical settings.

Gap statement. The need of the hour is a diagnostic method that can detect carbapenem resistance conferred by intrinsic or acquired carbapenem resistance mechanisms or both.

Aim. The study investigates the performance of a novel screening chromogenic method for detection of CREco.

Methodology. Carbapenem-susceptible (n=23) and non-susceptible (n=90)

E. coli

were used to investigate the efficiency of the blue chromogenic test. All of the isolates were received from a tertiary referral hospital in Silchar, India and subjected to the blue chromogenic test and observed for colour change. A colour change from colourless to blue is interpreted as a positive result. The test results were further compared with available methods for detection of carbapenem resistance conferred by carbapenemase production or other carbapenem resistance mechanisms.

Results. The blue chromogenic test generated 100 % (CI: 95.98–100 %) sensitive and 100 % (CI: 85.75–100 %) specific results for the detection of CREco with no false-positive or false-negative results. Within 3 h after incubation, the test detects all CREco with carbapenemase activity. Additionally, the blue chromogenic test also positively detected

E. coli

harbouring carbapenemase variants and with efflux and porin activity, compared to other phenotypic-based approaches.

Conclusion. The study highlights a novel method that is highly sensitive and specific, inexpensive, rapid and user-friendly for the detection of CREco. With the surge and expansion of CREco, this sensitive, specific, user-friendly and inexpensive method can be used in laboratories with limited facilities for early detection of CREco, thereby improving infection control along with averting future outbreaks.
SARS-CoV-2 Omicron variants BA.4 and BA.5 dominated the fifth COVID-19 epidemiological wave in Mexico
Authors: Taboada Blanca Itzelt , Zárate Selene , García-López Rodrigo , Muñoz-Medina José Esteban , Gómez-Gil Bruno , Herrera-Estrella Alfredo , Sanchez-Flores Alejandro , Salas-Lais Angel Gustavo , Roche Benjamin , Martínez-Morales Gabriela , Domínguez Zárate Hermilo , Duque Molina Célida , Avilés Hernández Ricardo , López Susana , Arias Carlos F.
Published: December 2023

In Mexico, the BA.4 and BA.5 Omicron variants dominated the fifth epidemic wave (summer 2022), superseding BA.2, which had circulated during the inter-wave period. The present study uses genome sequencing and statistical and phylogenetic analyses to examine these variants' abundance, distribution, and genetic diversity in Mexico from April to August 2022. Over 35 % of the sequenced genomes in this period corresponded to the BA.2 variant, 8 % to the BA.4 and 56 % to the BA.5 variant. Multiple subvariants were identified, but the most abundant, BA.2.9, BA.2.12.1, BA.5.1, BA.5.2, BA.5.2.1 and BA.4.1, circulated across the entire country, not forming geographical clusters. Contrastingly, other subvariants exhibited a geographically restricted distribution, most notably in the Southeast region, which showed a distinct subvariant dynamic. This study supports previous results showing that this region may be a significant entry point and contributed to introducing and evolving novel variants in Mexico. Furthermore, a differential distribution was observed for certain subvariants among specific States through time, which may have contributed to the overall increased diversity observed during this wave compared to the previous ones. This study highlights the importance of sustaining genomic surveillance to identify novel variants that may impact public health.
Characteristics and outcomes of patients treated with sotrovimab to prevent progression to severe COVID-19 in Belgium
Authors: Drysdale Myriam , Hautekiet Thor , Singh Moushmi , Hautekiet Joris , Ludikhuyze Linda , Patel Vishal , Gibbons Daniel C , Roeck Dorothée De , Colpaert Kirsten , Lloyd Emily J , Braeckel Eva Van
Published: December 2023

Background

Sotrovimab, a dual-action, engineered human monoclonal antibody, has been demonstrated to significantly reduce the risk of hospitalization and death in high-risk patients with COVID-19. Here, we describe the real-world use of, and outcomes from, sotrovimab treatment in Belgium during the Delta and Omicron waves among patients with COVID-19 at high risk of developing severe disease.

Methods

This was a multicentric, single-arm observational cohort study of non-hospitalized patients receiving outpatient sotrovimab treatment between 1 November 2021 and 2 August 2022. We performed a retrospective analysis of hospital, pharmacy and administrative data from nine hospitals in Belgium. The primary outcomes were all-cause and COVID-19-related hospitalizations and all-cause deaths during the 29-day acute follow-up period from first administration of sotrovimab.

Results

A total of 634 patients were included in the analysis (63.4% aged <65 years; 50.3% male). A high proportion (67.7%;n= 429/634) of patients were immunocompromised, with 36.9% (n= 234/634) actively treated for malignancy. During the 29-day acute period, 12.5% (n= 79/634) of sotrovimab-treated patients were hospitalized due to any cause (median duration 4 days; median time to hospitalization 14 days) and 1.1% (n= 7/634) died due to any cause. In total, 0.8% (n= 5/634) of patients were admitted to an intensive care unit (ICU). COVID-19-related hospitalization was experienced by 2.5% (n= 16/634) of patients (median duration 10 days; median time to hospitalization 10.5 days), with 0.5% (n= 3/634) of patients admitted to an ICU. COVID-19-related hospitalization was experienced by 6.3% (n= 3/48) of patients during Delta predominance (04/11/2021–23/12/2021), 6.3% (n= 1/16) of patients during Delta/BA.1 codominance (24/12/2021–01/01/2022), 1.4% (n= 3/218) of patients during BA.1 predominance (02/01/2022–09/02/2022), 2.1% (n= 2/97) of patients during BA.1/BA.2 codominance (10/02/2022–07/03/2022) and 2.7% (n= 7/255) of patients during BA.2/BA.5 codominance (08/03/2022–02/08/2022).

Conclusions

This observational study demonstrated consistently low rates of COVID-19-related hospitalizations and all-cause deaths in sotrovimab-treated patients during the Omicron subvariant periods in Belgium, despite over two-thirds of the study population being immunocompromised. Comparative effectiveness studies are warranted to confirm sotrovimab effectiveness in highly immunocompromised patients with COVID-19.
“They provide the right kind of support.”A qualitative study of preferences for differentiated service delivery location among recipients of antiretroviral therapy at Lighthouse Trust in Lilongwe Malawi
Authors: Orii Lisa , Wilson Kate S. , Huwa Jacqueline , Kiruthu-Kamamia Christine , Sande Odala , Thawani Agness , Berner-Rodoreda Astrid , Viola Evelyn , Tweya Hannock , Tembo Petros , Masambuka Wapu , Anderson Richard , Feldacker Caryl
Published: December 2023

Differentiated service delivery (DSD) models for antiretroviral therapy (ART) allow stable recipients of care (RoC) to receive multi-month ART drug refills and complete rapid reviews in community sites. As DSD options expand across sub-Saharan Africa, RoC’s preferences and perspectives on community-versus clinic-based care models warrants attention. We describe the factors that influence RoC choice of ART delivery approaches at Lighthouse Trust (LT) clinics and community-based DSD sites in Lilongwe, Malawi. We conducted eight focus group discussions (FGDs) among LT RoC in the Nurse-led Community-based ART Program (NCAP) (n=4) and in clinic settings (n=4) to explore opinions, preferences, and perceptions about ART service delivery. FGDs were conducted and recorded in Chichewa and then translated and transcribed into English for analysis. Data was analyzed using thematic analysis and findings discussed with the LT and NCAP teams to jointly reflect on the findings. Sixty-three participants took part in the qualitative study. Results were largely similar across care locations. In both NCAP and clinic FGDs, RoC appreciated the convenience of integrating their appointment visits at their chosen care location into their daily lives, though some RoC traveled far to access LT’s high quality of care. RoC were satisfied with the quality of the care they received at their location of choice. Privacy protection was an important consideration for choosing care models. At LT clinics, RoC highlighted the importance of physical separation between LT’s HIV-specific service site and other service sites. In NCAP, RoC expressed that their choice of care model was reinforced by the sense of mutual support that they received through the peer support model. At LT, RoC in both clinic and NCAP care models expressed satisfaction with their chosen care model and preferred that choice over alternative options and locations. Overall, LT RoC appreciated the quality of care, the respectful provider-to-patient interactions, and the attention to privacy at community and clinic sites. These findings suggest continued emphasis on offering choices to RoC on where and how they receive ART delivery approaches may support ongoing engagement in care.
Mathematical modelling to estimate the impact of maternal and perinatal healthcare services and interventions on health in sub-Saharan Africa: A scoping review
Authors: Collins Joseph H , Cambiano Valentina , Phillips Andrew N. , Colbourn Tim
Published: December 2023

Mathematical modelling is a commonly utilised tool to predict the impact of policy on health outcomes globally. Given the persistently high levels of maternal and perinatal morbidity and mortality in sub-Saharan Africa, mathematical modelling is a potentially valuable tool to guide strategic planning for health and improve outcomes. The aim of this scoping review was to explore how modelling has been used to evaluate the delivery of maternal and/or perinatal healthcare interventions or services and predict their impact on health-related outcomes in the region. A search across three databases was conducted in November 2023 which returned 8660 potentially relevant studies, from which 60 were included in the final review. Characteristics of these studies, the interventions which were evaluated, the models utilised, and the analyses conducted were extracted and summarised. Findings suggest that the popularity of modelling within this field is increasing over time with most studies published after 2015 and that population-based, deterministic, linear models were most frequently utilised, with the Lives Saved Tool being applied in over half of the reviewed studies (n=34, 57%). Much less frequently (n=6) models utilising system-thinking approaches, such as individual-based modelling or systems dynamics modelling, were developed and applied. Models were most applied to estimate the impact of interventions or services on maternal or neonatal mortality outcomes with morbidity-related outcomes and stillbirth reported on much less often. Going forward, given that healthcare delivery systems have long been identified as complex adaptive systems, modellers may consider the advantages of applying systems-thinking approaches to evaluate the impact of maternal and perinatal health policy. Such approaches allow for a more realistic and explicit representation of the systems- and individual-level factors which impact the effectiveness of interventions delivered within health systems.
Effects of early childhood education on early childhood development in Bangladesh
Authors: Khanam Shimlin Jahan , Alam Md Badsha , Khan Md Nuruzzaman
Published: December 2023

Background

Early childhood education is considered as vital for the early childhood development (ECD) instead of scarcity of the relevant literature. This study aims to investigate the relationship between early childhood education and the early childhood development index (ECDI) in Bangladesh.

Methods

We analyzed data from 9,420 children (aged 3 and 4) extracted from the Multiple Indicator Cluster Survey conducted in 2019. The outcome variable considered was the Early Childhood Development Index, a composite index generated based on the responses to 10 items and categorized as children either developmentally on track (coded as 1) or not (coded as 0). Four domains of ECDI—physical, learning, emotional, and social well-being— were also considered as outcome variable. Attendance of the early childhood education program was the major exposure variable. The association between explanatory and outcome variables was determined using a multilevel logistic regression model, adjusting for potential covariates.

Results

Only one in every five children in Bangladesh was found to be enrolled in early childhood education. Non-participation in early childhood education was associated with a 44% lower likelihood (aOR, 0.56, 95% CI, 0.47-0.66) of positive ECDI compared to participation in early childhood education. Additionally, non-attendance of early childhood education, compared to attendance, was associated with lower odds in literacy-numeracy (aOR, 0.25, 95% CI, 0.21-0.28) and learning (aOR, 0.59, 95% CI, 0.45-0.77) domains of ECDI.

Conclusion

The findings provide evidence of the importance of early childhood education programs in ensuring early childhood development. This indicates the necessity of strengthening early childhood education programs in Bangladesh to ensure the overall well-being of children.
Salivary Biomarkers as Pioneering Indicators for Diagnosis and Severity Stratification of Pediatric Long COVID
Authors: Tyrkalska Sylwia D. , Pérez-Sanz Fernando , Franco-Martínez Lorena , Peres-Rubio Camila , Tvarijonaviciute Asta , Martínez-Subiela Silvia , Méndez-Hernández María , González-Aumatell Alba , Carreras-Abad Clara , Domènech-Marçal Èlia , Cerón José J. , Cayuela María L. , Mulero Victoriano , Candel Sergio
Published: December 2023

Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), manifests as persistent and often debilitating symptoms enduring well beyond the initial COVID-19 infection. Presently, a specific diagnostic test or definitive biomarker set for confirming long COVID is lacking, relying instead on the protracted presence of symptoms post-acute infection. In this study, we examined 105 saliva samples (49 from children with long COVID and 56 controls), revealing significant alterations in salivary biomarkers. Pediatric long COVID exhibited increased oxidant biomarkers, decreased antioxidant, immune response, and stress-related biomarkers. Correlation analyses unveiled distinct patterns between biomarkers in long COVID and controls. Notably, a multivariate logistic regression pinpointed TOS, ADA2, total proteins, and AOPP as pivotal variables, culminating in a remarkably accurate predictive model distinguishing long COVID from controls. Furthermore, total proteins and ADA1 were instrumental in discerning between mild and severe long COVID symptoms. This research sheds light on the potential clinical utility of salivary biomarkers in diagnosing and categorizing the severity of pediatric long COVID. It also lays the groundwork for future investigations aimed at unraveling the prognostic value of these biomarkers in predicting the trajectory of long COVID in affected individuals.
Implementation and Evaluation of a Home-Based Pre-Exposure Prophylaxis Monitoring Option: A Protocol for a Randomized Controlled Trial
Authors: Cannon Chase A. , Holzhauer Kate , Golden Matthew
Published: December 2023

Background

HIV prevention is a public health priority. Despite progress in recent years, PrEP use remains suboptimal especially among groups disproportionately impacted by new HIV diagnoses such as gender and sexual minorities of color. Multiple barriers including lack of PrEP providers and challenges with attending quarterly monitoring visits contribute to low PrEP uptake and retention. Home-based PrEP (HB-PrEP) services could reduce stigma, increase convenience, expand health system capacity for PrEP care, and improve PrEP retention.

Objective

HOT4PrEP (Home Option Testing for PrEP) is a hybrid randomized controlled trial (RCT) that aims to examine whether HB-PrEP care is acceptable to PrEP users, feasible to implement into a sexual health clinic setting, and impacts PrEP retention over time.

Methods

The RCT will recruit approximately 450 persons currently taking or soon to initiate PrEP at the Sexual Health Clinic in Seattle, WA and randomize them to continue standard of care or have the option to use HB-PrEP for two of three tri-annual PrEP follow-up visits. Participants in the intervention arm will be sent home kits containing gonorrhea and chlamydia swabs and Tasso devices for blood self-collection. The primary outcome is PrEP retention between groups at 20 months; secondary outcomes include user satisfaction/acceptability, feasibility, self-reported PrEP adherence, and STI incidence. Interviews with PrEP users and clinic staff will elucidate barriers and facilitators of implementation.

Results

The HOT4PrEP RCT began enrolling in March 2022, was on hold during the height of the US mpox epidemic, then resumed in December 2022. From the first 100 enrollees, median age is 34 years and most are cisgender gay men (89%) with at least some college education (91%). Among those randomized to the HB-PrEP option, 65% have opted at least once to self-collect samples at home and 84% have successfully returned test kits for HIV/STI testing. Primary PrEP retention and qualitative analyses are ongoing.

Conclusions

Implementation of HB-PrEP into a high-volume sexual health clinic seems to be feasible and acceptable to early RCT enrollees. This strategy has the potential to address individual and systemic barriers associated with initiating and persisting on PrEP such as increasing sexual health agency and expanding clinical capacity to serve greater numbers of PrEP users.

Trial Registration:ClinicalTrials.govNCT05856942
Investigating the Effects of Artificial Baroreflex Stimulation on Pain Perception: A Comparative Study in Healthy Participants and Individuals with Chronic Low Back Pain
Authors: Venezia Alessandra , Jones Harriet-Fawsitt , Hohenschurz-Schmidt David , Mancini Matteo , Howard Matthew , Makovac Elena
Published: December 2023

The autonomic nervous system (ANS) and pain exhibit a reciprocal relationship, whereupon acute pain triggers ANS responses, while resting ANS activity can influence pain perception. Nociceptive signalling can also be altered by “top-down” processes occurring in the brain, brainstem, and spinal cord, known asdescending modulation. By employing the Conditioned Pain Modulation (CPM) paradigm, our previous study revealed a connection between reduced low-frequency heart rate variability (HRV) and CPM. Chronic pain patients often experience both ANS dysregulation and impaired CPM. Baroreceptors, which contribute to blood pressure and HRV regulation, may play a significant role in this relationship, but their involvement in pain perception and their functioning in chronic pain have not been sufficiently explored. In this study, we combined artificialbaroreceptor stimulationin both pressure pain and CPM paradigms, seeking to explore the role of baroreceptors in pain perception and descending modulation. 22 patients with chronic low back pain (CLBP) and 29 healthy controls (HC) took part in this study. We identified a relationship between baroreflex functioning and perception of pressure pain, finding differential modulation of pressure pain between diagnostic groups. Specifically, HC participants perceived less pain in response to baroreflex activation, whereas CLBP patients exhibited increased pain sensitivity. CPM scores were associated with baseline measures of baroreflex efficiency in both patients and controls. Our data support the importance of the baroreflex in chronic pain and a possible mechanism of dysregulation involving the interaction between the autonomic nervous system and descending pain modulation.
The duration of lithium use and biological ageing: telomere length, frailty, metabolomic age and all-cause mortality
Authors: Mutz Julian , Wong Win Lee Edwin , Powell Timothy R. , Young Allan H. , Dawe Gavin S. , Lewis Cathryn M.
Published: December 2023

Background

Lithium is an established first-line treatment for bipolar disorder. Beyond its therapeutic effect as a mood stabiliser, lithium exhibits potential anti-ageing effects. This study aimed to examine the relationship between the duration of lithium use, biological ageing and mortality.

Methods

The UK Biobank is an observational study of middle-aged and older adults. We tested associations between the duration of lithium use (number of prescriptions, total duration of use, and duration of the first prescription period) and telomere length, frailty, metabolomic age, pulse rate and all-cause mortality.

Results

591 individuals (mean age = 57.49 years; 55% females) had been prescribed lithium. There was no evidence that the number of prescriptions (β= −0.022, 95% CI −0.081 to 0.037,p= 0.47), the total duration of use (β= −0.005, 95% CI −0.023 to 0.013,p= 0.57) or the duration of the first prescription period (β= −0.018, 95% CI −0.051 to 0.015,p= 0.29) correlated with telomere length. There was also no evidence that the duration of lithium use correlated with frailty or metabolomic age. However, a higher prescription count or a longer duration of use was associated with a lower pulse rate. The duration of lithium use did not predict mortality.

Conclusions

We observed no evidence of associations between the duration of lithium use and biological ageing markers, including telomere length. Our findings suggest that the potential anti-ageing effects of lithium do not differ by duration of use.
The gut-microbiome in adult Attention-deficit/hyperactivity disorder - A Meta-analysis
Authors: Jakobi Babette , Vlaming Priscilla , Mulder Danique , Ribases Marta , Richarte Vanesa , Ramos-Quiroga Josep Antoni , Tendolkar Indira , van Eijndhoven Philip , Vrijsen Janna N. , Buitelaar Jan , Franke Barbara , Hoogman Martine , Bloemendaal Mirjam , Arias-Vasquez Alejandro
Published: December 2023

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that persists into adulthood in the majority of individuals. While the gut-microbiome seems to be relevant for ADHD, the few publications on gut-microbial alterations in ADHD are inconsistent, in the investigated phenotypes, sequencing method/region, preprocessing, statistical approaches, and findings. To identify gut-microbiome alterations in adult ADHD, robust across studies and statistical approaches, we harmonized bioinformatic pipelines and analyses of raw 16S rRNA sequencing data from four adult ADHD case-control studies (NADHD=312, NNoADHD=305). We investigated diversity and differential abundance of selected genera (logistic regression and ANOVA-like Differential Expression tool), corrected for age and sex, and meta-analyzed the study results. Converging results were investigated for association with hyperactive/impulsive and inattentive symptoms across all participants. Beta diversity was associated with ADHD diagnosis but showed significant heterogeneity between cohorts, despite harmonized analyses. Several genera were robustly associated with adult ADHD; e.g.,Ruminococcus_torques_group(LogOdds=0.17, pfdr=4.42×10−2), which was more abundant in adults with ADHD, andEubacterium_xylanophilum_group(LogOdds= −0.12,pfdr=6.9 x 10−3), which was less abundant in ADHD.Ruminococcus_torques_groupwas further associated with hyperactivity/impulsivity symptoms andEisenbergiellawith inattention and hyperactivity/impulsivity (pfdr<0.05). The literature points towards a role of these genera in inflammatory processes. Irreproducible results in the field of gut-microbiota research, due to between study heterogeneity and small sample sizes, stress the need for meta-analytic approaches and large sample sizes. While we robustly identified genera associated with adult ADHD, that might overall be considered beneficial or risk-conferring, functional studies are needed to shed light on these properties.
Single cell AI-based detection of DNA mismatch repair deficiency in 1,988 colorectal cancers reveals prognostic and predictive value in the SCOT trial
Authors: Nowak Marta , Jabbar Faiz , Rodewald Ann-Katrin , Gneo Luciana , Tomasevic Tijana , Harkin Andrea , Iveson Tim , Saunders Mark , Kerr Rachel , Oein Karin , Maka Noori , Hay Jennifer , Edwards Joanne , Tomlinson Ian , Sansom Owen , Kelly Caroline , Easton Alistair , Domingo Enric ,   TransSCOT group, Koelzer Viktor H , Church David N
Published: December 2023

Testing for DNA mismatch repair deficiency (MMRd) is recommended for all colorectal cancers (CRC). Automation of this would facilitate precision medicine, particularly if it provided information on likely aetiology. We developed AIMMer, anAI-based method for determination ofMMRprotein expression at single cell level in routine pathology samples. We applied it to over 2,000 colorectal cancers (CRC) from the SCOT clinical trial, which compared 3 vs 6 months of oxaliplatin-based adjuvant chemotherapy (FOLFOX or CAPOX). Benchmarking of AIMMeR against pathologist ground truth MMR calls revealed AUROC of 0.98, and positive predictive value (PPV) greater than 95% for the commonest pa[ern of somatic MMRd, and for retained MMR expression. Analysis of CRC recurrence confirmed the prognostic value of MMRd in oxaliplatin-treated patients. While MMRd did not predict differential benefit from chemotherapy duration, it correlated with difference in clinical outcome by chemotherapy regimen (PInteraction=0.04). AIMMeR holds promise to reduce pathologist workflow and streamline clinical diagnostics in CRC.
Comparative basolateral amygdala connectomics reveals dissociable single-neuron projection patterns to frontal cortex in macaques and mice
Authors: Zeisler Zachary R , Heslin Kelsey A , Stoll Frederic M , Hof Patrick R , Clem Roger L , Rudebeck Peter H
Published: December 2023

Short abstract

The basolateral amygdala (BLA) projects to the frontal cortex (FC) in both rodents and primates, but the comparative organization of single-neuron BLA-FC projections is unknown. Using a barcoded connectomic approach, we found that BLA neurons are more likely to project to multiple distinct parts of FC in mice than in macaques. Further, while single BLA neuron projections to nucleus accumbens are similarly organized in mice and macaques, BLA-FC connections differ.
On the necessity to include multiple types of evidence when predicting molecular function of proteins
Authors: de Crécy-Lagard Valérie , Swairjo Manal A.
Published: December 2023

Machine learning-based platforms are currently revolutionizing many fields of molecular biology including structure prediction for monomers or complexes, predicting the consequences of mutations, or predicting the functions of proteins. However, these platforms use training sets based on currently available knowledge and, in essence, are not built to discover novelty. Hence, claims of discovering novel functions for protein families using artificial intelligence should be carefully dissected, as the dangers of overpredictions are real as we show in a detailed analysis of the prediction made by Kim et al1on the function of the YciO protein in the model organismEscherichia coli.
The Developmental Transcription Factor TBX3 Physically Engages with the Wnt/β-catenin Transcriptional Complex in Human Colorectal Cancer Cells to Regulate Metastasis Genes
Authors: Jauregi-Miguel Amaia , Söderholm Simon , Weiss Tamina , Nordin Anna , Ghezzi Valeria , Brütsch Salome M. , Pagella Pierfrancesco , van de Grift Yorick , Zambanini Gianluca , Ulisse Jacopo , Mattia Alessandro , Deviatiiarov Ruslan , Faustini Elena , Moparthi Lavanya , Lottersberger Francisca , Koch Stefan , Moor Andreas E. , Sun Xiao-Feng , von Castelmur Eleonore , Sheng Guojun , Cantù Claudio
Published: December 2023

Wnt signaling orchestrates gene expression in a plethora of processes during development and adult cell homeostasis via the action of nuclear β-catenin. Furthermore, neoplasia of the colorectal epithelium begins with aberrant Wnt/β-catenin signaling. Yet, little is known about how β-catenin generates context-specific transcriptional outcomes. We have previously identified the developmental transcription factor TBX3 as a tissue-specific component of the Wnt/β-catenin nuclear complex during mouse forelimb development. In this study, we show that TBX3 is present and functionally active in human colorectal cancers. TBX3’s genomic binding pattern suggests a regulatory role that broadly coincides with that of Wnt/β-catenin. Moreover, proteomics proximity labelling indicated that, during Wnt pathway activation, TBX3 is vicinal to several protein partners, including the transcription factors TCF/LEF and chromatin remodeling complexes which are usually found at Wnt responsive elements. Sequence and structure analysis revealed that TBX3 possesses an exposed Asp-Pro-Phe (NPF) motif predicted by AlphaFold2 Multimer to mediate direct interactions with several Wnt-activated TBX3 partners. Deletion of NPF abrogates TBX3 proximity to these partners and its ability to modulate Wnt-dependent transcription. TBX3 emerges as a key modulator of the oncogenic activity of Wnt/β-catenin in colorectal cancer, and its mechanism of action exposes a novel druggable protein-interaction surface.
JASPER: fast, powerful, multitrait association testing in structured samples gives insight on pleiotropy in gene expression
Authors: Mbatchou Joelle , McPeek Mary Sara
Published: December 2023

Joint association analysis of multiple traits with multiple genetic variants can provide insight into genetic architecture and pleiotropy, improve trait prediction and increase power for detecting association. Furthermore, some traits are naturally high-dimensional, e.g., images, networks or longitudinally measured traits. Assessing significance for multitrait genetic association can be challenging, especially when the sample has population sub-structure and/or related individuals. Failure to adequately adjust for sample structure can lead to power loss and inflated type 1 error, and commonly used methods for assessing significance can work poorly with a large number of traits or be computationally slow. We developed JASPER, a fast, powerful, robust method for assessing significance of multitrait association with a set of genetic variants, in samples that have population sub-structure, admixture and/or relatedness. In simulations, JASPER has higher power, better type 1 error control, and faster computation than existing methods, with the power and speed advantage of JASPER increasing with the number of traits. JASPER is potentially applicable to a wide range of association testing applications, including for multiple disease traits, expression traits, image-derived traits and microbiome abundances. It allows for covariates, ascertainment and rare variants and is robust to phenotype model misspecification. We apply JASPER to analyze gene expression in the Framingham Heart Study, where, compared to alternative approaches, JASPER finds more significant associations, including several that indicate pleiotropic effects, some of which replicate previous results, while others have not previously been reported. Our results demonstrate the promise of JASPER for powerful multitrait analysis in structured samples.
Chemotherapy synergizes with cancer vaccines and expands stem-like TCF1+CD8+ T cells
Authors: Noblecourt Laurine , Wicki Amanda , Pereira-Almeida Vinnycius , McAuliffe James , Steffke Emily , Panetti Silvia , Ramirez-Valdez Ramiro A. , Chandrasekar Vineethkrishna , Jainarayanan Ashwin , Hill Adrian V.S. , Van den Eynde Benoit J. , Leung Carol Sze Ki
Published: December 2023

Therapeutic cancer vaccines, whether based on neoantigens or shared antigens, will likely be given in the clinic together with the standard of care, which often comprises immune checkpoint blockade therapy and chemotherapy. It remains unclear, however, whether vaccines effectively synergize with chemotherapy. Here, we tested the combination of a heterologous prime-boost viral vector vaccine with chemotherapy (CarboTaxol) and anti-PD- 1. We show that this triple combination improves tumor control and survival in different murine tumor models. CarboTaxol, and also cyclophosphamide, acted as an immune adjuvant for the vaccines, enhancing tumor-specific CD8+ T-cell responses, irrespective of the presence of a tumor. These chemotherapies expanded stem-like T cell factor 1 (TCF1)+CD8+ T cells. Inhibition of the transcriptional activity of TCF1/β-catenin with a small molecule inhibitor abolished the immune adjuvant effect of CarboTaxol. This study sheds light on the new immunomodulatory roles of chemotherapies and holds promises for clinical testing of this combination strategy.

Highlights

The combination of CarboTaxol with viral vector cancer vaccines and anti-PD-1 promotes better tumor control, tumor clearance, and survival

CarboTaxol increases TCF1 expression in CD8+ T cells and expands stem-like TCF1+CD8+ T cells

CarboTaxol acts as an adjuvant for cancer vaccines irrespective of the presence of a tumor and this effect is mediated by TCF1/β-catenin activity
Genome-wide exploration of metabolic-based pyrethroid resistance mechanism inHelicoverpa armigera
Authors: Kim Juil , Rahman Md-Mafizur , Han Changhee , Jeon Jungwon , Kwon Min , Lee Si Hyeock , Omoto Celso
Published: December 2023

To elucidate the deltamethrin resistance mechanism inHelicoverpa armigera, we explored mutations at the deltamethrin target site, genomic level variations between insecticide-susceptible and -resistant strains, and differences in gene expression patterns between the strains. Known pyrethroid resistance-associated point mutations within the voltage-gated sodium channel were undetected in the cDNA and gDNA of resistant strains or field populations. The whole-genomede novoassembly of a Korean resistant strain was performed (GCA_026262555.1), and 13 genomes of susceptible and resistant individuals were re-sequenced using field populations. Approximately 3,369,837 variants (SNPs and indels) were compared with our referenceH. armigeragenome, and 1,032,689 variants were identified from open reading frames. A resistance-specific CYP3 subfamily gene with five variants (CYP321A1v1–v5) was identified in the resistant strains, indicating the potential role of these variants in resistance. RNA-seq analysis identified 36,720 transcripts from 45 Illumina RNA-seq datasets of the fat body, gut, and the rest of the body. Differential gene expression analysis revealed some differently overexpressed detoxification enzyme genes in the resistant strains, particularly cytochrome P450 genes. This finding was consistent with the results of bioassay tests using PBO-based synergists, further supporting the role of detoxification enzymes in resistance. Therefore,H. armigeramay acquire deltamethrin resistance through a combination of actions, including the overexpression of various detoxification enzymes, such as CYP3 subfamilies (CYP321A5) and cuticular proteins. The five variants of CYP321A subfamily identified in this study may serve as a basis for understanding insecticide resistance at the molecular level and can be applied as diagnostic markers for resistance.

Key Messages

Known resistance-related mutations were undetected in all the resistant strains or field populations.

No specific resistance-associated variations were identified at the genomic level.

The expression pattern of the CYP3 subfamily genes was strongly correlated with the level of resistance.

Genes other than CYP337B3 are also involved in the development of high-level resistance.

Resistance developed as a result of changes in the expression of detoxification genes rather than target site modification through mutation.
An approach to characterize mechanisms of action of anti-amyloidogenic compoundsin vitroandin situ
Authors: Stalder P. , Serdiuk T. , Ghosh D. , Fleischmann Y. , Malinovska L. , Davranche A. , Haenseler W. , Boudou C. , Tsika E. , Ouared A. , Stöhr J. , Melki R. , Riek R. , de Souza N. , Picotti P.
Published: December 2023

Aggregation of amyloidogenic proteins is associated with neurodegenerative disease and its modulation is a focus of drug development efforts. However, the physicochemical properties and structural heterogeneity of amyloidogenic proteins hinder the mechanistic understanding of anti- amyloidogenic compounds. Further, modes of interaction with amyloidogenic proteins are often probedin vitrousing purified protein samples, even though these models may not capturein vivoprotein structures and do not enable identification of off-target effects. We have developed a modular structural proteomic pipeline based on limited proteolysis coupled to mass spectrometry (LiP-MS) with improved, amino acid level-resolution, to probe the mechanism of action of anti- amyloidogenic compounds. We demonstrate our approach by analysing the interactions of six known or putative anti-amyloidogenic compounds and the amyloid binder Thioflavin T (ThT) with different structural forms of the amyloidogenic Parkinson’s disease (PD) protein α-Synuclein. Our approach enables determination of putative interaction sites, identification of whether interactions are covalent or non-covalent, and crucially, can probe for interactions of compounds with physiological structures of α-Synuclein in complex cell and tissue extracts and identify off-targets.In vitroanalyses with our pipeline showed that the green tea polyphenol EGCG induces an N- and C-terminus- dependent compaction of the unstructured α-Synuclein monomer, detected preferential interactions of ThT with the N-terminus of α-Synuclein fibrils compared to the amyloid core, and showed that the most potent inhibitors of aggregation in our study (EGCG, baicalein and AC Immune compound #2) induced similar non-fibrillar end structures despite different interactions with α-Synuclein monomers. Importantly, in mammalian cell lysates, α-Synuclein was either a low-affinity target (for EGCG and Baicalein) or did not show evidence of compound interaction (for ThT and doxycycline) in our experimental conditions, despite both monomeric and fibrillar forms interacting with these compoundsin vitro. For EGCG, we validated this result in postmortem brain homogenates from PD patients. Thesein situanalyses identified many additional putative cellular targets of Doxycycline, EGCG, Baicalein and ThT, suggesting that their effects in cellular or animal models of neurodegeneration are likely due to interactions with proteins other than α-Synuclein and showing that anti-amyloidogenic compounds should be analyzedin situas well asin vitro. Our modular pipeline will enablein situscreening of drugs and PET tracers for amyloid aggregates of interest as well as detailed mechanistic studies of compound actionin vitro.
Mussels on the move: new records of the invasive non-native quagga mussel (Dreissena rostriformis bugensis) in Great Britain using eDNA and a new probe-based qPCR assay
Authors: Peixoto Sara , Blackman Rosetta C. , Porter Jonathan , Wan Alan , Gerrard Chris , Aston Ben , Handley Lori Lawson
Published: December 2023

Invasive non-native species (INNS) pose a worldwide environmental threat, negatively impacting invaded ecosystems on an ecological and economical scale. In recent decades, quagga mussels (Dreissena rostriformis bugensis) have successfully invaded several countries in Western Europe from the Ponto-Caspian region, being recorded for the first time in Great Britain (GB) in 2014, in Wraysbury, near London. In recent years, environmental DNA (eDNA) analysis has proven to be a sensitive and effective method for early detection and monitoring of a number of INNS. Previously, a dye-based quantitative PCR (qPCR) assay was developed for the detection of quagga mussels from eDNA samples. Here, a target-specific probe was designed to further increase the specificity of this assay and used to obtain an updated distribution of this species in GB. Twenty-four sites were sampled, including sites with established populations near London and sites spread across the East Midlands and East Anglia regions. Positive detections were obtained for 11 of the 24 sites, and these were widely spread, as far as Nottingham (East Midlands) and Norfolk (East Anglia). Detection rates were 100% at the three sites with known established populations, while rates were lower (3-50% of positive replicates) in the eight newly-identified sites, consistent with an early stage of invasion. Of particular concern was the detection of quagga mussels in major waterways and in popular recreational sites, highlighting urgent measures are needed to control pathways and spread. Our study demonstrates that quagga mussels are considerably more widespread in GB than previously thought and provides a much-needed step towards operational use of eDNA for monitoring quagga mussels.
The dynamics of oligodendrocyte populations following permanent ischemia promotes long-term spontaneous remyelination of damaged area
Authors: Martín-Lopez Gerardo , Mallavibarrena Paula R. , Villa-Gonzalez Mario , Vidal Noemi , Pérez-Alvarez Maria José
Published: December 2023

Stroke is a major public health concern, whit limited clinically approved interventions available to enhance sensorimotor recovery beyond reperfusion. Remarkably, spontaneous recovery is observed in certain stroke patients, suggesting the existence of a self-brain repair mechanism not yet fully understood. In a rat model of permanent cerebral ischemia, we described an increase in oligodendrocytes expressing 3RTau in damaged area. Considering that restoration of myelin integrity ameliorates symptoms in many neurodegenerative diseases, here we hypothesize that this cellular response could trigger remyelination. Our results revealed after ischemia an early recruitment of OPCs to damaged area, followed by their differentiation into 3RTau+pre-myelinating cells and subsequent into remyelinating oligodendrocytes. Using rat brain slices and mouse primary culture we confirmed the presence of 3RTau in pre-myelinating oligodendrocytes and a subset of mature. The myelin status analysis confirmed long-term remyelination in the damaged area. Postmortem samples from stroke subjects showed a reduction in oligodendrocytes, 3RTau+cells, and myelin complexity in subcortical white matter. In conclusion, the dynamics of oligodendrocytes populations after ischemia reveals a spontaneous brain self-repair mechanism which restores the functionality of neuronal circuits long-term by remyelination of damage area. This is evidenced by the improvement of sensorimotor functions in ischemic rats. A deep understanding of this mechanism could be valuable in the search for alternative oligodendrocyte-based, therapeutic interventions to reduce the effects of stroke.