bluuebunny/crossref_metadata_2025 huggingface dataset:
A systematic review on the efficacy of CBT interventions for the mental and sexual health of survivors of prostate cancer
Authors: Pieramico Sonia , Castro Rita , Aguiar Sandra , Bismarck Francisca , Ferreira Diana , Carvalho Joana , Quinta Gomes Ana Luisa , Nobre Pedro
Published: June 2023

Introduction

Prostate cancer (PCa) is the second-most frequently diagnosed oncologic condition among biological men, affecting physical and psychological well-being, as well as sexual health and quality of life. Prior research has shown that cognitive-behavioral therapy (CBT) can be effective in addressing a range of psychological and sexual problems but also in improving the sexual and mental health of survivors of PCa.

Objectives

This systematic review aimed to methodically research and summarize results concerning the efficacy of CBT in the mental and sexual health of survivors of PCa.

Methods

A systematic search was carried out via electronic databases until August 2022 (EBSCO, MEDLINE, Cochrane Library, and Web of Science). By combining specific search words and following the PRISMA checklist, we identified 15 eligible articles among 8616 initial records.

Results

Four studies showed evidence of intervention efficacy for the improvement of sexual health, specifically for overall sexual function, erectile function, sexual desire, and sexual satisfaction. Eight studies found intervention efficacy for the improvement of mental health dimensions, such as psychological distress, depressive symptoms, anxiety, and quality of life.

Conclusion

There is evidence that CBT interventions have the potential to effectively promote mental and sexual health in survivors of PCa, but further research comprising larger and more diverse populations is needed. Future studies should focus on understanding mechanisms of change through CBT interventions to ensure the mental and sexual health of survivors of PCa.
DETECTION OF THE HYPERTENSION-MEDIATED COGNITIVE BRAIN DAMAGE. CLOCK DRAWING TEST UTILITY
Authors: Vicario Augusto , Cerchio Alejandro Erasmo De , Cesario Diego , Patron Facundo Risso , Plunkett Ricardo , Spósito Paola , Romano José Rene , Cerezo Gustavo Hernán
Published: June 2023

Objective:

Hypertension (HTN) is the main modifiable vascular risk factor for developing cognitive impairment and dementia. ‘Cognitive status’ could be a “surrogate” or ‘potential biomarker’ of HTN-mediated brain damage. Thirty percent of the hypertensive patients have cognitive impairment and/or silent brain damage (white matter hyperintensities) without cardio-renal damage. However, the involvement of the brain as a HTN-related target-organ damage (TOD) is not systematically evaluated. Then our objective were : 1) to know the prevalence of cerebral, cardiac, and renal TOD in a sample of hypertensive patients, and 2) to demonstrate the usefulness of the clock drawing test (CDT) as a cognitive screening tool to assess brain TOD HTN-mediated.

Design and method:

Multicentre study (4 centres in Argentina, 1 centre in Uruguay), 441 hypertensive patients were included. Age, gender, weight, height and other variables were recorded. Hypertension was defined according to ESH guidelines. TOD were defined as: renal compromise when, creatinine >1.2 mg/dl and/or creatinine clearance < 60 mL/min (Cockcroft-Gault equation), cardiac compromise when: left ventricular mass index > 95 gr/m2 in female and > 115 gr/m2 in male (transthoracic cardiac ultrasound) and cerebral impairment when: the score of the CDT </ = 5 points.

Results:

Average age 63.2±11.8 years, 53.4% female. The 60.5% of the sample presented some TO damage. The heart was affected in 32.8% and the kidney in 20.4% while the brain damage (abnormal CDT) was observed in 38% of the total sample, in 47.2% of the hypertensive patients with cardiac and/or renal damage, and in 30.7% of hypertensive patients without cardiac and/or renal damage.

Conclusions:

The CDT turned out to be a useful, fast and simple tool to be used in routine clinical practice to detect cerebral TOD (cognitive impairment) in hypertensive patients. The clinical expression of the cerebral TOD was more prevalent than pre-clinical cardiac and/or renal TOD.
The P300 Auditory Evoked Potential: A Physiological Measure of the Engagement of Cognitive Systems Contributing to Listening Effort?
Authors: Kestens Katrien , Van Yper Lindsey , Degeest Sofie , Keppler Hannah
Published: June 2023

Objectives:

This study aimed to explore the potential of the P300 (P3b) as a physiological measure of the engagement of cognitive systems contributing to listening effort.

Design:

Nineteen right-handed young adults (mean age: 24.79 years) and 20 right-handed older adults (mean age: 58.90 years) with age-appropriate hearing were included. The P300 was recorded at Fz, Cz, and Pz using a two-stimulus oddball paradigm with the Flemish monosyllabic numbers “one” and “three” as standard and deviant stimuli, respectively. This oddball paradigm was conducted in three listening conditions, varying in listening demand: one quiet and two noisy listening conditions (+4 and −2 dB signal to noise ratio [SNR]). At each listening condition, physiological, behavioral, and subjective tests of listening effort were administered. P300 amplitude and latency served as a potential physiological measure of the engagement of cognitive systems contributing to listening effort. In addition, the mean reaction time to respond to the deviant stimuli was used as a behavioral listening effort measurement. Last, subjective listening effort was administered through a visual analog scale. To assess the effects of listening condition and age group on each of these measures, linear mixed models were conducted. Correlation coefficients were calculated to determine the relationship between the physiological, behavioral, and subjective measures.

Results:

P300 amplitude and latency, mean reaction time, and subjective scores significantly increased as the listening condition became more taxing. Moreover, a significant group effect was found for all physiological, behavioral, and subjective measures, favoring young adults. Last, no clear relationships between the physiological, behavioral, and subjective measures were found.

Conclusions:

The P300 was considered a physiological measure of the engagement of cognitive systems contributing to listening effort. Because advancing age is associated with hearing loss and cognitive decline, more research is needed on the effects of all these variables on the P300 to further explore its usefulness as a listening effort measurement for research and clinical purposes.
Reductions in kinesiophobia and distress after pain neuroscience education and exercise lead to favourable outcomes: a secondary mediation analysis of a randomized controlled trial in primary care
Authors: Murillo Carlos , Galán-Martín Miguel Ángel , Montero-Cuadrado Federico , Lluch Enrique , Meeus Mira , Loh Wen Wei
Published: June 2023

Pain neuroscience education combined with exercise (PNE + exercise) is an effective treatment for patients with chronic spinal pain. Yet, however, little is known about its underlying therapeutic mechanisms. Thus, this study aimed to provide the first insights by performing a novel mediation analysis approach in a published randomized controlled trial in primary care where PNE + exercise was compared with standard physiotherapy. Four mediators (catastrophizing, kinesiophobia, central sensitization–related distress, and pain intensity) measured at postintervention and 3 outcomes (disability, health-related quality of life, and pain medication intake) measured at 6-month follow-up were included into the analysis. The postintervention measure of each outcome was also introduced as a competing candidate mediator in each respective model. In addition, we repeated the analysis by including all pairwise mediator–mediator interactions to allow the effect of each mediator to differ based on the other mediators' values. Postintervention improvements in disability, medication intake, and health-related quality of life strongly mediated PNE + exercise effects on each of these outcomes at 6-month follow-up, respectively. Reductions in disability and medication intake were also mediated by reductions in kinesiophobia and central sensitization–related distress. Reductions in kinesiophobia also mediated gains in the quality of life. Changes in catastrophizing and pain intensity did not mediate improvements in any outcome. The mediation analyses with mediator–mediator interactions suggested a potential effect modification rather than causal independence among the mediators. The current results, therefore, support the PNE framework to some extent as well as highlight the need for implementing the recent approaches for mediation analysis to accommodate dependencies among the mediators.
Preference for daily oral pills over long-acting antiretroviral therapy options among people with HIV
Authors: Barthold Douglas , Saldarriaga Enrique M. , Brah Aaron T. , Hauber Brett , Banerjee Pallavi , Fuller Shanil M. , McCaslin Divine , Moldoveanu Ana Maria , Marconi Vincent C. , Simoni Jane M. , Graham Susan M.
Published: June 2023

Objective:

To examine the characteristics of people with HIV (PWH) who prefer remaining on daily oral antiretroviral therapy (ART), rather than switching to long-acting ART (LA-ART).

Design:

Building upon a discrete choice experiment (DCE), we examined characteristics of individuals who always selected their current daily oral tablet regimen over either of two hypothetical LA-ART options presented in a series of 17 choice tasks.

Methods:

We used LASSO to select sociodemographic, HIV-related, and other health-related predictors of preferring current therapy over LA-ART, and logistic regression to measure the associations with those characteristics.

Results:

Among 700 PWH in Washington State and Atlanta, Georgia, 11% of participants (n = 74) chose their current daily treatment over LA-ART in all DCE choice tasks. We found that people with lower educational attainment, good adherence, more aversion to injections, and who participated from Atlanta to be more likely to prefer their current daily regimen over LA-ART.

Conclusions:

Gaps in ART uptake and adherence remain, and emerging LA-ART treatments show promise to address these challenges and help a larger portion of PWH to achieve viral suppression, but preferences for these new treatments are understudied. Our results show that certain drawbacks of LA-ART may help to maintain demand for daily oral tablets, especially for PWH with certain characteristics. Some of these characteristics (lower educational attainment and Atlanta participation) were also associated with a lack of viral suppression. Future research should focus on overcoming barriers that impact preferences for LA-ART among those patients who could benefit most from this innovation.
Peritoneal Carcinomatosis From Metastatic Prostate Cancer Identified on 68Ga-Prostate-Specific Membrane Antigen PET/CT
Authors: Lau Kin Sing , Le Ken , Bui Chuong , Wong Veronica Chi Ken , Mansberg Robert
Published: June 2023

A 69-year-old man with locally advanced prostate adenocarcinoma (Gleason score 9), who had completed hormone therapy and definitive radiotherapy, presented to hospital with abdominal pain and distension. A CT scan of the abdomen and pelvis revealed ascites and extensive peritoneal/omental nodules. Serum prostate-specific antigen was not raised (0.07 μg/L). 68Ga-prostate-specific membrane antigen (PSMA) PET/CT demonstrated PSMA-avid disease in the prostate and widespread PSMA-avid peritoneal/omental and liver metastases but with no PSMA-avid bony metastases. Peritoneal nodule biopsy confirmed metastatic prostate cancer.
Subtly Increased Focal FDG Activity in the Liver Due to Paragonimiasis
Authors: Dai Jiaona , Wang Haitao , Wang Hui , Tian Rong
Published: June 2023

A 32-year-old man underwent 18F-FDG PET/CT to evaluate suspicious hepatic metastases, which were revealed by ultrasonography and MRI. The FDG PET/CT images demonstrated only one focus of subtly increased activity in the liver without abnormality elsewhere. The pathological result from hepatic biopsy was consistent with Paragonimus westermani infection.
Sex, T Cells, and the Microbiome in Natural ABO Antibody Production in Mice
Authors: Adam Ibrahim , Motyka Bruce , Tao Kesheng , Jeyakanthan Mylvaganam , Alegre Maria-Luisa , Cowan Peter J. , West Lori J.
Published: June 2023

Background.

“Natural” ABO antibodies (Abs) are produced without known exposure to A/B carbohydrate antigens, posing significant risks for hyperacute rejection during ABO-incompatible transplantation. We investigated anti-A "natural" ABO antibodies versus intentionally induced Abs with regard to the need for T-cell help, the impact of sex, and stimulation by the microbiome.

Methods.

Anti-A was measured by hemagglutination assay of sera from untreated C57BL/6 wild-type (WT) or T cell–deficient mice of both sexes. Human ABO-A reagent blood cell membranes were injected intraperitoneally to induce anti-A Abs. The gut microbiome was eliminated by maintenance of mice in germ-free housing.

Results.

Compared with WT mice, CD4+ T-cell knockout (KO), major histocompability complex–II KO, and αβ/γδ T-cell receptor KO mice produced much higher levels of anti-A nAbs; females produced dramatically more anti-A nAbs than males, rising substantially with puberty. Sensitization with human ABO-A reagent blood cell membranes did not induce additional anti-A in KO mice, unlike WT. Sex-matched CD4+ T-cell transfer significantly suppressed anti-A nAbs in KO mice and rendered mice responsive to A-sensitization. Even under germ-free conditions, WT mice of several strains produced anti-A nAbs, with significantly higher anti-A nAbs levels in females than males.

Conclusions.

Anti-A nAbs were produced without T-cell help, without microbiome stimulation, in a sex- and age-dependent manner, suggestive of a role for sex hormones in regulating anti-A nAbs. Although CD4+ T cells were not required for anti-A nAbs, our findings indicate that T cells regulate anti-A nAb production. In contrast to anti-A nAbs, induced anti-A production was T-cell dependent without a sex bias.
Rapid Diagnostic Work-Up of Streptococcus dysgalactiae Endophthalmitis by a Novel Culture Processing System
Authors: Su Erin , Chang Jessica , Ugaban Khay , She Rosemary
Published: June 2023

The diagnosis of infective endophthalmitis is supported by microbiologic work-up. Rapid work-up is critical to confirm clinical suspicion and enable appropriate antimicrobial therapy. We report the novel use of an automated liquid culture processing system (Fast System, Qvella Corporation) in a vitreous fluid culture. A 59-year-old patient with post-operative endophthalmitis presented with acute right eye pain and blurred vision. Vitreous fluid collected for microbiology culture was of limited quantity and only inoculated to thioglycolate broth. Broth culture recovered beta-hemolytic, group G Streptococcus dysgalactiae susceptible to penicillin and vancomycin. Experimental application of the Fast System to isolate and concentrate the organism from the broth culture yielded the same identification and susceptibility test results but one day sooner than the standard workflow. Despite prompt treatment with appropriate antibiotics including vancomycin and ceftriaxone, disease progressed rapidly and required enucleation to achieve a stable therapeutic outcome. Use of automated processors such as the FAST System for monomicrobial broth cultures has thus far focused on positive blood culture broths, but could potentially include other liquid-based cultures such as for sterile body fluids of critical nature.
Impact of the COVID-19 restrictions on the epidemiology of Cryptosporidium spp. in England and Wales, 2015–2021: a time series analysis
Authors: Adamson James P. , Chalmers Rachel M. , Thomas Daniel Rh. , Elwin Kristin , Robinson Guy , Barrasa Alicia
Published: June 2023

Introduction. In England and Wales, cryptosporidiosis cases peak in spring and autumn, associated with zoonotic/environmental exposures (Cryptosporidium parvum, spring/autumn) and overseas travel/water-based activities (Cryptosporidium hominis, autumn). Coronavirus disease 2019 (COVID-19) restrictions prevented social mixing, overseas travel and access to venues (swimming pools/restaurants) for many months, potentially increasing environmental exposures as people sought alternative countryside activities.

Hypothesis. COVID-19 restrictions reduced incidence of C. hominis cases and potentially increased incidence of C. parvum cases.

Aim. To inform/strengthen surveillance programmes, we investigated the impact of COVID-19 restrictions on the epidemiology of C. hominis and C. parvum cases.

Methodology. Cases were extracted from the Cryptosporidium Reference Unit (CRU) database (1 January 2015 to 31 December 2021). We defined two periods for pre- and post-COVID-19 restrictions implementation, corresponding to before and after the first UK-wide lockdown on 23 March 2020. We conducted a time series analysis, assessing differences in C. parvum and C. hominis incidence, trends and periodicity between these periods.

Results. There were 21 304 cases (C. parvum=12 246; C. hominis=9058). Post-restrictions implementation incidence of C. hominis dropped by 97.5 % (95 % CI: 95.4–98.6 %; P<0.001). The decreasing incidence trend pre-restrictions was not observed post-restrictions implementation due to lack of cases. No periodicity change was observed post-restrictions implementation. There was a strong social gradient; there was a higher proportion of cases in deprived areas. For C. parvum, post-restrictions implementation incidence fell by 49.0 % (95 % CI: 38.4–58.3 %; P<0.001). There was no pre-restrictions incidence trend but an increasing incidence trend post-restrictions implementation. A periodicity change was observed post-restriction implementation, peaking 1 week earlier in spring and 2 weeks later in autumn. The social gradient was the inverse of that for C. hominis. Where recorded, 22 % of C. hominis and 8 % of C. parvum cases had travelled abroad.

Conclusion.
C. hominis cases almost entirely ceased post-restrictions implementation, reinforcing that foreign travel seeds infections. C. parvum incidence fell sharply but recovered post-restrictions implementation, consistent with relaxation of restrictions. Future exceedance reporting for C. hominis should exclude the post-restriction implementation period but retain it for C. parvum (except the first 6 weeks post-restrictions implementation). Infection prevention and control advice should be improved for people with gastrointestinal illness (GI) symptoms to ensure hand hygiene and swimming pool avoidance.
Serotypes and antimicrobial resistance of Streptococcus pneumoniae in children under 5 years of age pre- and post-pneumococcal conjugate vaccine introduction in Paraguay
Authors: León María Eugenia , Samudio Margarita , Kawabata Aníbal , Nagai Minako , Rojas Liliana , Zárate Noemí , Irala Juan , Leguizamón Myrian , Gómez Gloria , Ortellado Juana , Blasco Raquel , Franco Rossana , Chamorro Gustavo
Published: June 2023

Introduction.

Streptococcus pneumoniae

remains a major cause of mortality and morbidity worldwide in children <5 years of age, even with advances in vaccination programmes.

Hypothesis/Gap Statement. Reviewing and reporting trends in the distribution of pneumococcal serotypes and antimicrobial resistance in Paraguay will be useful for decision-making in public health.

Aim. This study analysed the serotype distribution and antimicrobial resistance of

S. pneumoniae

and the characteristics of pneumococcal disease in children <5 years old before and after the introduction of pneumococcal conjugate vaccines (PCVs).

Methodology. A total of 885 isolates and 278

S. pneumoniae

PCR-positive clinical specimens were referred to the Central Laboratory of Public Health (LCSP) within the meningitis and pneumonia laboratory based-surveillance network in the period 2006–2020. Conventional and molecular microbiological techniques were used for confirmation and characterization.

Results. We identified 563 cases of pneumococcal disease in the pre-vaccination period, 325 cases in the post-PCV10 period and 275 cases in the post-PCV13 period. The serotypes covered by PCV10 decreased from 78.6–6.5 %. However, additional serotypes covered by PCV13 increased from 6.6–57.5% and non-PCV13 serotypes increased from 14.8–36.0 % (P<0.001) in the post-PCV13 period. In cases of meningitis, the rate of resistance to penicillin decreased after the introduction of conjugate vaccines. No resistance to ceftriaxone was found in any period. In cases without meningitis, the rate of resistance to penicillin and ceftriaxone decreased slightly. However, the rate of resistance to erythromycin and tetracycline increased and that to trimethoprim–sulfamethoxazole (SXT) decreased in the post-PCV13 period compared to the pre-PCV period. The multidrug resistance rate was 8.5 %.

Conclusion. A change in the circulating serotypes and antimicrobial resistance to certain antibiotics was observed. Non-vaccine serotype circulation and multidrug resistance may compromise the success of the conjugate vaccines.
Analysis of Protein-Protein Interactions networks and cross-species transfer learning comparison for seven organisms
Authors: Martins Yasmmin C
Published: June 2023

Motivation

Protein-protein interactions (PPIs) can be used for a plenty of applications like inferring protein functions or even helping the drug discovery process. For human specie, there is a lot of validated information and functional annotations for the proteins in its interactome. In other species, the known interactome is much smaller compared with human and there are many proteins with few or no annotations by specialists. Understanding the interactome of other species helps to trace evolutionary characteristics, compare important biological processes and also build interactomes for new organisms according to other organisms more related with it instead of relying just to the human interactome.

Results

In this study, we evaluate the performance of PredPrIn workflow in predicting interactome for seven organisms in terms of scalability and precision showing that PredPrIn gets over than 70% of precision and it takes less than three days even on the largest datasets. We made a transfer learning analysis predicting an organism interactome from each other organism, we then showed an implication regarding to their evolutionary relation in the number of ortholog proteins shared between these organisms. We also present an analysis of functional enrichment showing the proportion of shared annotations between positive and false interactions predicted and extraction of topological features of each organism interactome such as proteins acting as hubs and bridge between modules. From each organism, one of the most frequent biological processes was selected and the proteins and pairs present in it were compared in terms of quantity in the interactome available in HINT database for that organism and the one predicted by PredPrIn. In this comparison we showed that we covered those proteins and pairs covered in HINT and also enriched these processes for almost all organisms.

Conclusions

In this work, we have proved the efficiency of PredPrIn workflow for protein interaction prediction for seven different organisms using scalability, performance and transfer learning analyses. We have also made cross-species interactome comparisons showing the most frequent biological processes for each organism as well as the topological features of each organism interactome showing the consistency with hypothesis about biological networks. Finally, we described the enrichment made by PredPrIn in selected biological processes showing that its prediction was important to enhance information about these organisms interactomes.
The relevance of accounting for parasympathetic as well as sympathetic arousal in threat conditioning: methodological and clinical considerations
Authors: Jaswetz Lars , de Voogd Lycia D. , Becker Eni S. , Roelofs Karin
Published: June 2023

Alterations in associative threat learning have been thought to underlie the aetiology and maintenance of anxiety disorders. Recent insights into the facilitatory role of parasympathetic arousal for threat coping have raised the question whether individual differences in parasympathetic versus sympathetic dominance during threat learning may explain the unstable relationship with anxiety vulnerability versus resilience. We applied an established threat-conditioning paradigm in 78 neurotypical individuals and assessed parasympathetic responses (relative bradycardia), as well as sympathetic response patterns (relative tachycardia and increased skin conductance responses -SCR). We observed threat-induced bradycardia as well as tachycardia during associative learning. Additionally, participants not showing conditioned SCR still exhibit significant conditioned threat responses expressed in parasympathetically driven threat bradycardia. Critically, tachycardia, rather than bradycardia, was linked to stronger initial conditioned SCRs and higher trait anxiety. These results suggest individual differences in sympathetic versus parasympathetic dominance may underlie anxiety vulnerability versus resilience.

Statement of relevance

Our findings underscore the relevance of assessing the whole spectrum of autonomic nervous system responses to threat. By assessing sympathetic and parasympathetic threat responses, we demonstrate associations with anxiety vulnerability, which could not be unveiled by assessing sympathetic arousal alone. Since alterations in associative threat learning are thought to underlie anxiety-related psychopathology, it is of clinical and methodological relevance to assess threat responses with measures that are sensitive to both parasympathetic and sympathetic arousal. Additionally, we show that individuals that lack sympathetically-driven conditioned SCRs -- often classified as non-learners -- in fact do show a parasympathetically-driven HR threat response (bradycardia). Critically, bradycardia was linked to lower trait anxiety. These results imply a paradigm shift in the field of threat learning, shifting the predominant focus on sympathetic arousal towards the balance between sympathetic and parasympathetic arousal. This could advance insights in the role of threat learning in anxiety vulnerability and resilience.
Rare coding variants inNOX4link high superoxide levels to psoriatic arthritis mutilans
Authors: Wang Sailan , Nikamo Pernilla , Laasonen Leena , Gudbjornsson Bjorn , Ejstrup Leif , Iversen Lars , Lindqvist Ulla , Alm Jessica J. , Eisfeldt Jesper , Zheng Xiaowei , Catrina Sergiu-Bogdan , Taylan Fulya , Vaz Raquel , Ståhle Mona , Tapia-Paez Isabel
Published: June 2023

Psoriatic arthritis mutilans (PAM) is the rarest and most severe form of psoriatic arthritis. PAM is characterized by erosions of the small joints of hands and feet and osteolysis leading to joint disruption. Despite its severity, the underlying mechanisms are unknown, and no candidate susceptibility genes have hitherto been identified. We aimed to investigate the genetic basis of PAM. We performed massive parallel sequencing of sixty-one patients’ genomes from the PAM Nordic cohort. We validated the rare variants found by Sanger sequencing and genotyped additional psoriasis, psoriatic arthritis, and control cohorts. We then tested the role of the variants usingin vivoandin vitromodels. We found rare variants with a minor allele frequency (MAF) below 0.0001 in the NADPH oxidase 4 (NOX4) in four patients.In silicopredictions show that the identified variants are potentially damaging. NOXs are the only enzymes producing reactive oxygen species (ROS). ROS are highly reactive molecules important role in the regulation of signal transduction. NOX4 is specifically involved in the differentiation of osteoclasts, the cells implicated in bone resorption. Functional follow-up studies using cell culture, zebrafish models, and measurement of ROS in patients uncovered that theNOX4variants found in this study increase the levels of ROS both invitroandin vivo.We proposeNOX4as the first candidate susceptibility gene for PAM. Our study links high levels of ROS caused byNOX4variants to the development of PAM, opening the possibility for a potential therapeutic target.
Intraspecific genetic variation is critical to robust toxicological predictions of aquatic contaminants
Authors: Shahmohamadloo René S. , Rudman Seth M. , Clare Catherine I. , Westrick Judy A. , Wang Xueqi , De Meester Luc , Fryxell John M.
Published: June 2023

Environmental risk assessment is a critical tool for protecting aquatic life and its effectiveness is predicated on predicting how natural populations respond to contaminants. Yet, routine toxicity testing typically examines only one genotype, which may render risk assessments inaccurate as populations are most often composed of genetically distinct individuals. To determine the importance of intraspecific variation in the translation of toxicity testing to populations, we quantified the magnitude of genetic variation within 20Daphnia magnaclones derived from one lake using whole genome sequencing and phenotypic assays. We repeated these assays across two exposure levels of microcystins, a cosmopolitan and lethal aquatic contaminant produced by harmful algal blooms. We found considerable intraspecific genetic variation in survival, growth, and reproduction, which was amplified by microcystins exposure. Finally, using simulations we demonstrate that the common practice of employing a single genotype to calculate toxicity tolerance failed to produce an estimate within the 95% confidence interval over half of the time. These results illuminate the importance of incorporating intraspecific genetic variation into toxicity testing to reliably predict how natural populations will respond to aquatic contaminants.
Genomes of historical specimens reveal multiple invasions of LTR retrotransposons inDrosophila melanogasterpopulations during the 19thcentury
Authors: Scarpa Almorò , Pianezza Riccardo , Wierzbicki Filip , Kofler Robert
Published: June 2023

Transposable element invasions have a profound impact on the evolution of genomes and phenotype. It is thus an important open question on how often such TE invasions occur. Based on strains sampled at different times, previous work showed that four different TE families invadedD. melanogasterduring the 20thcentury. Here we utilize the genomes of historical specimens to extend this work by another 100 years. We found that the LTR retrotransposons Blood, Opus and 412 spread inD. melanogasterin the 19thcentury. These invasions were found to constitute second waves, as degraded fragments were found for all three TEs. We show that two of the three invasions, Opus and 412, led to pronounced geographic heterogeneity, likely due to founder effects during the invasions. Finally, we identified species from the simulans complex as the likely origin of the TEs. In total, seven TE families invadedD. melanogasterduring the last 200 years, increasing the genome size by 1.2 Mbp. Based on the analysis of strains and specimens sampled at different times, we provide a detailed timeline of TE invasions, makingD. melanogasterthe first organism where we could infer the invasion history of TEs during the last two centuries.
Scattered differentiation of unlinked loci across the genome underlines ecological divergence of the selfing grassBrachypodium stacei
Authors: Mu Wenjie , Li Kexin , Yang Yongzhi , Breiman Adina , Yang Jiao , Wu Ying , Wu Shuang , Zhu Mingjia , Liu Jianquan , Nevo Eviatar , Catalan Pilar
Published: June 2023

Ecological divergence without geographic isolation, as an early speciation process that may lead finally to reproductive isolation through natural selection, remains one of the most interesting issues in evolutionary biology. However, the patterns of the underlying genetic divergences across the genome vary between different groups. Here we report thatBrachypodium stacei, an inbreeding grass species, has been involved in sympatric ecological divergence without geographic isolation. Genomic, transcriptomic, and metabolomic analyses suggest that diploidB. staceidiverged sympatrically in two slopes with contrasting biomes at Evolution Canyon I (ECI), Mount Carmel, Israel, where gene flow has continued freely but reduced with the time. This ecological divergence involved the scattered divergence of many unlinked loci across the total genome that include both coding and non-coding regions. We also identified significantly differential expressions of ABA signaling pathway genes, and contrasting metabolome composition between the arid-vsforest-adaptedB. staceiECI populations. These results suggest that many small loci involved in environmental responses act additively to account for the ecological usages of this species in contrasted environments with gene flow.

Significance

Ecological divergence provides evidence for the origin of species through natural selection that has governed evolutionists’ attention since Darwin. In this study, we present multiple-omics analyses of two plant populations growing sympatrically in contrasted environments and revealed their distinct differentiation across all examined data. These two populations share the most recent ancestor compared with other populations and their divergence started in the early Holocene. We revealed that gene flow had continued but with a progressive reduction over time. The genetic divergences are scattered across the total genome involving many unlinked coding and non-coding regions. These findings highlight the significance of natural selection in the ecological divergence that may finally lead to species formation without geographic isolation.
Estimating individuals’ exposure to predation risk in group-living baboons,Papio anubis
Authors: Suire Alexandre , Kunita Itsuki , Harel Roi , Crofoot Margaret , Mutinda Mathew , Kamau Maureen , Hassel James M. , Murray Suzan , Matsumoto-Oda Akiko
Published: June 2023

In environments with multiple predators, the vulnerabilities attached to the spatial positions of group-living prey are not uniform and depend on the hunting styles of the predators. Coursing predators, mainly canids and hyenas, follow their prey over long distances and attack open areas, making individuals at the edge of the group more dangerous than those at the center (marginal predation). In contrast, ambush predators, mainly cats, approach their prey undetected and appear randomly anywhere in the group; therefore, isolated individuals are at a greater risk of predation. However, identifying individuals at high risk of predation requires the simultaneous recording of predator locations and direct observation of predation events, which are both difficult. Therefore, several theoretical methods have been proposed to assess predation risk (predation risk proxies). In a group of wild anubis baboons exposed to predation by leopards, lions, and hyenas, we calculated predation risk proxies using movement data collected from global positioning system (GPS) collars and found that adult males were on the edge of the group with a higher risk of predation (Hypothesis 1). In addition, adult males were more isolated within this group (Hypothesis 2). None of the predation risks differed among the other age-sex classes. The most dominant male was expected to be in the safety center of the group (Hypothesis 3) but was isolated on the periphery, like the other males. Therefore, we discussed why adult males were more peripheral and isolated.
Modeling the 3D structure and conformational dynamics of very large RNAs using coarse-grained molecular simulations
Authors: Henderson Aaron N. , McDonnell Robert T. , Elcock Adrian H.
Published: June 2023

We describe a computational approach to building and simulating realistic 3D models of very large RNA molecules (>1000 nucleotides) at a resolution of one “bead” per nucleotide. The method starts with a predicted secondary structure and uses several stages of energy minimization and Brownian dynamics (BD) simulation to build 3D models. A key step in the protocol is the temporary addition of a 4thspatial dimension that allows all predicted helical elements to become disentangled from each other in an effectively automated way. We then use the resulting 3D models as input to Brownian dynamics simulations that include hydrodynamic interactions (HIs) that allow the diffusive properties of the RNA to be modelled as well as enabling its conformational dynamics to be simulated. To validate the dynamics part of the method, we first show that when applied to small RNAs with known 3D structures the BD-HI simulation models accurately reproduce their experimental hydrodynamic radii (Rh). We then apply the modelling and simulation protocol to a variety of RNAs for which experimental Rh values have been reported ranging in size from 85 to 3569 nucleotides. We show that the 3D models, when used in BD-HI simulations, produce hydrodynamic radii that are usually in good agreement with experimental estimates for RNAs that do not contain tertiary contacts that persist even under very low salt conditions. Finally, we show that sampling of the conformational dynamics of large RNAs on timescales of 100 µs is computationally feasible with BD-HI simulations.
Sex-specific mechanisms of cerebral microvascular BKCadysfunction in a mouse model of Alzheimer’s disease
Authors: Silva Josiane F. , Polk Felipe D. , Martin Paige E. , Thai Stephenie H. , Savu Andrea , Gonzales Matthew , Kath Allison M. , Gee Michael T. , Pires Paulo W.
Published: June 2023

Background

Cerebral microvascular dysfunction and nitro-oxidative stress are present in patients with Alzheimer’s disease (AD) and may contribute to disease progression and severity. Large conductance Ca2+-activated K+channels (BKCa) play an essential role in vasodilatory responses and maintenance of myogenic tone in resistance arteries. BKCaimpairment can lead to microvascular dysfunction and hemodynamic deficits in the brain. We hypothesized that reduced BKCafunction in cerebral arteries mediates microvascular and neurovascular responses in the5x-FADmodel of AD.

Methods

BKCaactivity in the cerebral microcirculation was assessed by patch clamp electrophysiology and pressure myography, in situ Ca2+sparks by spinning disk confocal microscopy, hemodynamics by laser speckle contrast imaging. Molecular and biochemical analyses were conducted by affinity-purification assays, qPCR, Western blots and immunofluorescence.

Results

We observed that pial arteries from 5-6 months-old male and female5x-FADmice exhibited a hyper-contractile phenotype than wild-type (WT) littermates, which was linked to lower vascular BKCaactivity and reduced open probability. In males, BKCadysfunction is likely a consequence of an observed lower expression of the pore-forming subunit BKαand blunted frequency of Ca2+sparks, which are required for BKCaactivity. However, in females, impaired BKCafunction is, in part, a consequence of reversible nitro-oxidative changes in the BKαsubunit, which reduces its open probability and regulation of vascular tone. We further show that BKCafunction is involved in neurovascular coupling in mice, and its dysfunction is linked to neurovascular dysfunction in the model.

Conclusion

These data highlight the central role played by BKCain cerebral microvascular and neurovascular regulation, as well as sex-dependent mechanisms underlying its dysfunction in a mouse model of AD.
The full spectrum of OCT1 (SLC22A1) mutations bridges transporter biophysics to drug pharmacogenomics
Authors: Yee Sook Wah , Macdonald Christian , Mitrovic Darko , Zhou Xujia , Koleske Megan L. , Yang Jia , Silva Dina Buitrago , Grimes Patrick Rockefeller , Trinidad Donovan , More Swati S. , Kachuri Linda , Witte John S. , Delemotte Lucie , Giacomini Kathleen M. , Coyote-Maestas Willow
Published: June 2023

Membrane transporters play a fundamental role in the tissue distribution of endogenous compounds and xenobiotics and are major determinants of efficacy and side effects profiles. Polymorphisms within these drug transporters result in inter-individual variation in drug response, with some patients not responding to the recommended dosage of drug whereas others experience catastrophic side effects. For example, variants within the major hepatic Human organic cation transporter OCT1 (SLC22A1) can change endogenous organic cations and many prescription drug levels. To understand how variants mechanistically impact drug uptake, we systematically study how all known and possible single missense and single amino acid deletion variants impact expression and substrate uptake of OCT1. We find that human variants primarily disrupt function via folding rather than substrate uptake. Our study revealed that the major determinants of folding reside in the first 300 amino acids, including the first 6 transmembrane domains and the extracellular domain (ECD) with a stabilizing and highly conserved stabilizing helical motif making key interactions between the ECD and transmembrane domains. Using the functional data combined with computational approaches, we determine and validate a structure-function model of OCT1s conformational ensemble without experimental structures. Using this model and molecular dynamic simulations of key mutants, we determine biophysical mechanisms for how specific human variants alter transport phenotypes. We identify differences in frequencies of reduced function alleles across populations with East Asians vs European populations having the lowest and highest frequency of reduced function variants, respectively. Mining human population databases reveals that reduced function alleles of OCT1 identified in this study associate significantly with high LDL cholesterol levels. Our general approach broadly applied could transform the landscape of precision medicine by producing a mechanistic basis for understanding the effects of human mutations on disease and drug response.
Boundary Bypass Activity in theAbdominal-BRegion of theDrosophilaBithorax Complex is Position Dependent and Regulated
Authors: Kyrchanova Olga , Ibragimov Airat , Postika Nikolay , Georgiev Pavel , Schedl Paul
Published: June 2023

Expression ofAbdominal-B(Abd-B) in abdominal segments A5–A8 is controlled by four regulatory domains,iab-5 – iab-8. Each domain has an initiator element (which sets the activity state), elements that maintain this state and tissue-specific enhancers. To ensure their functional autonomy, each domain is bracketed by boundary elements (Mcp,Fab-7,Fab-7andFab-8). In addition to blocking crosstalk between adjacent regulatory domains, theFabboundaries must also have bypass activity so the relevant regulatory domains can “jump over” intervening boundaries and activate theAbd-Bpromoter. In the studies reported here we have investigated the parameters governing bypass activity. We find that the bypass elements in theFab-7andFab-8boundaries must be located in the regulatory domain that is responsible for drivingAbd-Bexpression. We suggest that bypass activity may also be subject to regulation.

Summary Statement

Boundaries separatingAbd-Bregulatory domains block crosstalk between domains and mediate their interactions withAbd-B. The latter function is location but not orientation dependent.
Benefits and limits of biological nitrification inhibitors for plant N uptake and the environment
Authors: Kuppe Christian W. , Postma Johannes A.
Published: June 2023

Does root-exudation of biological nitrification inhibitors (BNIs) facilitate nitrogen (N) uptake and reduce pollution by N loss to the environment? We modeled the spatial-temporal dynamics of nitrifiers, ammonium, nitrate, and BNIs around a root and simulated root N uptake and net rhizosphere N loss over the plant’s life cycle. We determined the sensitivity of N uptake and loss to variation in the parameters, testing a broad range of soil-plant-microbial conditions.

An increase in BNI exudation reduces net N loss and, under most conditions, plant N uptake. BNIs decrease uptake in the case of (1) low ammonium concentrations, (2) high ammonium adsorption to the soil, (3) rapid nitrate-or slow ammonium uptake by the plant, and (4) a slowly growing or fast-declining nitrifier population.

Bactericidal inhibitors facilitate uptake more than bacteriostatic ones. Some nitrification, however, is necessary to maximize uptake by both ammonium and nitrate transporter systems. Selection for increased BNI exudation should co-select for improved ammonium uptake. BNIs can reduce N uptake, which may explain why not all species exude BNIs but have a generally positive effect on the environment by increasing rhizosphere N retention.
Long-term cytotoxic NK cells with broad anti-tumour capacity proliferate selectively, without exhaustion, after BCG priming and extremely low doses of cytokines
Authors: Felgueres María-José , Esteso Gloria , García-Jiménez Álvaro F. , Dopazo Ana , Martínez-Piñeiro Luis , Reyburn Hugh T. , Valés-Gómez Mar
Published: June 2023

Background:Natural killer (NK) cell-based immunotherapies, currently under investigation, appear to be safe, efficient treatments in patients with haematological tumours. Nevertheless, the short-lived nature of these cells combined with the need to infuse large number of cells for efficient tumour elimination represent important challenges for the development of NK cell-based therapies. Although NK cell anti-tumour activity is regulated by cytokines, constant stimulation together with the immunosuppressive tumour environment can result in NK cell exhaustion. Therefore, improved approaches to produce highly cytotoxic and longer-lived NK cells are of considerable clinical interest.

Methods:Peripheral blood mononuclear cells (PBMC) are primedin vitrowith a pulse of eitherBacillus Calmette-Guérin(BCG) vaccine or a cell wall extract ofM. bovis, followed by weekly stimulations with low doses of IL12, 15 and 21. The phenotype and anti-tumour fitness of the activated NK cell culture were examined using scRNA-seq, flow cytometry and functional assays, including degranulation, specific cytotoxicity and IFNγ release.

Results:we describe a novel strategy for the generation of long-lived activated NK cells capable of killing a broad range of solid tumours. A unique subset of cytotoxic NK cells (CD56highCD16+NKG2A+) specifically proliferatedin vitro, and was further expanded without functional exhaustion under minimal survival cytokine combinations. Mycobacterial cell-wall fractions also activated NK cells that recognised tumours efficiently, and proliferated well, and this approach has the advantage that no live bacteria are present in the cultures.

Conclusions:We propose that BCG-priming to expand anti-tumour NK cells, without cell sorting, could be a scalable and economical basis for the development of safe and universal cellular immunotherapies against solid tumours.

Key messages

Adoptive therapy with sorted NK cells grown in IL12, 15, 18 are being tested in clinical trials, but are only efficient for haematological tumours. In addition, their survivalin vivois limited. Here, we define culture conditions that drive the selective proliferation of long-lived natural killer (NK) cells, without the need of cell sorting, in minimal doses of cytokines, after priming with BCG or mycobacteria components. BCG-primed NK cells grow and maintain effective cytotoxic function against a variety of solid tumoursin vitro, without exhaustion for at least 28 days of culture. This new approach provides the basis for the generation of innate adoptive cell therapy tools.