bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of nonfermenting gram-negative infections: a critique of the guidelines
Authors: Bassetti Matteo , Vena Antonio , Giacobbe Daniele Roberto
Published: September 2023

Purpose of review

In the present narrative review, we discuss the characteristics and differences between the Infectious Diseases Society of America (IDSA) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines in terms on their recommendations/suggestions for the treatment of Pseudomonas aeruginosa and Acinetobacter baumannii infections.

Recent findings

Treatment of severe infections caused by nonfermenting gram-negative bacteria (NF-GNB) is posing both novel hopes and novel challenges to physicians worldwide, and both the IDSA and the ESCMID have recently updated/released their guidelines or guidance documents, based on different philosophies and providing recommendations for the treatment of NF-GNB infections. In order to correctly exploit recent advances in the treatment of such infections, IDSA and ESCMID approaches should be viewed as complementary and evolving, and should not preclude further revision based on accumulating evidence on the use of novel β-lactams and β-lactam/β-lactamase inhibitor combinations.

A joint consideration of both philosophies should leave the door opened for the wise use of novel agents, ultimately building precious experience on their use that could favorably influence future guidelines revisions.
One size does not fit all – Trehalose metabolism by Clostridioides difficile is variable across the five phylogenetic lineages
Authors: Marshall Andrew , McGrath John W. , Mitchell Molly , Fanning Séamus , McMullan Geoff
Published: September 2023

Clostridioides difficile

, the leading cause of antibiotic-associated diarrhoea worldwide, is a genetically diverse species which can metabolise a number of nutrient sources upon colonising a dysbiotic gut environment. Trehalose, a disaccharide sugar consisting of two glucose molecules bonded by an α 1,1-glycosidic bond, has been hypothesised to be involved in the emergence of

C. difficile

hypervirulence due to its increased utilisation by the RT027 and RT078 strains. Here, growth in trehalose as the sole carbon source was shown to be non-uniform across representative

C. difficile

strains, even though the genes for its metabolism were induced. Growth in trehalose reduced the expression of genes associated with toxin production and sporulation in the

C. difficile

R20291 (RT027) and M120 (RT078) strains in vitro, suggesting an inhibitory effect on virulence factors. Interestingly, the R20291 TreR transcriptional regulatory protein appeared to possess an activator function as its DNA-binding ability was increased in the presence of its effector, trehalose-6-phosphate. Using RNA-sequencing analysis, we report the identification of a putative trehalose metabolism pathway which is induced during growth in trehalose: this has not been previously described within the

C. difficile

species. These data demonstrate the metabolic diversity exhibited by

C. difficile

which warrants further investigation to elucidate the molecular basis of trehalose metabolism within this important gut pathogen.
Mediodorsal thalamic nucleus mediates resistance to ethanol through Cav3.1 T-type Ca2+regulation of neural activity
Authors: Latchoumane Charles-Francois V. , Lee Joon-Hyuk , Kim Seong-Wook , Kim Jinhyun , Shin Hee-Sup
Published: September 2023

Thalamocortical activity is known to orchestrate sensory gating and consciousness switching. The precise thalamic regions involved, or the firing patterns related to the unconsciousness remain unclear. Interestingly, the highly-expressed thalamic T-type calcium currents have been considered as a candidate for the ionic mechanism for the generation of thalamo-cortically-driven change in conscious state. Here, we tested the hypothesis that Cav3.1 T-type channels in the mediodorsal thalamic nucleus (MD) might control neuronal firing during unconsciousness using Cav3.1 T-type channel knock-out (KO) and knock-down (KD) mice under natural sleep and ethanol-induced unconsciousness. During natural sleep, the MD neurons in KO mice showed general characteristics of sustained firing across sleep stages. We found that KO and MD-specific KD mice showed enhanced resistance to ethanol. During ethanol-induced unconscious state, wild-type (WT) MD neurons showed a significant reduction in neuronal firing from baseline with increased burst firing, whereas Cav3.1 KO neurons showed well sustained neural firing, within the level of wakefulness, and no burst firing. Further, 20 Hz optogenetic and electrical activation of MD neurons mimicked the ethanol resistance behavior in WT mice. These results suggest that maintaining MD neural firing at a wakeful level is sufficient to induce resistance to ethanol-induced hypnosis in WT mice. This work has important implications for the design of treatments for consciousness disorders using thalamic stimulation of deeper nuclei including the targeting of the mediodorsal thalamic nucleus.

GRAPHICAL ABSTRACT
EZH2 deletion does not impact acinar cell regeneration but restricts progression to pancreatic cancer in mice
Authors: Jaune-Pons Emilie , Wang Xiaoyi , Mousavi Fatemeh , Elkaoutari Samad , Berger Kurt , Johnson Charis , Martin Mickenzie M. , Aggarwal Saloni , Brar Sukhman , Muhammad Khalid , Ryan Joanna , Shooshtari Parisa , Mathison Angela J. , Dusetti Nelson , Urrutia Raul , Lomberk Gwen , Pin Christopher L.
Published: September 2023

Enhancer of Zeste Homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which induces trimethylation of lysine 27 on histone 3 (H3K27me3) and promotes genes repression. EZH2 is overexpressed in many cancers including pancreatic ductal adenocarcinoma (PDAC). Previous studies in mice attributed both pro-oncogenic and tumor suppressive functions to EZH2. Deletion of the EZH2 enhancesde novoKRAS-driven neoplasia following pancreatic injury by preventing acinar cell regeneration, while increased EZH2 expression in PDAC is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression. In this study, we examined EZH2 function in pre-and early neoplastic stages of PDAC. Using an inducible model to generate deletion of EZH2 only in adult acinar cells (EZH2ΔSET), we showed loss of EZH2 activity did not prevent acinar cell regeneration in the absence of oncogenic KRAS (KRASG12D), nor lead to increased PanIN formation in the presence of KRASG12Din adult mice. However, loss of EZH2 did reduce recruitment of inflammatory cells and, when combined with a PDAC model, promoted widespread PDAC progression. Loss of EZH2 function also correlated to remodeling of the tumor microenvironment, which favors cancer cell progression. This study suggests expression of EZH2 in adult acinar cells restricts PDAC initiation and progression by affecting both the tumour microenvironment and acinar cell differentiation.
Individual Behavioral Variability Across Time and Contexts inDendrobates tinctoriusPoison Frogs
Authors: Soto Katharina M , Hardin Faith O , Alleyne Harmen P , Fischer Eva K
Published: September 2023

Consistent individual differences in behavior (“animal personality”) have consequences for individual fitness, evolutionary trajectories, and species’ persistence. Such differences have been documented across a wide range of animals, though amphibians are generally underrepresented in this research area. The aim of our study was to examine consistent individual differences in Dyeing poison frogs,Dendrobates tinctorius. We evaluated repeatability in behaviors including activity, exploration, and boldness to assess consistency of behaviors across different temporal, experimental, and environmental contexts. We found repeatability in activity and exploration across time and contexts. In contrast, we observed context-specific behavior for our metrics of boldness, with consistent individual differences only for some measures. Further, while activity and exploration displayed consistent correlations across contexts, relationships between activity and boldness were context dependent. Our findings document the presence of consistent individual differences in behavior inD. tinctoriuspoison frogs, and also reveal context-dependent behavioral differences, highlighting the complex relationship between consistent individual differences and context-specific responses in animal behavior.

Statement of Significance

The concept of animal personality centers on the existence of consistent individual differences in behavior. However, behavioral responses can depend on context, and consistent individual differences in one context do not guarantee consistent differences in another. To address this question, we assessed activity, exploration, and boldness in captive-bred poison frogs (Dendrobates tinctorius) across time and environmental contexts. Our comprehensive approach revealed consistent individual differences in some behaviors and context-specificity in others. While activity and exploration were generally repeatable and correlated with one another, boldness was not. Especially in view of the emphasis on measures of boldness in the animal personality literature, our findings emphasize the importance of reiterative and holistic approaches in the study of animal behavior.
Leaf δ13C reveals post-photosynthetic fractionation during ontogeny in a C4grass
Authors: Yu Yong Zhi , Liu Hai Tao , Yang Fang , Li Lei , Schäufele Rudi , Tcherkez Guillaume , Schnyder Hans , Gong Xiao Ying
Published: September 2023

The13C isotope composition (δ13C) of leaf dry matter is a useful tool for physiological and ecological studies. However, how post-photosynthetic fractionation associated with respiration and carbon export influences δ13C remains uncertain. We investigated the effects of post-photosynthetic fractionation on δ13C of mature leaves ofCleistogenes squarrosa, a perennial C4grass, in controlled experiments with different levels of vapour pressure deficit and nitrogen supply. With the increase of leaf age classes, the12C/13C fractionation of leaf organic matter relative to the δ13C of atmosphere CO2(ΔDM) increased while that of cellulose (Δcel) was almost constant. The divergence between ΔDMand Δcelincreased with leaf age classes with a maximum value of 1.6‰, indicating the accumulation post-photosynthetic fractionation. Applying a new mass balance model that accounts for respiration and export of photosynthates, we found an apparent12C/13C fractionation associated with carbon export of –0.5 to –1.0‰. Different ΔDMamong leaves, pseudostems, daughter tillers and roots indicate that post-photosynthetic fractionation happens at the whole-plant level. Compared with ΔDMof old leaves, ΔDMof young leaves and Δcelare more reliable proxies for predicting physiological parameters due to the smaller sensitivity to post-photosynthetic fractionation and the similar sensitivity in responses to environmental changes.

BRIEF SUMMARY STATEMENT

Δ13C of bulk organic matter increases with leaf age classes while Δ13C of cellulose remain constant, lending support to the use of Δ13C of cellulose as a more reliable proxy for predicting physiological parameters due to the smaller sensitivity to post-photosynthetic fractionation.
Hematopoietic Stem Cells Undergo Differentiation State Reprogramming to Overcome Venetoclax Sensitivity in Patients with Myelodysplastic Syndromes
Authors: Rodriguez-Sevilla Juan Jose , Ganan-Gomez Irene , Ma Feiyang , Chien Kelly , Montalban-Bravo Guillermo , Kanagal-Shamanna Rashmi , Loghavi Sanam , Adema Vera , Bazinet Alexandre , Garcia-Manero Guillermo , Colla Simona
Published: September 2023

While the molecular mechanisms of acute myeloid leukemia failure to venetoclax-based therapy have been recently clarified, the mechanisms whereby patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated.

Here, we show for the first time that MDS hematopoietic stem cells (HSCs) can undergo hierarchical differentiation reprogramming toward a granulo-monocytic-biased transcriptional state through the acquisition or expansion of clones with an isolated trisomy 8 cytogenetic aberration andSTAG2orRUNX1mutations. This hierarchical rewiring changes HSCs’ survival dependence from BCL-2-mediated anti-apoptotic pathways to TNFα-induced pro-survival NF-κB signaling and overcomes venetoclax-mediated cytotoxic effect. These findings underscore the importance of close molecular monitoring of patients with MDS enrolled in clinical trials of venetoclax to prevent HSC transcriptional reprogramming before the disease becomes resistant to this therapy.
Description ofProtosticta sexcoloratussp. nov. (Odonata, Platystictidae) from the Western Ghats, India
Authors: Chandran Ayikkara Vivek , Muneer P K , Madhavan M , Jose Subin K.
Published: September 2023

ProtostictaSelys, 1885 is a speciose genus of damselflies distributed in the tropical and subtropical forests of Asia. During an ongoing study to document the odonate diversity of the Western Ghats, we came across a colony ofProtostictaspecies in Wayanad, Kerala, that appeared different from all other species hitherto described. We describe this population as a new species after detailed morphological comparison with closely similar species occurring in the region.
Unintended events in long-distance neonatal interhospital transport in Western Australia: A comparison of neonatal specialist and non-neonatal specialist transport teams
Authors: Gardiner Jacqueline , McDonald Kylie , Blacker Joanne , Athikarisamy Sam , Sharp Mary , Davis Jonathan
Published: September 2023

Objective

To compare unintended events in transport performed by neonatal specialist (NS) and non-neonatal specialist (NNS) teams in Western Australia (WA).

Study design: Retrospective comparison of neonatal transports from the Kimberley and Pilbara regions (WA) to tertiary services, King Edward Memorial (perinatal) and Perth Children’s Hospital NICU, in Perth (state capital, distance up to 2200km) between January 2018 - June 2021. NS teams travelled from the tertiary to the referring center and back. NNS travelled from the referring to the tertiary center. Transport time, team composition, total unintended clinical, endotracheal tube (ETT), and logistic events were compared. Categorial data are expressed as numbers (%) and compared by chi-squared test; continuous data are expressed as median (interquartile range) and compared by Mann-Whitney U test.

Results

During the study period, 3,709 infants were transported in WA to tertiary services for escalation of care: 119(3.2%) from the Kimberley and Pilbara, 49 with NS and 70 with NNS teams. NNS had shorter transport times than NS teams (508(435 – 609) vs 871(615 – 735) min; p<0.00001). Neonatal nurses were on NS more than NNS teams (36/49(73.5%) vs 6/70(9%); p<0.001). Total unintended clinical and ETT events were less in NS vs. NSS teams (28/49(57%) vs. 54/70(77%); p=0.02) and (0/26(0%) vs. 7/23(30%); p=0.004). Unintended logistic events were greater involving NS than NNS teams (31/49 (63%) vs. 33/70 (47%); p=0.05).

Conclusion

Although NS teams had longer transport times and more unintended logistic events, there were fewer unintended clinical and ETT events. NS teams should be considered as the first choice to undertake neonatal transport.
Soil surveillance for monitoring soil-transmitted helminth infections: method development and field testing in three countries
Authors: Manuel Malathi , Amato Heather K. , Pilotte Nils , Chieng Benard , Araka Sylvie B. , Siko Joël Edoux Eric , Harris Michael , Nadimpalli Maya , Janagaraj Venkateshprabhu , Houngbegnon Parfait , Rajendiran Rajeshkumar , Thamburaj Joel , Kaliappan Saravanakumar Puthupalayam , Sirois Allison R. , Walch Gretchen , Oswald William E. , Asbjornsdottir Kristjana H. , Galagan Sean R. , Walson Judd L. , Williams Steven A. , Luty Adrian J. F. , Njenga Sammy M. , Ibikounlé Moudachirou , Ajjampur Sitara S.R. , Pickering Amy J.
Published: September 2023

One-fifth of the global population is infected with soil-transmitted helminths (STH). Mass drug administration (MDA) with deworming medication is widely implemented to control morbidity associated with STH infections. However, surveillance of human infection prevalence by collecting individual stool samples is time-consuming, costly, often stigmatized, and logistically challenging. Current methods of STH detection are poorly sensitive, particularly in low-intensity and low-prevalence populations. Here, we developed a sensitive and specific molecular method for detecting STH DNA in large volumes of soil by conducting laboratory and proof of concept studies across field sites in Kenya, Benin, and India. We collected human stool (n=669) and soil (n= 478) from 322 households across the three study sites. The overall prevalence of STH in soil was 31% forAscaris lumbricoides, 3% forT. trichuris, and 24% for any hookworm species. Detection of an STH species in household soil was strongly associated with increased odds of a household member being infected with that species. Soil surveillance for STH has several benefits over stool-based surveillance, including lower cost and higher success rates for sample collection. Considering that delivery of MDA occurs at the community level, environmental surveillance using molecular methods could be a cost-effective alternate strategy for monitoring STH in these populations.

Synopsis

Limited data exists on the prevalence and reliability of environmental soil-transmitted helminth (STH) DNA as a marker of human infections in endemic populations. We developed a new molecular detection method for STH DNA in large-volume soil samples and field-tested it across three countries.
Association between Body Mass Index and Risk of Aortic Stenosis in Women
Authors: Kontogeorgos Silvana , Rosengren Annika , Sandström Tatiana Zverkova , Fu Michael , Lindgren Martin , Basic Carmen , Svanvik Maria-Teresia , Djekic Demir , Thunström Erik
Published: September 2023

Background

Overweight and obesity are increasing globally, as are life expectancy and disorders associated with aging, including calcific aortic stenosis (AS). Studies investigating the correlation between high body mass index (BMI) and AS are contradictory and inconclusive. This study examines a potential association between BMI and early AS in women.

Methods

By linking the Swedish Medical Birth Register (MBR) and the Swedish National Patient Register (NPR), we included women between 18 and 55 years with a first childbirth from 1982 to 2020. Diagnosis of subsequent AS and comorbidities were defined according to the International Classification of Diseases (ICD) 8, 9, and 10 codes. The women were divided into eight groups based on their BMI, with BMI 20 kg/m2-<22.5 kg/m2as reference. Cox proportional hazards regression models were used to investigate the difference in the risk of being diagnosed with AS.

Results

The mean age at inclusion among 1,722,798 women was 28 years, and the mean BMI was 24 kg/m2. Some 21% were overweight (BMI 30 kg/m2-<35 kg/m2) and 10.7% were obese (BMI≥35 kg/m2). During a median follow-up of 19.5 years, 2,513 women (0.15%) were diagnosed with AS. The age-adjusted risk of being diagnosed with AS, compared to a reference group with BMI 20 -<22.5 kg/m2, increased with higher BMI to 2.8 (95%CI 2.43-3.24) times higher in women with BMI 30 -<35 kg/m2, and to 3.67 (95%CI 2.91-4.64) times higher in those with severe obesity (BMI ≥35 kg/m2). Similar results were found after excluding AS of rheumatic and congenital etiology.

Conclusions

Higher BMI correlated with a higher risk of developing AS in women, regardless of etiology, beginning with increased risk even within the upper normal range, reaching a three times higher risk in women with severe obesity.

Clinical perspective

What is new?

This study investigates a subpopulation seldom included in valvular heart diseases studies, younger women, showing that women with overweight and obesity have approximately three times higher risk to be diagnosed with AS.

Even women in the BMI group considered high-normal (BMI 22.5 -<25 kg/m2) had higher risk for AS compared those with BMI 20 -<22.5 kg/m2.

What are the clinical implications?

The percentage of individuals with overweight and obesity increases and in the same time, AS becomes more prevalent as the population ages. Considering that there is no medical treatment that can ameliorate AS prognosis, prevention by maintaining a low-normal or normal BMI becomes even more important.
Intimate partner violence and its correlates in middle-aged and older adults during the COVID-19 pandemic: A multi-country secondary analysis
Authors: Chang Gwendolyn , Tucker Joseph , Walker Kate , Chu Claire , Miall Naomi , Tan Rayner , Wu Dan
Published: September 2023

Background

Intimate partner violence (IPV) may have been exacerbated during the COVID-19 pandemic. Middle-aged and older adults, ages 45 years or older, are at higher risk of COVID-19 mortality and social isolation. However, most studies on IPV during the pandemic do not focus on this important subpopulation. Informed by the social-ecological theory, this study examines individual, household, community, and country-level correlates of IPV among middle-aged and older adults in multiple countries using a cross-sectional online survey.

Methods

Data from 2867 participants aged over 45 in the International Sexual Health and Reproductive Health (I-SHARE) survey from July 2020 to February 2021 were described using univariate analysis. IPV was defined using four validated WHO measures. Individual characteristics included self-isolation and food security. At the country-level, we examined social distancing stringency. Logistic regression models with a random intercept for country were conducted to explore IPV correlates among 1730 eligible individuals from 20 countries with complete data.

Results

Most participants were heterosexual (2469/2867), cisgender (2531/2867) females (1589/2867) between the ages of 45-54 (1539/2867). 12.1% (346/2867) of participants experienced IPV during social distancing measures. After adjustment, participants who self-isolated experienced 1.4 (95% CI 1.0, 2.0, p=0.04) times the odds of IPV compared to those who had not isolated. Those who reported an increase in food insecurity compared to pre-pandemic experienced 2.2 times the odds (95% CI 1.6, 3.0, p<0.0001) of IPV compared to those who did not report increased food insecurity. People in countries with more stringent social distancing policies were less likely to experience IPV compared to people in countries with lower levels of stringency (aOR=0.6, 95% CI 0.4, 0.9, p=0.04).

Conclusions

IPV was common among middle-aged and older adults during the COVID-19 pandemic. Our data suggest the need for further crisis management and social protection measures for middle-aged and older adults who have intersecting vulnerabilities to IPV to mitigate COVID-19 impact.
Wild sulphur-crested cockatoos match human activity rhythms to access food in the urban environment
Authors: Fehlmann G. , Martin J. M. , Safi K. , Aplin L. M.
Published: September 2023

Abstract

Urban areas are growing rapidly across the globe, and wild species are occupying this new environment. Despite offering potential resources, disparities in the urban matrix can lead to specific challenges, with pathways and resources fragmented in space and time. Urban-dwelling species would therefore benefit from learning when and where to exploit human derived food. Here, we investigate whether birds synchronize the exploitation of the most urbanized areas to match food-provisioning patterns, using the example of the popular hand-feeding of sulphur-crested cockatoos (Cacatua galerita) in Sydney, Australia. We monitored the provisioning behaviour of people via a large-scale citizen science program, and tested for synchrony with the spatial behaviour of eight birds equipped with GPS loggers. Our data show that sulphur-crested cockatoos exploited the urban environment, relying on the green areas of the city; importantly, they also visited buildings within more urbanized areas. Sulphur-crested cockatoos used urban space with specific time patterns particularly matching human recreational feeding routines, suggestive of time-place learning. We show that urban environments provide daily temporal foraging resources for which species adjust behaviorally. Thus, our data support the general claim that retaining green spaces in cities is essential to sustainable urban planning, and key to allow species to exploit the urban environment, particularly in areas of high human density. This study builds on the literature investigating human-animal interactions, expanding our understanding of animals’ exploitation of human behavior. Further research should include the impact of such interactions on urban wildlife’s fitness according to their cognitive and behavioral traits.
Quantifying brain connectivity signatures by means of polyconnectomic scoring
Authors: Libedinsky Ilan , Helwegen Koen , Guerrero Simón Laura , Gruber Marius , Repple Jonathan , Kircher Tilo , Dannlowski Udo , van den Heuvel Martijn P.
Published: September 2023

A broad range of neuropsychiatric disorders are associated with alterations in macroscale brain circuitry and connectivity. Identifying consistent brain patterns underlying these disorders by means of structural and functional MRI has proven challenging, partly due to the vast number of tests required to examine the entire brain, which can lead to an increase in missed findings. In this study, we propose polyconnectomic score (PCS) as a metric designed to quantify the presence of disease-related brain connectivity signatures in connectomes. PCS summarizes evidence of brain patterns related to a phenotype across the entire landscape of brain connectivity into a subject-level score. We evaluated PCS across four brain disorders (autism spectrum disorder, schizophrenia, attention deficit hyperactivity disorder, and Alzheimer’s disease) and 14 studies encompassing ∼35,000 individuals. Our findings consistently show that patients exhibit significantly higher PCS compared to controls, with effect sizes that go beyond other single MRI metrics ([min, max]: Cohen’sd= [0.30, 0.87],AUC= [0.58, 0.73]). We further demonstrate that PCS serves as a valuable tool for stratifying individuals, for example within the psychosis continuum, distinguishing patients with schizophrenia from their first-degree relatives (d= 0.42,p= 4 x 10−3, FDR-corrected), and first-degree relatives from healthy controls (d= 0.34,p= 0.034, FDR-corrected). We also show that PCS is useful to uncover associations between brain connectivity patterns related to neuropsychiatric disorders and mental health, psychosocial factors, and body measurements.
A simple theory for finding related sequences by adding probabilities of alternative alignments
Authors: Frith Martin C.
Published: September 2023

The main way of analyzing genetic sequences is by finding sequence regions that are related to each other. There are many methods to do that, usually based on this idea: find an alignment of two sequence regions, which would be unlikely to exist between unrelated sequences. Unfortunately, it is hard to tell if an alignment is likely to exist by chance. Also, the precise alignment of related regions is uncertain. One alignment does not hold all evidence that they are related. We should consider alternative alignments too. This is rarely done, because we lack a simple and fast method that fits easily into practical sequence-search software. Here is described a simplest-possible change to standard sequence alignment, which sums probabilities of alternative alignments. Remarkably, this makes it easier to tell if a similarity is likely to occur by chance. This approach is better than standard alignment at finding distant relationships, at least in a few tests. It can be used in practical sequence-search software, with minimal increase in implementation difficulty or run time. It generalizes to different kinds of alignment, e.g. DNA-versus-protein with frameshifts. Thus, it can widely contribute to finding subtle relationships between sequences.
Endometrial zinc transporterSlc39a10/Zip10is indispensable for progesterone responsiveness and successful pregnancy in mice
Authors: Kawata Yui , Terakawa Jumpei , Takeshita Ayuu , Namiki Takafumi , Kageyama Atsuko , Noguchi Michiko , Murakami Hironobu , Fukada Toshiyuki , Ito Junya , Kashiwazaki Naomi
Published: September 2023

Zinc is a critical trace element that is important for various biological functions including male and female reproductive systems, but the molecular mechanisms that underlie fertility have been unclear. We show here for the first time that zinc signaling in the endometrial tissue is indispensable for successful embryo implantation in mice. We observed that a uterine-specific genetic deletion ofSlc39a10/Zip10, which encodes one of the zinc transporters to elevate the cytoplasmic level of zinc, results in severe female infertility due to failure of embryo invasion into the endometrium.Zip10mRNA is expressed in uterine tissues, especially in the decidualizing stromal cells during embryo implantation. Absence ofZip10results in the suppression of zinc ion influx in the uterine stromal cells and an attenuation of progesterone – progesterone receptor signals between the epithelium and the stroma, leading to failure of embryo invasion due to sustained epithelial integrity and subsequent embryonic loss. Our findings (i) highlight a biological relevance of ZIP10-mediated zinc homeostatic regulation in the establishment of a successful pregnancy and (ii) will help to prevent infertility in humans.
Adaptive Group Behavior of Fragile X Mice in Unfamiliar Environments
Authors: Giua Gabriele , Strauss Benjamin , Lassalle Olivier , Chavis Pascale , Manzoni Olivier J.
Published: September 2023

Fragile X Syndrome (FXS) stands out as a prominent cause of inherited intellectual disability and a prevalent disorder closely linked to autism. FXS is characterized by substantial alterations in social behavior, encompassing social withdrawal, avoidance of eye contact, heightened social anxiety, increased arousal levels, language deficits, and challenges in regulating emotions. Conventional behavioral assessments primarily focus on short-term interactions within controlled settings. In this study, we conducted a comprehensive examination of the adaptive group behavior of FXS mice over a three-day period, without introducing experimental interventions or task-based evaluations. The data unveiled intricate behavioral anomalies, with the most significant changes manifesting during the initial adaptation to unfamiliar environments. Notably, certain behaviors exhibited a gradual return to typical patterns over time. This dynamic FXS phenotype exhibited heightened activity, featuring increased exploration, amplified social interest, and an unconventional approach to social interactions characterized by a higher frequency of shorter engagements. These findings contribute to the growing understanding of social behavior in individuals with FXS and underscore the significance of comprehending their adaptive responses in various environmental contexts.
Emergence of a somatosensory tonotopic map for substrate vibration in the brainstem
Authors: Lee Kuo-Sheng , Wagner Dominica de Thomas , Sanders Mark , Huber Daniel
Published: September 2023

Perceiving substrate vibrations is a fundamental component of tactile perception. The wide frequency spectrum of vibrations is covered by integrating responses of multiple mechanoreceptors that innervate various subtypes of mechanosensitive end organs, each preferring a specific range: Merkel cells (0.5-10Hz), Meissner corpuscles (10-150Hz) and Pacinian corpuscles (150-1000Hz) in primates. As the density of different end organs greatly varies across the body, each body part potentially has a specific frequency preference. How location (somatotopy) and frequency tuning (tonotopy) are processed along the ascending neuraxis and how they converge to drive responses of individual neurons is poorly understood. In this study, we address this question by combiningin vivoperipheral electrophysiology and two-photon calcium imaging along the entire dorsal column-medial lemniscal pathway, including the dorsal root ganglia, dorsal column nuclei (DCN), the thalamus and the cortex. Surprisingly, we found that both frequency, as well as location, are organised into structured maps in the DCN. Furthermore, both maps are intimately related at the fine spatial scale with parallel map gradients that are consistent across the depth of the DCN and preserved along the ascending pathway. Additional sensory mapping experiments based on peripheral characterisation revealed that the tonotopic map only partially reflects the distribution of end organs in the skin and deep tissue. Instead, we show that the emergence of the finescale tonotopy is probably due to the selective dendritic sampling from axonal afferents, right at the first synaptic relay. Taken together, we conclude DCN neural circuits are key to the emergence of these two fine-scale topological organisations in early somatosensory pathways. The underlying computational principle is intriguingly similar to the integration of multiple functional maps along the ascending visual pathways, suggesting a universal law governing the optimization of sensory systems.
An amphioxus neurula stage cell atlas supports a complex scenario for the emergence of vertebrate head mesoderm
Authors: Grau-Bové Xavier , Subirana Lucie , Meister Lydvina , Soubigou Anaël , Neto Ana , Elek Anamaria , Fornas Oscar , Gomez-Skarmeta Jose Luis , Tena Juan J. , Irimia Manuel , Bertrand Stéphanie , Sebé-Pedrós Arnau , Escriva Hector
Published: September 2023

The emergence of new structures can often be linked to the evolution of novel cell types that follows the rewiring of developmental gene regulatory subnetworks. Vertebrates are characterized by a complex body plan compared to the other chordate clades and the question remains of whether and how the emergence of vertebrate morphological innovations can be related to the appearance of new embryonic cell populations. We already proposed, by studying mesoderm development in the cephalochordate amphioxus, a scenario for the evolution of the vertebrate head mesoderm. To further test this scenario at the cell population level, we used scRNA-seq to construct a cell atlas of the amphioxus neurula, stage at which the main mesodermal compartments are specified. Our data allowed us to confirm the presence of a prechordal-plate like territory in amphioxus, and shows that cell populations of the anteriormost somites and of the ventral part of the somites present a transcriptomic profile supporting the homology with vertebrate cranial/pharyngeal and lateral plate mesoderm. Finally, our work provides evidence that the appearance of the specific mesodermal structures of the vertebrate head was associated to both segregation of pre-existing cell populations, and co-option of new genes for the control of myogenesis.
A multiplexed, single-cell sequencing screen identifies compounds that increase neurogenic reprogramming of murine Muller glia
Authors: Tresenrider Amy , Hooper Marcus , Todd Levi , Kierney Faith , Blasdel Nicolai , Trapnell Cole , Reh Thomas A.
Published: September 2023

Retinal degeneration in mammals causes permanent loss of vision, due to an inability to regenerate naturally. Some non-mammalian vertebrates show robust regeneration, via Muller glia (MG). We have recently made significant progress in stimulating adult mouse MG to regenerate functional neurons by transgenic expression of the proneural transcription factor Ascl1. While these results showed that MG can serve as an endogenous source of neuronal replacement, the efficacy of this process is limited. With the goal of improving this in mammals, we designed a small molecule screen using sci-Plex, a method to multiplex up to thousands of single nucleus RNA-seq conditions into a single experiment. We used this technology to screen a library of 92 compounds, identified, and validated two that promote neurogenesisin vivo. Our results demonstrate that high-throughput single-cell molecular profiling can substantially improve the discovery process for molecules and pathways that can stimulate neural regeneration and further demonstrate the potential for this approach to restore vision in patients with retinal disease.
Differential Patterns of Associations within Audiovisual Integration Networks in Children with ADHD
Authors: Zamanzadeh Mohammad , Pourhedayat Abbas , Bakouie Fatemeh , Hadaeghi Fatemeh
Published: September 2023

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by symptoms of inattention and impulsivity and has been linked to disruptions in functional brain connectivity and structural alterations in large-scale brain networks. While anomalies in sensory pathways have also been implicated in the pathogenesis of ADHD, exploration of sensory integration regions remains limited. In this study, we adopted an exploratory approach to investigate the connectivity profile of auditory-visual integration networks (AVIN) in children with ADHD and neurotypical controls, utilizing the ADHD-200 rs-fMRI dataset. In addition to network-based statistics (NBS) analysis, we expanded our exploration by extracting a diverse range of graph theoretical features. These features served as the foundation for our application of machine learning (ML) techniques, aiming to discern distinguishing patterns between the control group and children with ADHD. Given the significant class imbalance in the dataset, ensemble learning models like balanced random forest (BRF), XGBoost, and EasyEnsemble classifier (EEC) were employed, designed to cope with unbalanced class observations. Our findings revealed significant AVIN differences between ADHD individuals and neurotypical controls, enabling automated diagnosis with moderate accuracy. Notably, the XGBoost model demonstrated balanced sensitivity and specificity metrics, critical for diagnostic applications, providing valuable insights for potential clinical use.

These findings offer further insights into ADHD’s neural underpinnings and high-light the potential diagnostic utility of AVIN measures, but the exploratory nature of the study underscores the need for future research to confirm and refine these findings with specific hypotheses and rigorous statistical controls.
Short- and long-term experience-dependent neuroplasticity interact during the perceptual learning of concurrent speech
Authors: MacLean Jessica , Stirn Jack , Sisson Alexandria , Bidelman Gavin M.
Published: September 2023

Plasticity from auditory experiences shapes brain encoding and perception of sound. However, whether such long-term plasticity alters the trajectory of short-term plasticity during speech processing has yet to be investigated. Here, we explored the neural mechanisms and interplay between short- and long-term neuroplasticity for rapid auditory perceptual learning of concurrent speech sounds in young, normal-hearing musicians and nonmusicians. Participants learned to identify double-vowel mixtures during ∼45 minute training sessions recorded simultaneously with high-density EEG. We analyzed frequency-following responses (FFRs) and event-related potentials (ERPs) to investigate neural correlates of learning at subcortical and cortical levels, respectively. While both groups showed rapid perceptual learning, musicians showed faster behavioral decisions than nonmusicians overall. Learning-related changes were not apparent in brainstem FFRs. However, plasticity was highly evident in cortex, where ERPs revealed unique hemispheric asymmetries between groups suggestive of different neural strategies (musicians: right hemisphere bias; nonmusicians: left hemisphere). Source reconstruction and the early (150-200 ms) time course of these effects localized learning-induced cortical plasticity to auditory-sensory brain areas. Our findings confirm domain-general benefits for musicianship but reveal successful speech sound learning is driven by a critical interplay between long- and short-term mechanisms of auditory plasticity that first emerge at a cortical level.
ElegansBot: Development of equation of motion deciphering locomotion including omega turns ofCaenorhabditis elegans
Authors: Chung Taegon , Chang Iksoo , Kim Sangyeol
Published: September 2023

Locomotion is a fundamental behavior ofCaenorhabditis elegans(C. elegans). Previous works on kinetic simulations of animals helped researchers understand the physical mechanisms of locomotion and the muscle-controlling principles of neuronal circuits as an actuator part. It has yet to be understood howC. elegansutilizes the frictional forces caused by the tension of its muscles to perform sequenced locomotive behaviors. Here, we present a two-dimensional rigid body chain model for the locomotion ofC. elegansby developing Newtonian equations of motion for each body segment ofC. elegans. Having accounted for friction-coefficients of the surrounding environment, elastic constants ofC. elegans, and its kymogram from experiments, our kinetic model (ElegansBot) reproduced various locomotion ofC. eleganssuch as, but not limited to, forward-backward-(omega turn)-forward locomotion constituting escaping behavior and delta-turn navigation. Additionally, ElegansBot precisely quantified the forces acting on each body segment ofC. elegansto allow investigation of the force distribution. This model will facilitate our understanding of the detailed mechanism of various locomotive behaviors at any given friction-coefficients of the surrounding environment. Furthermore, as the model ensures the performance of realistic behavior, it can be used to research actuator-controller interaction between muscles and neuronal circuits.
Blood-based multivariate methylation risk score for cognitive impairment and dementia
Authors: Koetsier Jarno , Cavill Rachel , Reijnders Rick , Harvey Joshua , Deckers Kay , Köhler Sebastian , Eijssen Lars , Smith Rebecca G. , Smith Adam R. , Burrage Joe , Walker Emma M. , Shireby Gemma , Hannon Eilis , Dempster Emma , Frayling Tim , Mill Jonathan , Dobricic Valerija , Sommerer Yasmine , Johannsen Peter , Wittig Michael , Franke Andre , Vandenberghe Rik , Schaeverbeke Jolien , Freund-Levi Yvonne , Frölich Lutz , Scheltens Philip , Teunissen Charlotte , Frisoni Giovanni , Blin Olivier , Richardson Jill , Bordet Régis , Engelborghs Sebastiaan , de Roeck Ellen , Martinez-Lage Pablo , Tainta Mikel , Lleó Alberto , Sala Isabel , Popp Julius , Peyratout Gwedoline , Verhey Frans , Tsolaki Magda , Andreasson Ulf , Blennow Kaj , Zetterberg Henrik , Streffer Johannes , Vos Stephanie J. B. , Lovestone Simon , Visser Pieter-Jelle , Bertram Lars , Lunnon Katie , Pishva Ehsan
Published: September 2023

INTRODUCTION

Given the established association between DNA methylation and the pathophysiology of dementia and its plausible role as a molecular mediator of lifestyle and environment, blood-derived DNA methylation data could enable early detection of dementia risk.

METHODS

In conjunction with an extensive array of machine learning techniques, we employed whole blood genome-wide DNA methylation data as a surrogate for 14 modifiable and non-modifiable factors in the assessment of dementia risk in two independent cohorts of Alzheimer’s disease (AD) and Parkinson’s disease (PD).

RESULTS

We established a multivariate methylation risk score (MMRS) to identify the status of mild cognitive impairment (MCI) cross-sectionally, independent of age and sex. We further demonstrated significant predictive capability of this score for the prospective onset of cognitive decline in AD and PD.

DISCUSSION

Our work shows the potential of employing blood-derived DNA methylation data in the assessment of dementia risk.
Associations of Combined Phenotypic Aging and Genetic Risk with Incident Cancer: A Prospective Cohort Study
Authors: Bian Lijun , Ma Zhimin , Fu Xiangjin , Ji Chen , Wang Tianpei , Yan Caiwang , Dai Juncheng , Ma Hongxia , Hu Zhibin , Shen Hongbing , Wang Lu , Zhu Meng , Jin Guangfu
Published: September 2023

Background

Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer.

Methods

Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and 9 biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs).

Results

Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18-1.27) in men, 1.26 (1.22-1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10-2.51) for men and 1.94 (1.78-2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = -1.01 in men,P< 0.001; Beta = -0.98 in women,P< 0.001).

Conclusions

Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle.
Multi-task analysis of gene expression data on cancer public datasets
Authors: Martins Yasmmin
Published: September 2023

Background

There is an availability of omics and often multi-omics cancer datasets on public databases such as Gene Expression Omnibus (GEO), International Cancer Genome Consortium and The Cancer Genome Atlas Program. Most of these databases provide at least the gene expression data for the samples contained in the project. Multi-omics has been an advantageous strategy to leverage personalized medicine, but few works explore strategies to extract knowledge relying only on gene expression level for decisions on tasks such as disease outcome prediction and drug response simulation. The models and information acquired on projects based only on expression data could provide decision making background for future projects that have other level of omics data such as DNA methylation or miRNAs.

Results

We extended previous methodologies to predict disease outcome from the combination of protein interaction networks and gene expression profiling by proposing an automated pipeline to perform the graph feature encoding and further patient networks outcome classification derived from RNA-Seq. We integrated biological networks from protein interactions and gene expression profiling to assess patient specificity combining the treatment/control ratio with the patient normalized counts of the deferentially expressed genes. We also tackled the disease outcome prediction from the gene set enrichment perspective, combining gene expression with pathway gene sets information as features source for this task. We also explored the drug response outcome perspective of the cancer disease still evaluating the relationship among gene expression profiling with single sample gene set enrichment analysis (ssGSEA), proposing a workflow to perform drug response screening according to the patient enriched pathways.

Conclusion

We showed the importance of the patient network modeling for the clinical task of disease outcome prediction using graph kernel matrices strategy and showed how ssGSEA improved the prediction only using transcriptomic data combined with pathway scores. We also demonstrated a detailed screening analysis showing the impact of pathway-based gene sets and normalization types for the drug response simulation. We deployed two fully automatized Screening workflows following the FAIR principles for the disease outcome prediction and drug response simulation tasks.

Availability

The ScreenDOP code is available athttps://github.com/yascoma/screendopwhile the DReCaS is available athttps://github.com/YasCoMa/caliscoma_pipeline/