bluuebunny/crossref_metadata_2025 huggingface dataset:
Examining speech-brain tracking during early bidirectional, free-flowing caregiver-infant interactions
Authors: Phillips E.A.M. , Goupil L. , Ives J. E. , Labendzki P. , Whitehorn M. , Marriott Haresign I. , Wass S.V.
Published: May 2024

Neural entrainment to slow modulations in the amplitude envelope of infant-directed speech is thought to drive early language learning. Most previous research with infants examining speech-brain tracking has been conducted in controlled, experimental settings, which are far from the complex environments of everyday interactions. Whilst recent work has begun to investigate speech-brain tracking to naturalistic speech, this work has been conducted in semi-structured paradigms, where infants listen to live adult speakers, without engaging in free-flowing social interactions. Here, we test the applicability of mTRF modelling to measure speech-brain tracking in naturalistic and bidirectional free-play interactions of 9-12-month-olds with their caregivers. Using a backwards modelling approach, we test individual and generic training procedures, and examine the effects of data quantity and quality on model fitting. We show model fitting is most optimal using an individual approach, trained on continuous segments of interaction data. Corresponding to previous findings, individual models showed significant speech-brain tracking at delta modulation frequencies, but not in alpha and theta bands. These findings open new methods for studying the interpersonal micro-processes that support early language learning. In future work, it will be important to develop a mechanistic framework for understanding how our brains track naturalistic speech during infancy.
RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability
Authors: Provasek Vincent E. , Bacolla Albino , Rangaswamy Suganya , Mitra Joy , Kodavati Manohar , Yusuf Issa O. , Malojirao Vikas H. , Vasquez Velmarini , Britz Gavin W. , Li Guo-Min , Xu Zuoshang , Mitra Sankar , Garruto Ralph M. , Tainer John A. , Hegde Muralidhar L.
Published: May 2024

TAR DNA-binding protein 43 (TDP43) is increasingly recognized for its involvement in neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 proteinopathy, characterized by dysregulated nuclear export and cytoplasmic aggregation, is present in most ALS/FTD cases and is associated with a loss of nuclear function and genomic instability in neurons. Building on prior evidence linking TDP43 pathology to DNA double-strand breaks (DSBs), this study identifies a novel regulatory role for TDP43 in the DNA mismatch repair (MMR) pathway. We demonstrate that depletion or overexpression of TDP43 affects the expression of key MMR genes, including MLH1, MSH6, MSH2, MSH3, and PMS2. Specifically, TDP43 modulates the expression of MLH1 and MSH6 proteins through alternative splicing and transcript stability. These findings are validated in ALS mice models, patient-derived neural progenitor cells and autopsied brain tissues from ALS patients. Furthermore, MMR depletion showed a partial rescue of TDP43-induced DNA damage in neuronal cells. Bioinformatics analysis of TCGA cancer database reveals significant correlations between TDP43 and MMR gene expressions and mutational burden across various cancer subtypes. These results collectively establish TDP43 as a critical regulator of the MMR pathway, with broad implications for understanding the genomic instability underlying neurodegenerative and neoplastic diseases.
The phylogenetic position of the Yunxian cranium elucidates the origin of Dragon Man and the Denisovans
Authors: Feng Xiaobo , Lu Dan , Gao Feng , Fang Qin , Feng Yilu , Huang Xuchu , Tan Chen , Zhou Hanwen , Li Qiang , Zhang Chi , Stringer Chris , Ni Xijun
Published: May 2024

Diverse Middle Pleistocene forms ofHomocoexisted in Africa, Europe, and Asia. It is very controversial whether these fossil humans represent different species or lineages. The ∼1 Ma old Yunxian 2 fossil from China is crucial for understanding the cladogenesis ofHomoand the origin ofHomo sapiens. Here, we restored and reconstructed the distorted Yunxian 2 cranium using new technology. The results show that this cranium displays mosaic features of plesiomorphy and apomorphy. Phylogenetic analyses and Bayesian tip-dating including the reconstructed Yunxian 2 suggest that it is an early member of the Asian ‘Dragon Man’ lineage, which probably includes the Denisovans, and is the sister group of theHomo sapienslineage. Both theH. sapiensand Dragon Man lineages had deep roots extending beyond the Middle Pleistocene, and the basal position of the Yunxian fossil cranium suggests it represents a population lying close to the last common ancestor of the two lineages.

One-Sentence Summary

The newly-reconstructed Yunxian 2 cranium represents a basal member of the Dragon Man and Denisovan lineage, and probably lies close to the last common ancestor of that lineage and the lineage ofH. sapiens.
Kinetic Analysis of Lanthipeptide Cyclization by Substrate-Tolerant ProcM
Authors: Desormeaux Emily K. , van der Donk Wilfred A.
Published: May 2024

Lanthipeptides are ribosomally synthesized and post-translationally modified peptides characterized by the presence of thioether crosslinks. Class II lanthipeptide synthetases are bifunctional enzymes responsible for the multistep chemical modification of these natural products. ProcM is a class II lanthipeptide synthetase known for its remarkable substrate tolerance and ability to install diverse (methyl)lanthionine rings with high accuracy. Previous studies suggested that the final ring pattern of the lanthipeptide product may be determined by the substrate sequence rather than by ProcM, and that ProcM operates by a kinetically controlled mechanism, wherein the ring pattern is dictated by the relative rates of the individual cyclization reactions. This study utilizes kinetic assays to determine if rates of isolated modifications can predict the final ring pattern present in prochlorosins. Changes in the core substrate sequence resulted in changes to the reaction rates of ring formation as well as a change in the order of modifications. Additionally, individual chemical reaction rates were significantly impacted by the presence of other modifications on the peptide. These findings indicate that the rates of isolated modifications are capable of predicting the final ring pattern but are not necessarily a good predictor of the order of modification in WT ProcA3.3 and its variants.
Highly heterogeneous human herpes virus-8 oral shedding kinetics among people with and without Kaposi sarcoma and HIV- co-infection
Authors: Krantz Elizabeth M. , Mutyaba Innocent , Nankoma Janet , Okuku Fred , Casper Corey , Orem Jackson , Swan David A. , Phipps Warren , Schiffer Joshua T.
Published: May 2024

Background

An improved understanding of oral human herpesvirus-8 (HHV-8) viral dynamics could provide insights into transmission risk and guide vaccine development.

Methods

We evaluated HHV-8 oral shedding dynamics in Ugandan adults stratified by Kaposi sarcoma (KS) and HIV status. Participants were followed for ≥4 weeks, with daily home oral swab collection to quantify HHV-8 using Polymerase Chain Reaction. Shedding rates were defined by the number of days with HHV-8 detected divided by the total days with swabs and compared by group using hurdle models.

Results

295 participants were enrolled; median age was 35 years (range 18-71), 134 (45%) were male. HHV-8 was detected more frequently among participants with KS (HIV+/KS+ 56/76, 74%; HIV-/KS+ 9/18, 50%) than those without KS (HIV+/KS-36/125, 29%; HIV-/KS-16/76, 21%); odds of shedding did not differ significantly by HIV status. Among participants with HHV-8 detected, shedding rates did not differ significantly by group. Median per-participant viral loads among positive samples were lowest in HIV+/KS+ (3.1 log10copies/mL) and HIV-/KS+ participants (3.3 log10copies/mL) relative to HIV+/KS-(3.8 log10copies/mL) and HIV-/KS-participants (4.0 log10copies/mL). All groups had participants with low-viral load intermittent shedding and those with high-viral load persistent shedding. Within each group, individual HHV-8 shedding rate positively correlated with median HHV-8 log10copies/mL, and episode duration positively correlated with peak viral load.

Conclusions

Oral HHV-8 shedding is highly heterogeneous across Ugandan adults with and without KS and HIV. Persistent shedding is associated with higher median viral loads regardless of HIV and KS status.
Simulating genetic risk scores from summary statistics with an application to type 1 diabetes
Authors: Squires Steven , Weedon Michael N. , Oram Richard A.
Published: May 2024

Motivation

Genetic risk scores (GRS) summarise genetic data into a single number and allow for discrimination between cases and controls. Many applications of GRSs would benefit from comparisons with multiple datasets to assess quality of the GRS across different groups. However, genetic data is often unavailable. If summary statistics of the genetic data could be used to simulate GRSs more comparisons could be made, potentially leading to improved research.

Results

We present a methodology that utilises only summary statistics of genetic data to simulate GRSs with an example of a type 1 diabetes (T1D) GRS. An example on European populations of the mean T1D GRS for real and simulated data are 10.31 (10.12-10.48) and 10.38 (10.24-10.53) respectively. An example of a case-control set for T1D has a area under the receiver operating characteristic curve of 0.917 (0.903-0.93) for real data and 0.914 (0.898-0.929) for simulated data.

Availability

The code is available athttps://github.com/stevensquires/simulating_genetic_risk_scores.

Contact

s.squires@exeter.ac.uk
Remote Ischemic Conditioning for Neonatal Hypoxic-Ischemic Encephalopathy: A Safety and Feasibility Trial
Authors: Lo Emily , Cizmeci Mehmet N. , Wilson Diane , Ly Linh G. , El-Shahed Amr , Offringa Martin , Pierro Agostino , Kalish Brian T.
Published: May 2024

Objective

To test the hypothesis that remote ischemic conditioning (RIC) is safe and feasible as an adjunctive neuroprotective treatment in neonates with hypoxic-ischemic encephalopathy (HIE) during therapeutic hypothermia (TH).

Study design

In this prospective, randomized, safety and dose escalation study in 32 neonates with HIE undergoing TH at a single quaternary referral NICU, four cohorts of consecutive patients received escalating therapy as follows: the first cohort of four patients received 3 minutes of limb ischemia by inflating a blood pressure cuff followed by 3 minutes of reperfusion; the second cohort of four patients received 5 minutes of limb ischemia followed by 5 minutes of reperfusion; the third cohort of four patients received 5 minutes of limb ischemia followed by 5 minutes of reperfusion on days 1 and 2 of TH; and the last cohort of four patients received 5 minutes of limb ischemia followed by 5 minutes of reperfusion on days 1, 2, and 3 of TH. For patients randomized to the control arm (n=16), a blood pressure cuff was applied without inflation. Each patient received 4 cycles of RIC or sham. Clinical, biochemical, and safety outcomes were monitored in both groups.

Results

All patients received the designated RIC therapy without interruption or delay on days 1-3 of TH. RIC was not associated with increased pain, vascular, cutaneous, muscular, or neural safety events. There was no difference in the incidence of seizures, brain injury, or mortality between the two groups with the escalation of RIC dose and frequency.

Conclusion

RIC is a safe and feasible adjunctive therapy for neonates with HIE undergoing TH. Future studies to investigate the potential efficacy of RIC for HIE are warranted.
Enhancing Healthcare Accessibility: A Comprehensive Usability Study of Pathpoint® eDerma Software
Authors: Subramaniyan Balamurugan , Naqvi Atlas , Mohamud Muna , Mahapatra Piyush
Published: May 2024

This research presents a comprehensive usability evaluation of Pathpoint® eDerma Software, conducted in accordance with IEC 62366-1:2015 standards. The study encompasses four diverse user groups, that includes administrators, medical photographers, dermatologists, and patients, ensuring a holistic assessment of the software’s usability and effectiveness. Through a combination of quantitative metrics and qualitative feedback, the study explores various aspects such as accessibility, navigation, safety, and user satisfaction. Potential risks to user experience and patient data security are identified and addressed to ensure compliance with safety standards. The findings highlight the software’s effectiveness in facilitating remote assessments, streamlining workflows, and improving patient care. This research contributes valuable insights to the ongoing refinement and optimisation of eDerma Software, aiming to enhance its usability, safety, and overall effectiveness in real-world healthcare settings.
EEG Correlates of Delayed Emergence after Remimazolam-Induced Anaesthesia Compared to Propofol
Authors: Lee Yeji , Park Sujung , Kim Hyoungkyu , Kim Jeongmin , Kim Eun Jung , Park Youngjai , Lee Uncheol , Kwon Jeongwook , Moon Joon-Young , Koo Bon-Nyeo
Published: May 2024

Background

Delayed emergence from anaesthesia presents clinical challenges, including prolonged stays in the post-anaesthesia care unit (PACU). The neurobiological mechanisms underlying delayed emergence, particularly in remimazolam-induced anaesthesia, remain poorly understood. This study aimed to elucidate these mechanisms by comparing remimazolam and propofol anaesthesia, focusing on prefrontal electroencephalogram (EEG).

Methods

Patients (age > 18,n= 48) underwent laparoscopic cholecystectomy randomly received remimazolam or propofol general anaesthesia. Power spectrogram analysis and functional connectivity measures, phase lag entropy (PLE) and phase lag index (PLI), were employed to the prefrontal EEG data collected at baseline, unconsciousness, and emergence. Correlation between EEG measures and Patient State Index (PSI) at PACU, as well as time to Aldrete 9, were compared.

Results

PSI values (P< 0.0001,P= 0.006) and time to Aldrete 9 at PACU (P< 0.001) revealed slower recovery in remimazolam-induced anaesthesia. Remimazolam group exhibited residual effects in power at theta (P= 0.018) and alpha (Ps< 0.001) bands and lower PLE during emergence in the alpha (P< 0.0001,P= 0.015) and beta (P= 0.016,P< 0.001) bands. Delayed consciousness recovery (time to Aldrete 9) under remimazolam was significantly correlated with PLE (Pearson’sr= -.78,P< 0.0001), and PLI (Pearson’sr= .69,P= 0.028) in the alpha band during deep anaesthesia.

Conclusion

Dynamic changes in prefrontal EEG and the correlation analyses show the potential of EEG in predicting emergence speed, providing insights into the neurobiological mechanisms of short-term delayed emergence in remimazolam anaesthesia.
Mentorship in Health Research Institutions in Africa: A Systematic Review of Approaches, Benefits, Successes, Gaps and Challenges
Authors: Ng’oda Maurine , Gatheru Peter Muriuki , Oyeyemi Oyetunde , Busienei Phylis , Karugu Caroline H. , Mugo Sharon , Okoth Lilian , Nampijja Margaret , Kiwuwa-Muyingo Sylvia , Wado Yohaness Dibaba , Kitsao-Wekulo Patricia , Asiki Gershim , Gitau Evelyn
Published: May 2024

Background

In Africa, where the burden of diseases is disproportionately high, significant challenges arise from a shortage of skilled researchers, lack of research funding, and limited mentorship opportunities. The continent faces a substantial gap in research output largely attributed to the dearth of mentorship opportunities for early career researchers.

Objective

To explore existing mentorship approaches, identify challenges, gaps, successes, and benefits, and provide insights for strengthening mentorship programs in African health research institutions.

Methods

We registered the review protocol on the International Prospective Register of Systematic Reviews [CRD42021285018] and searched six electronic databases – EMBASE, AJOL, Web of Science, PubMed, DOAJ and JSTOR from inception to 10 November 2023, for studies published in English reporting on approaches of mentorship in health research in African countries. We also searched grey literature repositories, institutional websites, and reference lists of included studies for additional literature. Two independent reviewers conducted screening of titles and abstracts of identified studies, full-text screening, assessment of methodological quality, and data extraction. We assessed study quality against the Mixed Methods Appraisal Tool (MMAT). We resolved any disagreements through discussion and consensus. We employed a narrative approach to synthesize the findings.

Results

We retrieved 1799 articles and after screening, included 21 studies in the review. The reviewers identified 20 mentorship programs for health researchers (N=1198) in 12 African countries mostly focusing on early career researchers and junior faculty members. A few included mid-career and senior researchers. We categorized the programs under three key mentoring approaches: international collaborative programs, regional and in-country collaborations, and specialized capacity-building initiatives. Our review highlighted the following successes and benefits of health research mentorship programs: the establishment of collaborations and partnerships, development of research programs and capacities, improvement of individual skills and confidence, increased publications, and successful grant applications. The gaps identified were limited funding, lack of a mentorship culture, negative attitudes towards research careers, and lack of prioritization of research mentorship.

Conclusion

Our review highlights a diverse landscape of health research mentorship aspects predominantly targeting early career researchers and heavily driven by the North. There is a need for locally driven mentorship initiatives in Africa to strengthen mentorship in order to advance health research in the region.
Effects of prenatal small-quantity lipid-based nutrient supplements on pregnancy, birth and infant outcomes: a systematic review and meta-analysis of individual participant data from randomized controlled trials in low- and middle-income countries
Authors: Dewey Kathryn G. , Wessells K. Ryan , Arnold Charles D. , Adu-Afarwuah Seth , Arnold Benjamin F. , Ashorn Ulla , Ashorn Per , Garcés Ana , Huybregts Lieven , Krebs Nancy F. , Lartey Anna , Leroy Jef L. , Maleta Kenneth , Matias Susana L. , Moore Sophie E. , Mridha Malay K. , Okronipa Harriet , Stewart Christine P.
Published: May 2024

Background

Undernutrition during pregnancy increases the risk of giving birth to a small vulnerable newborn. Small-quantity lipid-based nutrient supplements (SQ-LNS) contain both macro- and micronutrients and can help prevent nutritional deficiencies during pregnancy and lactation.

Objectives

We examined effects of SQ-LNS provided to pregnant women, compared to a) iron and folic acid or standard of care (IFA/SOC) or b) multiple micronutrient supplements (MMS), and identified characteristics that modified effects of SQ-LNS on birth outcomes.

Methods

We conducted a 2-stage meta-analysis of individual participant data from 4 randomized controlled trials of SQ-LNS provided to pregnant women (n = 5,273). We generated study-specific and subgroup estimates of SQ-LNS compared with IFA/SOC or MMS and pooled the estimates. In sensitivity analyses, we examined whether results differed depending on methods for gestational age dating, birth anthropometry, or study design.

Results

SQ-LNS (vs IFA/SOC) increased birth weight (mean difference: +49g; 95% CI: 26, 71g), duration of gestation (+0.12 wk; 95% CI: 0.01, 0.24 wk), and all birth anthropometric z-scores (+0.10-0.13 SD); it reduced risk of low birthweight by 11%, newborn stunting by 17%, newborn wasting by 11%, and small head size by 11%. Only 2 trials compared SQ-LNS and MMS; birth outcomes did not differ except for a marginal increase in head circumference for gestational age (+0.11; 95% CI: -0.01, 0.23). Effect estimates for SQ-LNS vs IFA/SOC were greater among female infants and among women with body mass index < 20 kg/m2, inflammation, malaria, or household food insecurity. Effect estimates for SQ-LNS vs MMS were greater among female infants, first-born infants, and women < 25 y.

Conclusions

SQ-LNS had positive impacts on multiple outcomes compared to IFA/SOC, but further research directly comparing SQ-LNS and MMS is needed. Targeting SQ-LNS to vulnerable subgroups may be worth considering. Analysis registered atwww.crd.york.ac.uk/PROSPERO(CRD42021283391).
Human genetics implicate thromboembolism in the pathogenesis of long COVID in individuals of European ancestry
Authors: Schuermans Art , Verstraete Andreas , Lammi Vilma , Nakanishi Tomoko , Ardissino Maddalena , Van den Eynde Jef , Sun Benjamin B. , Georgakis Marios K. , Guillen-Guio Beatriz , Wain Louise V. , Brightling Christopher E. ,   PHOSP-COVID Collaborative Group, Van Weyenbergh Johan , Lewandowski Adam J. , Raman Betty , Zeberg Hugo , Ollila Hanna M. , Burgess Stephen , Natarajan Pradeep , Honigberg Michael C. , Freson Kathleen , Vanassche Thomas , Verhamme Peter
Published: May 2024

SARS-CoV-2 infection can result in long COVID, characterized by post-acute symptoms from multiple organs. Current hypotheses on mechanisms underlying long COVID include persistent inflammation and thromboembolism; however, compelling evidence from humans is limited and causal associations remain unclear. Here, we tested the association of thromboembolism-related genetic variants with long COVID in the Long COVID Host Genetics Initiative (ncases=3,018;ncontrols=994,582). Primary analyses revealed that each unit increase in the log-odds of genetically predicted venous thromboembolism risk was associated with 1.21-fold odds of long COVID (95%CI: 1.08-1.35;P=1.2×10-3). This association was independent of acute COVID-19 severity, robust across genetic instruments and methods, and replicated in external datasets for both venous thromboembolism and long COVID. Downstream analyses using gene-specific instruments, along with protein and gene expression data, suggested the protease-activated receptor 1 (PAR-1) as a potential molecular contributor to long COVID. These findings provide human genetic evidence implicating thromboembolism in long COVID pathogenesis.
Assessment of Cardiovascular Disease Risk Factors in Korean Children: Impact of Various Pediatric Hypertension Guidelines and Application of the Korean Blood Pressure Reference
Authors: Kim Jeong Yeon , Park Sangshin , Cho Heeyeon
Published: May 2024

Background

The global prevalence of pediatric hypertension (HTN) is increasing and is a significant precursor of cardiovascular disease (CVD). We performed a comparative analysis of two guidelines for pediatric HTN: the 2017 American Academy of Pediatrics (AAP) and the 2016 European Society for Hypertension (ESH); the Korean blood pressure (BP) reference was applied to the Korean pediatric population.

Methods

Data from 2,060 children and adolescents aged 10-18 years from the Korean National Health and Nutrition Examination Survey (2016-2018) were analyzed. BP was classified according to the AAP, ESH, and Korea Regional BP Classification (KRC). High BP was defined as BP exceeding the normotensive range.

Results

The prevalence of high BP in Korean youth was notably higher in the AAP group than that in the ESH group (19.5% vs. 10.6%, p<0.0001). There were variations in the prevalence based on age, sex, and obesity. No significant disparities were observed between the AAP and KRC groups in terms of high BP prevalence. The application of the AAP and KRC demonstrated a more comprehensive reflection of CVD risk factors, including obesity and metabolic profiles, compared to the ESH. The KRC showed a tendency for more non-obese individuals to be categorized as having elevated BP, although this difference was not statistically significant.

Conclusions

This study advocates the adoption of the KRC for defining pediatric HTN in Korea. The KRC identified individuals with CVD risk as having a high BP, which raises the potential of the KRC for early intervention in CVD risk control.
Select DYRK1A Inhibitors Enhance Both Proliferation and Differentiation in Human Pancreatic Beta Cells
Authors: Wang Peng , Wood Olivia , Choleva Lauryn , Liu Hongtao , Karakose Esra , Lambertini Luca , Pillard Aidan , Wu Vickie , Garcia-Ocana Adolfo , Scott Donald K. , Kumar Kunal , DeVita Robert J. , Stewart Andrew F.
Published: May 2024

The small molecule DYRK1A inhibitor, harmine, induces human beta cell proliferation, expands beta cell mass, enhances expression of beta cell phenotypic genes, and improves human beta cell function in vitroandin vivo. It is unknown whether the “pro-differentiation effect” is a DYRK1A inhibitor class-wide effect. Here we compare multiple commonly studied DYRK1A inhibitors. Harmine, 2-2c and 5-IT increase expression of PDX1, MAFA, NKX6.1, SLC2A2, PCSK1, MAFB, SIX2, SLC2A2, SLC30A8, ENTPD3 in normal and T2D human islets. Unexpectedly, GNF4877, CC-401, INDY, CC-401 and Leucettine fail to induce expression of these essential beta cell molecules. Remarkably, the pro-differentiation effect is independent of DYRK1A inhibition: although silencing DYRK1A induces human beta cell proliferation, it has no effect on differentiation; conversely, harmine treatment enhances beta cell differentiation in DYRK1A-silenced islets. A careful screen of multiple DYRK1A inhibitor kinase candidate targets was unable to identify pro-differentiation pathways. Overall, harmine, 2-2c and 5-IT are unique among DYRK1A inhibitors in their ability to enhance both beta cell proliferation and differentiation. While beta cellproliferationis mediated by DYRK1A inhibition,the pro-differentiationeffects of harmine,2-2cand 5-IT are distinct, and unexplained in mechanistic terms. These considerations have important implications for DYRK1A inhibitor pharmaceutical development.
Bacterial sensor evolved by decreasing complexity
Authors: Monteagudo-Cascales Elizabet , Gavira José A. , Xing Jiawei , Velando Félix , Matilla Miguel A. , Zhulin Igor B. , Krell Tino
Published: May 2024

Bacterial receptors feed into multiple signal transduction pathways that regulate a variety of cellular processes including gene expression, second messenger levels and motility. Receptors are typically activated by signal binding to ligand binding domains (LBD). Cache domains are omnipresent LBDs found in bacteria, archaea, and eukaryotes, including humans. They form the predominant family of extracytosolic bacterial LBDs and were identified in all major receptor types. Cache domains are composed of either a single (sCache) or a double (dCache) structural module. The functional relevance of bimodular LBDs remains poorly understood. Here, we identify the PacF chemoreceptor in the phytopathogenPectobacterium atrosepticumthat recognizes formate at the membrane distal module of its dCache domain, triggering chemoattraction. We further demonstrate that a family of formate-specific sCache domains has evolved from a dCache domain, exemplified by PacF, by losing the membrane proximal module. By solving high-resolution structures of two family members in complex with formate, we show that the molecular basis for formate binding at sCache and dCache domains is highly similar, despite their low sequence identity. The apparent loss of the membrane proximal module may be related to the observation that dCache domains bind ligands typically at the membrane distal module, whereas the membrane proximal module is not involved in signal sensing. This work advances our understanding of signal sensing in bacterial receptors and suggests that evolution by reducing complexity may be a common trend shaping their diversity.

Significance

Many bacterial receptors contain multi-modular sensing domains indicative of complex sensory processes. The presence of more than one sensing module likely permits the integration of multiple signals, although, the molecular detail and functional relevance for these complex sensors remain poorly understood. Bimodular sensory domains are likely to have arisen from the fusion or duplication of monomodular domains. Evolution by increasing complexity is generally believed to be a dominant force. Here we reveal the opposite – how a monomodular sensing domain has evolved from a bimodular one. Our findings will thus motivate research to establish whether evolution by decreasing complexity is typical of other sensory domains.
Comparative transcriptomics reveal a highly polymorphicXanthomonasHrpG virulence regulon
Authors: Quiroz Monnens Thomas , Roux Brice , Cunnac Sébastien , Charbit Erika , Carrère Sébastien , Lauber Emmanuelle , Jardinaud Marie-Françoise , Darrasse Armelle , Arlat Matthieu , Szurek Boris , Pruvost Olivier , Jacques Marie-Agnès , Gagnevin Lionel , Koebnik Ralf , Noël Laurent D. , Boulanger Alice
Published: May 2024

Bacteria of the genusXanthomonascause economically significant diseases in various crops. Their virulence is dependent on the translocation of type III effectors (T3Es) into plant cells by the type III secretion system (T3SS), a process regulated by the master response regulator HrpG. Although HrpG has been studied for over two decades, its regulon across diverseXanthomonasspecies, particularly beyond type III secretion, remains understudied. In this study, we conducted transcriptome sequencing to explore the HrpG regulons of 17Xanthomonasstrains, encompassing six species and nine pathovars, each exhibiting distinct host and tissue specificities. We employed constitutive expression of plasmid-bornehrpG*, which encodes a constitutively active form of HrpG, to induce the regulon. Our findings reveal substantial inter- and intra-specific diversity in the HrpG* regulons across the strains. Besides 21 genes directly involved in the biosynthesis of the T3SS, the core HrpG* regulon is limited to only five additional genes encoding the transcriptional activator HrpX, the two T3E proteins XopR and XopL, a major facility superfamily (MFS) transporter, and the phosphatase PhoC. Interestingly, genes involved in chemotaxis and genes encoding enzymes with carbohydrate-active and proteolytic activities are variably regulated by HrpG*. The diversity in the HrpG* regulon suggests that HrpG-dependent virulence inXanthomonasmight be achieved through several distinct strain-specific strategies, potentially reflecting adaptation to diverse ecological niches. These findings enhance our understanding of the complex role of HrpG in regulating various virulence and adaptive pathways, extending beyond T3Es and the T3SS.

IMPORTANCE

In the decades since its discovery, HrpG and its role in the regulation of the type III secretion system (T3SS) and its associated type III effectors (T3Es) inXanthomonashas been the subject of extensive research. Despite notable progress in understanding its molecular regulatory mechanisms, the full spectrum of processes under control of HrpG, particularly beyond the T3SS and T3Es, and the degree of regulatory conservation across plant-pathogenicXanthomonasspecies, remained unclear. To address this knowledge gap, we systematically compared the transcriptomes of 17Xanthomonasstrains, expressing a constitutively active form of HrpG, called HrpG*. We showed that HrpG* regulates different physiological processes other than the T3SS and T3Es and that this regulation shows substantial variation across the different strains. Taken together, our results provide new insights intoXanthomonas-plant interactions through the regulation of different metabolic and virulence pathways by the master response regulator HrpG.
Brain-wide functional connectome analysis of 40,000 individuals reveals brain networks that show aging effects in older adults
Authors: Pan Yezhi , Bi Chuan , Kochunov Peter , Shardell Michelle , Smith J. Carson , McCoy Rozalina G. , Ye Zhenyao , Yu Jiaao , Lu Tong , Yang Yifan , Lee Hwiyoung , Liu Song , Gao Si , Ma Yizhou , Li Yiran , Chen Chixiang , Ma Tianzhou , Wang Ze , Nichols Thomas , Hong L. Elliot , Chen Shuo
Published: May 2024

The functional connectome changes with aging. We systematically evaluated aging related alterations in the functional connectome using a whole-brain connectome network analysis in 39,675 participants in UK Biobank project. We used adaptive dense network discovery tools to identify networks directly associated with aging from resting-state fMRI data. We replicated our findings in 499 participants from the Lifespan Human Connectome Project in Aging study. The results consistently revealed two motor-related subnetworks (both permutation test p-values <0.001) that showed a decline in resting-state functional connectivity (rsFC) with increasing age. The first network primarily comprises sensorimotor and dorsal/ventral attention regions from precentral gyrus, postcentral gyrus, superior temporal gyrus, and insular gyrus, while the second network is exclusively composed of basal ganglia regions, namely the caudate, putamen, and globus pallidus. Path analysis indicates that white matter fractional anisotropy mediates 19.6% (p<0.001, 95% CI [7.6% 36.0%]) and 11.5% (p<0.001, 95% CI [6.3% 17.0%]) of the age-related decrease in both networks, respectively. The total volume of white matter hyperintensity mediates 32.1% (p<0.001, 95% CI [16.8% 53.0%]) of the aging-related effect on rsFC in the first subnetwork.
Age-related constraints on the spatial geometry of the brain
Authors: Escalante Yuritza Y. , Adams Jenna N. , Yassa Michael A. , Janssen Niels
Published: May 2024

Age-related structural brain changes may be better captured by assessing complex spatial geometric differences rather than isolated changes to individual regions. We applied a novel analytic method to quantify age-related changes to the spatial anatomy of the brain by measuring expansion and compression of global brain shape and the distance between cross-hemisphere homologous regions. To test how global brain shape and regional distances are affected by aging, we analyzed 2,603 structural MRIs (range: 30-97 years). Increasing age was associated with global shape expansion across inferior-anterior gradients, global compression across superior-posterior gradients, and regional expansion between frontotemporal homologues. Specific patterns of global and regional expansion and compression were further associated with clinical impairment and distinctly related to deficits in various cognitive domains. These findings suggest that changes to the complex spatial anatomy and geometry of the aging brain may be associated with reduced efficiency and cognitive dysfunction in older adults.
Anterior pituitary gland volume mediates associations between pubertal hormones and changes in transdiagnostic symptoms in youth
Authors: Picci Giorgia , Petro Nathan M. , Casagrande Chloe C. , Ott Lauren R. , Okelberry Hannah J. , Rice Danielle L. , Coutant Anna T. , Ende Grace C. , Steiner Erica L. , Wang Yu-Ping , Stephen Julia M. , Calhoun Vince D. , Wilson Tony W.
Published: May 2024

The pituitary gland (PG) plays a central role in the production and secretion of pubertal hormones, with documented links to the emergence and increase in mental health symptoms known to occur during adolescence. Although much of the literature has focused on examining whole PG volume, recent findings suggest that there are associations among pubertal hormone levels, including dehydroepiandrosterone (DHEA), subregions of the PG, and elevated mental health symptoms (e.g., internalizing symptoms) during adolescence. Surprisingly, studies have not yet examined associations among these factors and increasing transdiagnostic symptomology, despite DHEA being a primary output of the anterior PG. Therefore, the current study sought to fill this gap by examining whether anterior PG volume specifically mediates associations between DHEA levels and changes in dysregulation symptoms in an adolescent sample (N= 114, 9 – 17 years, Mage= 12.87, SD = 1.88). Following manual tracing of the anterior and posterior PG, structural equation modeling revealed that greater anterior, not posterior, PG volume mediated the association between greater DHEA levels and increasing dysregulation symptoms across time, controlling for baseline dysregulation symptom levels. These results suggest specificity in the role of the anterior PG in adrenarcheal processes that may confer risk for psychopathology during adolescence. This work not only highlights the importance of separately tracing the anterior and posterior PG, but also suggests that transdiagnostic factors like dysregulation are useful in parsing hormone-related increases in mental health symptoms in youth.
Application of laboratory micro X-ray fluorescence devices for X-ray topography
Authors: Guguschev Christo , Hirschle Christian , Dadzis Kaspars , Kwasniewski Albert , Schulze Michael , Schellkopf Leonard , Richter Carsten
Published: May 2024

It is demonstrated that high-resolution energy-dispersive X-ray fluorescence mapping devices based on a micro-focused beam are not restricted to high-speed analyses of element distributions or to the detection of different grains, twins and subgrains in crystalline materials but can also be used for the detection of dislocations in high-quality single crystals. Si single crystals with low dislocation densities were selected as model materials to visualize the position of dislocations by the spatially resolved measurement of Bragg-peak intensity fluctuations. These originate from the most distorted planes caused by the stress fields of dislocations. The results obtained by this approach are compared with laboratory-based Lang X-ray topographs. The presented methodology yields comparable results and it is of particular interest in the field of crystal growth, where fast chemical and microstructural characterization feedback loops are indispensable for short and efficient development times. The beam divergence was reduced via an aperture management system to facilitate the visualization of dislocations for virtually as-grown, non-polished and non-planar samples with a very pronounced surface profile.
MatchMaps: non-isomorphous difference maps for X-ray crystallography
Authors: Brookner Dennis E. , Hekstra Doeke R.
Published: May 2024

Conformational change mediates the biological functions of macromolecules. Crystallographic measurements can map these changes with extraordinary sensitivity as a function of mutations, ligands and time. A popular method for detecting structural differences between crystallographic data sets is the isomorphous difference map. These maps combine the phases of a chosen reference state with the observed changes in structure factor amplitudes to yield a map of changes in electron density. Such maps are much more sensitive to conformational change than structure refinement is, and are unbiased in the sense that observed differences do not depend on refinement of the perturbed state. However, even modest changes in unit-cell properties can render isomorphous difference maps useless. This is unnecessary. Described here is a generalized procedure for calculating observed difference maps that retains the high sensitivity to conformational change and avoids structure refinement of the perturbed state. This procedure is implemented in an open-source Python package, MatchMaps, that can be run in any software environment supporting PHENIX [Liebschner et al. (2019). Acta Cryst. D75, 861–877] and CCP4 [Agirre et al. (2023). Acta Cryst. D79, 449–461]. Worked examples show that MatchMaps `rescues' observed difference electron-density maps for poorly isomorphous crystals, corrects artifacts in nominally isomorphous difference maps, and extends to detecting differences across copies within the asymmetric unit or across altogether different crystal forms.
Low-background ultrahigh-purity aluminium window for small-angle neutron scattering using monochromatic cold neutrons
Authors: Kumada Takayuki , Motokawa Ryuhei , Iwase Hiroki
Published: May 2024

The 500 mm-diameter aluminium alloy neutron window in the SANS diffractometer SANS-J at JRR-3, Tokai, Japan, has been replaced by an ultrahigh-purity aluminium (5N-Al, >99.999%) window. Although the 5N-Al window is three times thicker than the alloy window to compensate for the lower tensile strength, the background intensity in the small-angle neutron scattering (SANS) curve was successfully decreased by a factor of 10 at the maximum. The 5N-Al window is suitable not only for large-diameter neutron windows in SANS diffractometers but also for windows in their environmental apparatus which cannot be made of single-crystal silicon or other ceramics due to their poor availability, fracture strength, processability or affinity with metallic materials.
Start-ups’ scaling-up strategies at the regional periphery
Authors: Felzensztein Christian , Bagheri Afsaneh
Published: May 2024

Purpose

Our understanding of the strategies that lead to the success of start-ups when they scale-up is limited when it occurs at the regional periphery. The main purpose of this study is to explore the specific strategies that start-ups employ to scale-up, specifically in contexts with high resource constraints at the regional periphery.

Design/methodology/approach

Analyzing the data from personal in-depth interviews with engineering and science start-up founders in peripheral regions of upstate New York USA bordering the Canadian Ontario, we explored a combination of internal and external strategies that start-ups employed to scale-up.

Findings

The study found that start-ups prioritize building internal scaling capacity in their human capital, organizational structure, scalable business model, finance and business ownership. To foster the scaling process further, start-ups develop new effective external strategies that target the business environment.

Practical implications

Policymakers and regional governments can use our research to develop more effective industrial policies for supporting start-ups’ growth and subsiding strategic industry clusters for rebooting new competition policy, which is a current debate in many industrialized economies including the US. This targeted regional industrial policy is specially needed when scaling-up at the regional periphery.

Social implications

Our study is specially need it when scaling-up at the regional periphery and with limited resources.

Originality/value

This study enriches our understanding of the growth of start-ups and small ventures by providing context-based insights into how firms build the capacity to scale-up in highly challenging and uncertain business environments in a peripheral bordering region between the USA and Canada. It also offers useful managerial and policy implications.
Science mapping of the knowledge base on teacher autonomy: a bibliometric study
Authors: Çolak İbrahim
Published: May 2024

Purpose

This research sought to document the volume, development trend and geographical distribution of the research on teacher autonomy, identify high-impact journals, authors and documents and reveal the intellectual structure of the field.

Design/methodology/approach

This paper analyzed the articles published on the related subject in the Web of Science (WoS) and/or Scopus. Based on certain exclusion criteria, analyses were conducted on a total of 259 articles. The data were then subjected to descriptive analyses and bibliometric analyses.

Findings

The review found that the teacher autonomy knowledge base has grown dramatically since 2004. In the co-citation analysis, it was determined that four clusters focused on the themes of professionalism and professional development, leadership and self-efficacy, autonomy in language teaching and learning and self-determination theory. According to the co-word analysis in this review, the most co-occurring keywords were revealed to be “teacher autonomy,” “autonomy,” “teachers,” “teacher professionalism” and “professional development.”

Originality/value

Despite increasing numbers of systematic reviews focusing on educational administration and leadership, this paper represents the first bibliometric review conducted to reveal the development of research on teacher autonomy using both the WoS and Scopus databases. Teacher autonomy can be regarded as an emerging field of study backed up by a theoretical background. Although there are some distinct prominent scholars in the research area, autonomy research still needs more scholars to specialize in the field.
Chore or choice? Women and ethnic food entrepreneurship in the city
Authors: Nancheva Nevena
Published: May 2024

Purpose

This article explores in a qualitative manner the motivations of women entrepreneurs who start and run ethnic food businesses in London.

Design/methodology/approach

Our approach is qualitative and deploys phenomenographical analysis of interview narratives around categories of motivation.

Findings

We find that women ethnic food entrepreneurs are driven by a combination of desire for self-actualisation, identity-maintenance and community considerations. We demonstrate that women ethnic food entrepreneurs often go against the logic of the market, and they do so not because they lack other options, but for reasons that have to do with their (self-)identification as women and professionals, their prerogatives as mothers and daughters, their ethnic heritage, their emplacement in urban and global communities and their need to contribute. Our findings enrich understanding of female-led ethnic food entrepreneurship not as a demanding, overall unproductive undertaking for women with no other options, but as a realm of inspiration, community engagement and female-led innovation.

Originality/value

Our main contributions are the qualitative interrogation of perceptions and experiences of identity and difference in urban entrepreneurship from the point of view of our interviewees; providing concrete empirical evidence for it through our sample and proposing an approach to thinking women-led ethnic food entrepreneurship as a vehicle for translating urban superdiversity into social interactions across barriers of difference. We speak to the field of women entrepreneurship studies but specifically to the understudied realm of women-led food entrepreneurship, and to the cross-disciplinary field of (im)migrant entrepreneurship.
External quality assurance of cost estimates in major public projects: empirical evidence on cost performance
Authors: Berg Helene , Nyhus Ole Henning
Published: May 2024

Purpose

Value creation for society from public projects requires that the overall benefits exceed the use of taxpayers' money. At the same time, cost overruns in public projects are a well-documented feature in the literature, but practical guidance on reducing the extent and magnitude of overruns is rare. In 2000, Norway introduced a governance regime that includes mandatory external quality assurance (QA) of cost estimates for major public projects. This paper compares the cost performance of public projects on each side of this QA scheme.

Design/methodology/approach

We use an original dataset covering 1,704 projects from 2000 to 2021, reported first-hand from Norwegian public agencies. We apply quantitative methods in the form of descriptive statistics, regression models, and statistical testing of hypotheses to answer our research questions.

Findings

The mean cost overrun across projects in our dataset is smaller than several previous international studies have reported. We find no statistical support for different cost performances between QA and non-QA projects. Secondly, cost overruns seem to vary between different public sectors. A third finding is a small development with lower cost overruns over time for the non-QA projects, and we raise the question of whether the QA scheme has contributed to overall learning effects. The fourth finding is that cost deviations are quite independent of project size.

Originality/value

The paper offers novel insights for decision-makers and researchers on the effects of external quality assurance on cost performance in public projects.