bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated Plasma Interleukin-18 Identifies High-Risk Acute Respiratory Distress Syndrome Patients not Distinguished by Prior Latent Class Analyses Using Traditional Inflammatory Cytokines: A Retrospective Analysis of Two Randomized Clinical Trials
Authors: Moore Andrew R. , Pienkos Shaun M. , Sinha Pratik , Guan Jiazhen , O’Kane Cecilia M. , Levitt Joseph E. , Wilson Jennifer G. , Shankar-Hari Manu , Matthay Michael A. , Calfee Carolyn S. , Baron Rebecca M. , McAuley Daniel F. , Rogers Angela J.
Published: September 2023

OBJECTIVES:

Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct “high-risk” patients not captured by prior LCA classifications.

DESIGN:

Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar’s test and then tested the correlation between IL-18 and LCA biomarkers using Pearson’s exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup.

SETTING:

Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients.

SUBJECTS:

Six hundred eighty-three patients in SAILS and 511 patients in HARP-2.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17–0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8–6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2–3.8; p = 0.009).

CONCLUSIONS:

Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts.
Alaska Native Parents' Decision-Making About Food, Beverages, and Screen Time for Young Children
Authors: Ohle Kathryn A. , Koller Kathryn R. , Walch Amanda K. , Lee Flora R. , Palmer Lea , Nu Jennifer , Thomas Timothy K.
Published: September 2023

With rising childhood obesity rates, ensuring children adopt healthy habits early is imperative. Given the unique context for Alaska Native families living in rural remote communities, who are concurrently experiencing changes in traditional practices, we investigated what impacts parents' decisions as they relate to daily living before revising a preschool curriculum focused on healthy habits. The objective of this study was to explore factors influencing parents' decisions about their children's foods, beverages, and activities. In focus group discussions with AN parents of young children across 12 communities, we asked about meals, traditional foods, beverages, physical activity, and screen time. All sessions were recorded, transcribed, and analyzed using open and selective coding to allow the most important themes to emerge. As parents discussed how they make decisions, several trends emerged related to adults' and children's food and beverage preferences; the impact of adult modeling on children; and how convenience, seasonality, access, and a reluctance to engage in conflict all impact decision-making. Parents and other community members shared important perspectives on exposing children to traditional subsistence foods and activities and passing important traditional knowledge to them at an early age. These perspectives will form the basis for preschool curricula in these communities.
Assessment of Feasibility and Acceptability of the Pathways for Parents After Incarceration Program
Authors: Charles Pajarita , Muentner Luke , Grade Gene , Eddy J. Mark
Published: September 2023

Most incarcerated fathers have connections to their families, and the quality of their family relationships is important not only to their reentry success but also to shaping positive child and family outcomes. However, there is a lack of rigorous evidence about interventions designed to strengthen parent-child and other family relationships among formerly incarcerated parents. The purpose of this study was to develop and assess for feasibility and acceptability an intervention for formerly incarcerated fathers, co-parents, and their children. We created and implemented the Pathways for Parents after Incarceration Program (P4P), a multilevel intervention that focuses on strengthening positive parenting skills, building constructive co-parenting strategies, providing social support, and connecting families to needed specialized services. We delivered P4P virtually to 3 groups of participants, collecting data at several points. Results suggest that while the program was well liked and appreciated by participants and parent coaches and had a positive effect on parenting skills and attitudes, recruitment and retention were challenging. Findings suggest that P4P has the potential to support child and family well-being when fathers reenter by bolstering protective factors, and supporting access to necessary supports associated with improved reentry outcomes. Additional research is needed to address feasibility concerns and establish program efficacy.
Food Insecurity and Health
Authors: Chai Lei
Published: September 2023

Existing research has established the detrimental effects of food insecurity on health. However, understanding of the social conditions that may moderate this relationship remains limited. To address this gap, the study investigates two questions: First, does marital status moderate the association between food insecurity and self-rated health? Second, if such moderation exists, does its impact vary based on gender? Data from the 2017-2018 Canadian Community Health Survey, a nationally representative survey conducted by Statistics Canada (n =101 647), were utilized for this investigation. The findings demonstrated that individuals living in food-insecure households reported poorer self-rated mental and general health. However, the negative impact of food insecurity on both health outcomes was less pronounced among married individuals than among their unmarried counterparts. Furthermore, the stress-buffering role of marriage was found to be more substantial among men than among women. In light of the significant stress-buffering role of marriage revealed in this study, it is crucial for policies to aim at providing comparable coping resources to unmarried individuals, particularly women.
MACULAR CHORIORETINAL ATROPHY AND VISUAL OUTCOMES IN RANIBIZUMAB- OR AFLIBERCEPT-TREATED MYOPIC CHOROIDAL NEOVASCULARIZATION
Authors: Kawashima Yu , Hata Masayuki , Miyake Masahiro , Kusaka Mami , Oishi Akio , Ooto Sotaro , Tamura Hiroshi , MIYATA Manabu , Uji Akihito , Ueda-Arakawa Naoko , Takahashi Ayako , Tsujikawa Akitaka
Published: September 2023

Purpose:

To investigate the predictors of macular chorioretinal atrophy (CRA), consisting of patchy atrophy (PA) at the macula and choroidal neovascularization (CNV)-related macular atrophy (CNV-MA), during treatment with either ranibizumab or aflibercept for myopic CNV (mCNV) and its impact on visual outcomes.

Methods:

This retrospective study included 82 eyes with treatment-naïve mCNV who were treated with pro re nata injections of either ranibizumab or aflibercept.

Results:

Nine eyes (11.0%) presented with macular PA at baseline (PA group), and 73 eyes (89.0%) did not (non-PA group). VA improved during the first year in the non-PA group; a similar trend was noted in the PA group until 3 months after initial treatment. This improvement was maintained until 24 months (P<0.001) in the non-PA group, but not in the PA group. In the PA group, macular CRA progressed faster (P<0.0001), and CNV-MA was more frequent during the 2 years of treatments (P=0.04). Even non-PA group eyes sometimes developed CNV-MA (42% at month 24) if they had a larger CNV and thinner subfoveal CT at baseline, resulting in poorer visual prognosis (P<0.01).

Conclusion:

Macular PA at baseline was a risk factor for CNV-MA development and was associated with poor visual outcomes.
Genetic Factors and Characteristics on Spectral-Domain Optical Coherence Tomography Are Associated to Choroidal Thickness in ABCA4-Related Retinopathy Factors of Choroidal Thickness in ABCA4 Retinopathy
Authors: Wang Yimin , Chen Jieqiong , Zhang Min , Yu Suqin , Gong Yuanyuan , Lin Feng , Wu Yidong , Liu Wenjia , Sun Junran , Li Tong , Sun Xiaodong ,   Shanghai Inherited Retinal Disease (SHIRD) Study Group
Published: September 2023

Purpose:

To investigate the possible correlation factors of choroidal thickness in ABCA4-related retinopathy.

Methods:

A total of 66 patients were included in the cohort. It is a retrospective, cross-sectional laboratory investigation. The patients were tested using whole exon sequencing (WES) and ophthalmic exams, including slip lamp exams, best corrected visual acuity (BCVA), spectral-domain optical coherence tomography (SD-OCT), fundus photo (FP), and fundus autofluorescence (FAF).

Results:

Besides demographic characteristics (age, onset age, duration), we selected genetic factors and ocular characteristics on SD-OCT as the candidates related to choroidal thickness (CT). Mutation type (inframe mutation or premature termination codon), epiretinal membrane (ERM), RPE- Bruch’s membrane (BM) integrity and macular curvature changes were identified as related factors to choroidal thickness in ABCA4-related retinopathy after the adjustment of Logistic LASSO regression .

Conclusions:

Mutation type, ERM, RPE-BM integrity and macular curvature changes are related factors to choroidal thinning. These findings could provide us a further understanding for the pathological process and clinical features of ABCA4 mutation.
Monocyte to lymphocyte ratio and hemoglobin level to predict tuberculosis after antiretroviral therapy initiation
Authors: Gatechompol Sivaporn , Kerr Stephen J. , Cardoso Sandra W. , Samaneka Wadzanai , Tripathy Srikanth , Godbole Sheela , Ghate Manisha , Kanyama Cecilia , Nyirenda Mulinda , Sugandhavesa Patcharaphan , Machado Andre , Van Leth Frank , Campbell Thomas B. , Swindlells Susan , Avihingsanon Anchalee , Cobelens Frank
Published: September 2023

Objective:

To determine the performance of the baseline monocyte to lymphocyte ratio (MLR), baseline anemia severity and combination of these biomarkers, to predict tuberculosis (TB) incidence in people with HIV (PWH) after antiretroviral therapy (ART) initiation.

Design:

Multicenter, retrospective cohort study.

Methods:

We utilized the data from study A5175 (Prospective Evaluation of Antiretroviral Therapy in Resource-limited Settings: PEARLS). We assessed the utility of MLR, anemia severity and in combination, for predicting TB in the first year after ART. Cox regression was used to assess associations of MLR and anemia with incident TB. Harrell's C index was used to describe single model discrimination.

Results:

A total of 1455 participants with a median age of 34 [interquartile range (IQR) 29, 41] were included. Fifty-four participants were diagnosed with TB. The hazard ratio (HR) for incident TB was 1.77 [95% confidence interval (CI) 1.01–3.07]; P = 0.04 for those with MLR ≥0.23. The HR for mild/mod anemia was 3.35 (95% CI 1.78–6.29; P < 0.001) and 18.16 (95% CI 5.17–63.77; P < 0.001) for severe anemia. After combining parameters, there were increases in adjusted HR (aHR) for MLR ≥0.23 to 1.83 (95% CI 1.05–3.18), and degrees of anemia to 3.38 (95% CI 1.80–6.35) for mild/mod anemia and 19.09 (95% CI 5.43–67.12) for severe anemia.

Conclusions:

MLR and hemoglobin levels which are available in routine HIV care can be used at ART initiation for identifying patients at high risk of developing TB disease to guide diagnostic and management decisions.
The Surgical Treatment of Tuberous Breast Deformity
Authors: El Israwi Daniel , Makdessi Jean Paul , Bassilios Habre Samer
Published: September 2023

Tuberous breast is a common congenital deformity that might present as unilateral or bilateral breast base constriction, asymmetry, areolar herniation, hypoplasia, ptosis, and skin deficiency. Patients might present with one or more of the mentioned features, rendering a consensus about the optimal surgical technique to correct this deformity nonexistent. In our review article, we present the most common classifications of a tuberous breast, in addition to several surgical approaches that attempt to treat this deformity.
Wormian Bones: Prevalence, Topography, and Implications
Authors: Singh Rajani
Published: September 2023

Background:

Wormian bones also known as sutural bones are asymmetrical and shapeless bones occurring in cranial sutures and fontanelle of the skull. Their incidence is reported to vary in population. The exact etiology is debatable, but their formation is under the control of both genetic and environmental factors and has great anthropological and clinical implications related to the cranium. Due to high clinical relevance of Wormian bones, the study was carried out. The aim of the study is to expound the incidence and topography of Wormian bones along with clinical significance in dry adult skulls of Indian origin.

Methods:

The study was conducted in the Department of Anatomy using 200 complete adult dry skulls of unknown age and sex. All the sutures in the skull were inspected for the presence of Wormian bones. The Wormian bones were classified into 10 categories, and associated implications were brought out. The Wormian bones were photographed, and details were compared with the available literature.

Results:

The Wormian bones were observed in 190 (380 sides) skulls with 186 on the right side and 108 on the left side. The predominance site of sutural bone was lambdoid suture followed by sagittal suture. The least common site of Wormian bone was lambda.

Conclusion:

The detailed information of precise topography, frequency, and number of Wormian bones is of utmost use for surgeons performing surgery on the skull, anthropologists for identifying races, and forensic scientists for investigating child abuse cases.
SEPSIS LEADS TO IMPAIRED MITOCHONDRIAL CALCIUM UPTAKE AND SKELETAL MUSCLE WEAKNESS BY REDUCING THE MICU1:MCU PROTEIN RATIO
Authors: Li Xuexin , Sun Bowen , Li Jie , Ye Wanlin , Li Mingjuan , Guan Fasheng , Wu Songlin , Luo Xuerong , Feng Jianguo , Jia Jing , Liu Xueru , Li Tao , Liu Li
Published: September 2023

Purpose: Intensive care unit–acquired weakness (ICUAW) is a severe neuromuscular complication that frequently occurs in patients with sepsis. The precise molecular pathophysiology of mitochondrial calcium uptake 1 (MICU1) and mitochondrial calcium uniporter (MCU) in ICUAW has not been fully elucidated. Here, we speculate that ICUAW is associated with MICU1:MCU protein ratio–mediated mitochondrial calcium ([Ca2+]m) uptake dysfunction. Methods: Cecal ligation and perforation (CLP) was performed on C57BL/6J mice to induce sepsis. Sham-operated animals were used as controls. Lipopolysaccharide (LPS) (5 μg/mL) was used to induce inflammation in differentiated C2C12 myoblasts. Compound muscle action potential (CMAP) was detected using a biological signal acquisition system. Grip strength was measured using a grip-strength meter. Skeletal muscle inflammatory factors were detected using ELISA kits. The cross-sectional area (CSA) of the tibialis anterior (TA) muscle was detected by hematoxylin and eosin staining. Cytosolic calcium ([Ca2+]c) levels were measured using Fluo-4 AM. Adeno-associated virus (AAV) was injected into TA muscles for 4 weeks to overexpress MICU1 prophylactically. A lentivirus was used to infect C2C12 cells to increase MICU1 expression prophylactically. Findings: The results suggest that sepsis induces [Ca2+]m uptake disorder by reducing the MICU1:MCU protein ratio, resulting in skeletal muscle weakness and muscle fiber atrophy. However, MICU1 prophylactic overexpression reversed these effects by increasing the MICU1:MCU protein ratio. Conclusions: ICUAW is associated with impaired [Ca2+]m uptake caused by a decreased MICU1:MCU protein ratio. MICU1 overexpression improves sepsis-induced skeletal muscle weakness and atrophy by ameliorating the [Ca2+]m uptake disorder.
Nobiletin ameliorates heatstroke-induced acute lung injury by inhibiting ferroptosis via p53/SLC7A11 pathway
Authors: Chen Hui , Xie Weidang , Peng Zanling , Liu Yanan , Li Hongbo , Huang Wei
Published: September 2023

The molecular mechanism for nobiletin’s protective effect against heatstroke-induced acute lung injury (HS-ALI) remains largely unknown. Previous research has demonstrated that ferroptosis is an important pathogenic event in HS-ALI. Nobiletin is a natural polymethoxylated flavonoid. Herein, we investigated the potential contribution of nobiletin to HS-ALI by inhibiting ferroptosis. Heat stress was used to induce HS-ALI in mice, and MLE-12 cells were stimulated by heat stress in vitro. Nobiletin was administrated by gavage for 2 hours before HS induction. Biochemical kits, immunofluorescence staining, and western blotting were performed on the markers of ferroptosis. Our results showed that nobiletin administration significantly attenuated HS-induced lung injury and ferroptosis. Moreover, nobiletin pretreatment significantly reversed HS-induced p53 upregulation in vivo and in vitro. Pretreatment with a p53 agonist, Tenovin-6 partly abolished the protective effect of nobiletin in mice with HS-ALI. Meanwhile, p53 knockdown significantly increased GPX4 and SLC7A11 expression levels compared to the HS group in HS-induced MLE-12 cells. Subsequently, nobiletin ameliorated HS-induced MLE-12 cells ferroptosis by activating the SLC7A11/GPX4 pathway, while p53 overexpression effectively abolished the protective effect of nobiletin. Taken together, our findings reveal that nobiletin attenuates HS-ALI by inhibiting ferroptosis through the p53/SLC7A11 pathway, indicating it to be a potential therapeutic agent for HS-ALI prevention and treatment.
Long-term Catch-up Growth and Risk Factors for Short Adult Height After Pediatric Liver Transplantation: A Retrospective Study
Authors: Umemura Kentaro , Mita Atsuyoshi , Ohno Yasunari , Masuda Yuichi , Yoshizawa Kazuki , Kubota Koji , Notake Tsuyoshi , Hosoda Kiyotaka , Yasukawa Koya , Kamachi Atsushi , Goto Takamune , Tomida Hidenori , Yamazaki Shiori , Shimizu Akira , Soejima Yuji
Published: September 2023

Background.

Children requiring liver transplantation generally have severe growth retardation. Recipients experience posttransplantation catch-up growth, although some show short adult heights. We aimed to determine decades-long catch-up growth trends and risk factors for short adult height following liver transplantation.

Methods.

We analyzed long-term height Z scores and risk factors for short adult height in a single-center retrospective cohort of 117 pediatric liver transplantation recipients who survived >5 y, with 75 of them reaching adult height.

Results.

Median age at transplantation was 1.3 y, and the most common primary diagnosis was biliary atresia (76.9%). Mean height Z scores pretransplantation and 1, 3, and 8 y after transplantation were –2.26, –1.59, –0.91, and –0.59, respectively. The data then plateaued until 20 y posttransplantation when mean adult height Z score became –0.88, with a median follow-up of 18.6 y. Nineteen recipients did not show any catch-up growth, and one quarter of recipients had short adult height (<5th percentile of the healthy population). Multivariate analysis identified old age (odds ratio, 1.22 by 1 y; P = 0.002), low height Z scores at transplantation (odds ratio, 0.46 by 1 point; P < 0.001), and posttransplantation hospital stay ≥60 d (odds ratio, 4.95; P = 0.015) as risk factors for short adult height. In contrast, prolonged steroid use after transplantation was not considered a significant risk factor.

Conclusions.

Although tremendous posttransplantation catch-up growth was observed, final adult height remained inadequate. For healthy physical growth, liver transplantation should be performed as early as possible, before growth retardation becomes severe.
Prenatal Zika virus exposure is associated with lateral geniculate nucleus abnormalities in juvenile rhesus macaques
Authors: Ball Erin E. , Bennett Jeffrey L. , Keesler Rebekah I. , Van Rompay Koen K. A. , Coffey Lark L. , Bliss-Moreau Eliza
Published: September 2023

Zika virus’ neural tropism causes significant neural pathology, particularly in developing fetuses. One of the consistent findings from humans and animal models is that prenatal exposure to Zika virus (ZIKV) causes pathology in the eyes and visual pathways of the brain, although the extent to which this pathology persists over development is not clear. In the present report, we build upon our previous work which demonstrated that full-term rhesus monkey (Macaca mulatta) fetuses who were exposed to ZIKV early in gestation had significant pathological abnormalities to the organization of the lateral geniculate nucleus (LGN), a major hub of the visual network. The objective of the present work was to replicate those LGN findings and determine whether such pathology persisted across childhood development. We carried out histological analyses of the LGNs of two juvenile rhesus monkeys who were prenatally exposed to ZIKV and two age-matched controls. Pregnant rhesus monkeys were infected with ZIKV via the intravenous and intra-amniotic routes and tracked across development. Following sacrifice and perfusion, brains were subjected to quantitative neuroanatomical analyses with a focus on the size and structure of the LGN and its composite layers. Early fetal ZIKV exposure resulted in developmental abnormalities within the brains’ visual pathway: specifically disorganization, blending of layers, laminar discontinuities, and regions of low cell density within the LGN. These abnormalities were not observed in the control animals. Our findings demonstrate that the ZIKV’s damage to the LGN that occurs during fetal development persists into childhood.
Heat stress and the temporal dynamics of insect growth
Authors: Kingsolver Joel G. , Shlichta J. Gwen , Moore M. Elizabeth
Published: September 2023

Temperature affects rates of ingestion, growth and other key processes in insects and other ectotherms, a relationship described by the thermal performance curve. But the history of temperature exposure can cause stress or acclimation responses, altering the relationship between current temperature and performance. The temporal dynamics of such time-dependent effects for ectotherm growth are poorly understood. We quantify how growth and ingestion change over time at different constant temperatures during the final larval instar for two thermal-generalist insect species,Pieris rapae L.andManduca sexta L. Initial growth rates were greatest at higher temperatures for bothP. rapae(29-35 °C) andM. sexta(34-38 °C); but growth rates at higher temperatures declined over time. As a result, the optimal and maximal temperatures for growth declined over time (2-4 days) in both species. UnlikeP. rapae,M. sextacould maintain growth and survival to wandering and pupation at temperatures above 35 °C. ForM. sextalarvae at 40 °C, ingestion continues even as growth declines, suggesting that post-ingestive processes limit growth rates at these high temperatures. Our results show how time-dependent effects at higher temperatures develop over hourly to daily time scales, with important consequences for understanding and modeling organismal responses to heat waves and extreme temperature events.
Menopause status and within group differences in chronological age affect the functional neural correlates of spatial context memory in middle-aged females
Authors: Crestol Arielle , Rajagopal Sricharana , Lissaman Rikki , LaPlume Annalise , Pasvanis Stamatoula , Olsen Rosanna K. , Einstein Gillian , Jacobs Emily , Natasha Rajah M.
Published: September 2023

Reductions in the ability to encode and retrieve past experiences in rich spatial contextual detail (episodic memory) are apparent by midlife – a time when most females experience spontaneous menopause. Yet, little is known about how menopause status affects episodic memory-related brain activity at encoding and retrieval in middle-aged pre- and post-menopausal females, and whether any observed group differences in brain activity and memory performance correlate with chronological age within group. We conducted an event-related task fMRI study of episodic memory for spatial context to address this knowledge gap. Multivariate behavioral partial least squares (PLS) was used to investigate how chronological age and retrieval accuracy correlated with brain activity in 31 premenopausal (age range: 39.55 – 53.30 yrs,Mage= 44.28 yrs,SDage= 3.12 yrs) and 41 postmenopausal females (age range: 46.70 to 65.14 yrs,Mage= 57.56 yrs,SDage= 3.93 yrs). We found that postmenopausal status, and advanced age within post-menopause, was associated with lower spatial context memory. The fMRI analysis showed that only in postmenopausal females, advanced age was correlated with decreased activity in occipitotemporal, parahippocampal, and inferior parietal during encoding and retrieval, and poorer spatial context memory performance. In contrast, only premenopausal females exhibited an overlap in encoding and retrieval activity in angular gyrus, midline cortical regions, and prefrontal cortex, which correlated with better spatial context retrieval accuracy. These results highlight how menopause status and chronological age, nested within menopause group, affect episodic memory and its neural correlates at midlife.

Significance Statement

This is the first fMRI study to examine how pre- and post-menopause status affects the neural correlates of episodic memory encoding and retrieval, and how chronological age contributes to any observed group similarities and differences. We found that both menopause status (endocrine age) and chronological age affect spatial context memory and its neural correlates. Menopause status directly affected the direction of age- and performance-related correlations with brain activity in inferior parietal, parahippocampal and occipitotemporal cortices across encoding and retrieval. Moreover, we found that only premenopausal females exhibited cortical reinstatement of encoding-related activity in midline cortical, prefrontal, and angular gyrus, at retrieval. This suggests that spatial context memory abilities may rely on distinct brain systems at pre-compared to post-menopause.
GENETIC COUNSELING IN THE MIDDLE EAST
Authors: Shenbagam Shruti , Taylor Alan , Jain Ruchi , Fakhro Khalid A. , Alkuraya Fowzan S. , Abou Tayoun Ahmad N.
Published: September 2023

Genomic advancements have led to increased utilization of genetic testing in clinical care, yet barriers to accessing genetic counseling and genomics services remain, particularly in the Middle East where inherited diseases are highly prevalent due to consanguinity. Limited knowledge of healthcare professionals’ experiences in genetic counseling in the Middle East necessitates understanding their perspectives for better service improvement in the region.

A survey of 32 healthcare professionals providing genetic counseling services in the Middle East explored provider experiences, patient attitudes and cultural/psychosocial factors related to genetic testing. Among the respondents, 21 providers (65.6%), caring for patients of multiple ethnicities, including Arabs, recognised that there are unique challenges to counseling between these patient groups. Thematic data analysis identified that higher levels of consanguinity and stoic nature of the people are unique cultural considerations for this region. Language barriers and limited resources were identified as genetic counseling challenges. Overall, patients in the region demonstrated good coping abilities with a genetic diagnosis. Eighteen responses (56%) highlighted an overall positive attitude, with increasing awareness and acceptance towards genetic testing in this region. This study highlights the need for further research and interventions to address the unique challenges and improve genetic counseling services in the Middle East.

What is known about this topic?

Genetic counseling is typically provided by geneticists and genetic counselors, but due to the limited numbers in the Middle East, this service is also provided by other physicians across various specialties. There is limited knowledge regarding the experiences of healthcare providers offering genetic counseling services in the Middle East and the specific challenges they face in this region.

What this paper adds to the topic?

Our study offers valuable insights into the perspectives of healthcare providers regarding patient attitudes, cultural considerations, and psychosocial factors in genetic testing, with the aim of improving genetic counseling services and enhancing patient outcomes. These findings, along with our recommended strategies shed light on the unique dynamics of genetic counseling in the Middle East.
MetFinder: a neural network-based tool for automated quantitation of metastatic burden in histological sections from animal models
Authors: Karz Alcida , Coudray Nicolas , Bayraktar Erol , Galbraith Kristyn , Jour George , Shadaloey Arman Alberto Sorin , Eskow Nicole , Rubanov Andrey , Navarro Maya , Moubarak Rana , Baptiste Gillian , Levinson Grace , Mezzano Valeria , Alu Mark , Loomis Cynthia , Lima Daniel , Rubens Adam , Jilaveanu Lucia , Tsirigos Aristotelis , Hernando Eva
Published: September 2023

Diagnosis of most diseases relies on expert histopathological evaluation of tissue sections by an experienced pathologist. By using standardized staining techniques and an expanding repertoire of markers, a trained eye is able to recognize disease-specific patterns with high accuracy and determine a diagnosis. As efforts to study mechanisms of metastasis and novel therapeutic approaches multiply, researchers need accurate, high-throughput methods to evaluate effects on tumor burden resulting from specific interventions. However, current methods of quantifying tumor burden are low in either resolution or throughput. Artificial neural networks, which can perform in-depth image analyses of tissue sections, provide an opportunity for automated recognition of consistent histopathological patterns. In order to increase the outflow of data collection from preclinical studies, we trained a deep neural network for quantitative analysis of melanoma tumor content on histopathological sections of murine models. This AI-based algorithm, made freely available to academic labs through a web-interface called MetFinder, promises to become an asset for researchers and pathologists interested in accurate, quantitative assessment of metastasis burden.
Resolution of ring chromosomes, Robertsonian translocations, and complex structural variants from long-read sequencing and telomere-to-telomere assembly
Authors: Mostovoy Yulia , Boone Philip M. , Huang Yongqing , Garimella Kiran V. , Tan Kar-Tong , Russell Bianca E. , Salani Monica , Curall Benjamin , Lucente Diane , Bowers Tera , DeSmet Tim , Gabriel Stacey , Morton Cynthia C. , Meyerson Matthew , Gusella James , Quintero-Rivera Fabiola , Brand Harrison , Talkowski Michael E.
Published: September 2023

The capacity to resolve structural variants (SVs) at sequence resolution in highly repetitive genomic regions has long been intractable. Consequently, the properties, origins, and functional effects of multiple classes of complex rearrangement are unknown. To resolve these challenges, we leveraged recent technical milestones: 1) Oxford-Nanopore (ONT) sequencing; 2) the gapless Telomere-to-Telomere (T2T) genome assembly; and 3) a novel tool to discover large-scale rearrangements from long-reads. We applied these technologies across 13 patients with ring chromosomes, Robertsonian translocations, and complex balanced SVs that were unresolved by short-read sequencing. We resolved 10 of 13 events, including ring chromosomes, the complex SVs, and a Robertsonian translocation. Multiple breakpoints were localized to highly repetitive regions inaccessible to short-read alignment, such as acrocentric p-arms, ribosomal DNA arrays, and telomeric repeats, and involved complex structures such as a deletion-inversion and interchromosomal dispersed duplications. We also leveraged ONT native methylation detection to discover phased differential methylation in a gene promoter proximal to a ring fusion site, suggesting a long-range positional effect with heterochromatin spreading. Breakpoint sequences were consistent with common mechanisms of SV formation, including microhomology-mediated mechanisms, non-homologous end-joining, and non-allelic homologous recombination. These methods provide some of the first glimpses into the sequence resolution of ring chromosomes and Robertsonian translocations and illuminate the structural diversity of chromosomal rearrangements with implications for molecular diagnosis and genome biology.

Highlights

Cryptic rearrangements revealed in repetitive and previously inaccessible regions

Aligning long-reads to telomere-to-telomere assembly enabled breakpoint discovery

First sequence resolution of a Robertsonian translocation breakpoint

Haplotype-specific methylation changes associated with ring formation

Graphical abstract
Partial Face Visibility and Facial Cognition: An Electroencephalography and Eye-Tracking Investigation
Authors: Chanpornpakdi Ingon , Wongsawat Yodchanan , Tanaka Toshihisa
Published: September 2023

Face masks became a part of everyday life in the SARS-CoV-2 pandemic. Previous studies showed that the face cognition mechanism involves holistic face processing, and the absence of face features could lower cognition ability. This is opposed to the experience during the pandemic, when people were able to correctly recognize faces, although the mask covered a part of the face. This paper shows a strong correlation in face cognition based on the EEG and eye-tracking data between the full and partial faces. We observed two event-related potentials, P3a in the frontal lobe and P3b in the parietal lobe, as subcomponents of P300. Both P3a and P3b were lowered when the eyes were invisible, and P3a evoked by the nose covered was larger than the full face. The eye-tracking data showed that 16 out of 18 participants focused on the eyes associated with the EEG results. Our results demonstrate that the eyes are the most crucial feature of facial cognition. Moreover, the face with the nose covered might enhance cognition ability due to the visual working memory capacity. Our experiment shows the possibility of people recognizing faces using both holistic face processing and structural face processing. Furthermore, people can recognize the masked face as well as the full face in similar cognition patterns due to the high correlation in the cognition mechanism.
Developmental stage shapes the realized energy landscape for a flight specialist
Authors: Nourani Elham , Faure Louise , Brønnvik Hester , Scacco Martina , Bassi Enrico , Fiedler Wolfgang , Grüebler Martin U. , Hatzl Julia S. , Jenny David , Roverselli Andrea , Sumasgutner Petra , Tschumi Matthias , Wikelski Martin , Safi Kamran
Published: September 2023

The heterogeneity of the physical environment determines the cost of transport for animals, shaping their energy landscape. Animals respond to this energy landscape by adjusting their distribution and movement to maximize gains and reduce costs. Much of our knowledge about energy landscape dynamics focuses on factors external to the animal, particularly the spatio-temporal variations of the environment. However, an animal’s internal state can significantly impact its ability to perceive and utilize available energy, creating a distinction between the “fundamental” and the “realized” energy landscapes. Here we show that the realized energy landscape varies along the ontogenetic axis. Locomotor and cognitive capabilities of individuals change over time, especially during the early life stages. We investigate the development of the realized energy landscape in the Central European Alpine population of the golden eagleAquila chrysaetos, a large predator that requires negotiating the atmospheric environment to achieve energy-efficient soaring flight. We quantified weekly energy landscapes using environmental features for 55 juvenile golden eagles, demonstrating that energetic costs of traversing the landscape decreased with age. Consequently, the potentially flyable area within the Alpine region increased 2,170-fold during their first three years of independence. Our work contributes to a predictive understanding of animal movement by presenting ontogeny as a mechanism shaping the realized energy landscape.
Ketogenic diet administration later in life improves memory and regulates the synaptic cortical proteome through the cAMP/PKA signaling pathway in aging mice
Authors: Acuña-Catalán Diego , Shah Samah , Wehrfritz Cameron , Nomura Mitsunori , Acevedo Alejandro , Olmos Cristina , Quiroz Gabriel , Huerta Hernán , Bons Joanna , Ampuero Estibaliz , Wyneken Ursula , Sanhueza Magdalena , Arancibia Felipe , Contreras Darwin , Cárdenas Julio César , Morales Bernardo , Schilling Birgit , Newman John C. , González-Billault Christian
Published: September 2023

Aging is a complex biological process that compromises brain function and neuronal network activity, leading to cognitive decline and synaptic dysregulation. In recent years, a cyclic Ketogenic Diet (KD) has emerged as a potential treatment to ameliorate cognitive decline by improving memory in aged mice after long-term administration. However, the molecular mechanisms that govern such changes remains unclear. Additionally, whether short-term cyclic KD administration later in life preserves memory has not been addressed in detail. Accordingly, here we investigated how a short-term cyclic KD starting at 20-23 months-old regulates brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings revealed that a cyclic KD improves working memory and hippocampal LTP in 24-27 months-old mice after 16 weeks of treatment. Moreover, the diet also promotes higher dendritic arborization complexity and dendritic spine density in the prefrontal cortex. Furthermore, to elucidate the molecular mechanisms underlying the memory improvements elicited by a cyclic KD, cortical synaptosomes of aged mice fed with this diet for 1 year were analyzed by mass spectrometry. Bioinformatics analysis revealed that long-term cyclic KD administration predominantly modulates the presynaptic compartment by inducing changes in the cAMP/PKA signaling pathway, the synaptic vesicle cycle, and the actin/microtubule cytoskeleton. To test these findingsin vivo, synaptic proteins from cortices of 24–27-month-old mice fed with control or cyclic KD for 16 weeks were analyzed by western blot. Interestingly, increased Brain Derived Neurotrophic Factor abundance, MAP2 phosphorylation and PKA activity were observed. Overall, we show that a cyclic KD regulates brain function and memory even when it is administered at late mid-life and significantly triggers several molecular features of long-term administration, including the PKA signaling pathway and cytoskeleton dynamics, thus promoting synaptic plasticity at advanced age.
Nurturing care practices for children with developmental disabilities in sub-Saharan Africa: A scoping review protocol
Authors: Onyango Silas , Nampijja Margaret , Otwate Paul , Langat Nelson , Oloo Linda , Okelo Kenneth , Kitsao-Wekulo Patricia
Published: September 2023

Background

The majority of children with neurodevelopmental disorders(NDDs) reside in low- and middle-income countries (LMICs). NDDs is a public health concern in countries in sub-Saharan Africa (SSA). Nurturing care has been recommended as a pathway for addressing the developmental needs and unlocking the full potential of children, including those with NDDs. However, little information exists on the strategies to support children with NDDs using the Nurturing Care Framework in many SSA Countries. The proposed scoping review aims to identify, explore, and map the literature on nurturing care practices for children with NDDs in SSA. The review will also determine gaps in the provision of nurturing care for children with NDD. Further, the review will highlight the drivers of care as well as the experiences of the caregivers in relation to the care provided.

Methods

The review will be implemented in six steps: identification of the research question; identification of relevant studies, selection of studies to be included, charting the data and collating, summarizing, reporting the results, and stakeholder consultation. The selection of the articles will be completed in two parts: a database search followed by a manual search. We will search the following electronic databases: PubMed, ScienceDirect, Scopus, Open Grey and AJOL. All studies published after May 2018 to May 2023 that include relevant terms will be identified and included. The research team will develop a data extraction form for use in capturing relevant information from each of the included studies. A patterning chat that will summarize and analyze the key findings of each article will be created.

Discussion

We anticipate the study will provide evidence on the existing nurturing care practices for children with NDDs and unearth gaps in the provision of nurturing care for children with NDD. Key determinants of care and the experiences of the parents/caregivers of children will also be identified. The study will provide key recommendations on interventions to improve the quality of care for children with NDDs. Through this study, awareness of the unmet nurturing care needs of these children will be increased. The evidence generated may assist policymakers and stakeholders in addressing the needs of children with NDDs.
A dynamic bias in chromatin protein deposition at G-quadruplex sites
Authors: Lobo Thamar Jessurun , Chen Deng , Zwinderman Martijn R. H. , Lansdorp Peter M , Dekker Frank J. , Guryev Victor
Published: September 2023

Previous studies indicate that genomic loci harboring G-quadruplexes (G4s)—stacked structures that can form in single-stranded DNA—can be linked to epigenetic instability. However, the role of chromatin redistribution and the genome-wide nature of this process need further investigation. Here, we provide experimental evidence that connects G4s to alterations in the deposition of chromatin proteins. We have used metabolic labelling and immunoprecipitation of new and parental proteins in hRPE-1 cells to investigate global chromatin deposition dynamics.

We identify a reciprocal, local bias in chromatin protein deposition at G4 sites favoring the association of parental proteins with the G4 and new proteins with the C4 DNA strand. The deposition bias at G4 sites does not depend on replication directionality and is strengthened by G4 stabilization. Slowing down replication forks upon hydroxyurea treatment reverses the bias, supposedly affected by decoupling between helicase and polymerase. Interestingly, upon combined G4 stabilization and slowing of the replication forks, new proteins exhibit a redistribution pattern similar to G4 stabilization alone, while parental protein redistribution more resembles one after hydroxyurea treatment, hinting at mechanistic differences between parental and new histone distribution. We also report that the genomic distribution of putative quadruplexes is not random and depends on loop size, where G4s with shorter loops have a preference for the DNA strand replicated by leading and G4s with longer loops by lagging strand replication. These findings provide insight into the mechanisms behind G4 occurrence and its role in epigenetic instability and help to improve our understanding of the factors influencing biases in global chromatin protein redeposition.
Evolution of a large periplasmic disk inCampylobacterotaflagella facilitated efficient motility alongside autoagglutination
Authors: Cohen Eli J. , Drobnič Tina , Ribardo Deborah A. , Yoshioka Aoba , Umrekar Trishant , Guo Xuefei , Fernandez Jose-Jesus , Brock Emma , Wilson Laurence , Nakane Daisuke , Hendrixson David R. , Beeby Morgan
Published: September 2023

Although the bacterial flagella ofEscherichia coliandSalmonella entericaare distributed around the cell body, many bacteria instead place their flagella at their poles. This widespread form of flagellar motility is relatively poorly understood, but these polar flagellar motors invariably feature periplasmic disk structures of unknown function. The flagellar motor ofCampylobacter jejunifeatures a 100 nm-wide periplasmic disk associated with scaffolding a wider ring of motor proteins to increase torque, but the size of this disk is excessive for a role solely in scaffolding motor proteins. Here we show that the basal disk inC. jejuniis a flange that braces the motor during disentanglement of the flagellar filament from interactions with the cell body and other filaments, interactions that are otherwise important for host colonization. Our results reveal an entanglement of co-dependencies in the evolution of flagellar motor structure and cell plan in the Campylobacterota (previously epsilonproteobacteria). Note that this manuscript has a sibling manuscript titled’Molecular model of a bacterial flagellar motor in situ reveals a “parts-list” of protein adaptations to increase torque’that describes a molecular model of theCampylobacter jejuniflagellar motor discussed here.
Dynamic representation of multidimensional object properties in the human brain
Authors: Teichmann Lina , Hebart Martin N , Baker Chris I
Published: September 2023

Our visual world consists of an immense number of unique objects and yet, we are easily able to identify, distinguish, interact, and reason about the things we see within a few hundred milliseconds. This requires that we integrate and focus on a wide array of object properties to support diverse behavioral goals. In the current study, we used a large-scale and comprehensively sampled stimulus set and developed an analysis approach to determine if we could capture how rich, multidimensional object representations unfold over time in the human brain. We modelled time-resolved MEG signals evoked by viewing single presentations of tens of thousands of object images based on millions of behavioral judgments. Extracting behavior-derived object dimensions from similarity judgments, we developed a data-driven approach to guide our understanding of the neural representation of the object space and found that every dimension is reflected in the neural signal. Studying the temporal profiles for different object dimensions we found that the time courses fell into two broad types, with either a distinct and early peak (~125 ms) or a slow rise to a late peak (~300 ms). Further, early effects were stable across participants, in contrast to later effects which showed more variability, suggesting that early peaks may carry stimulus-specific and later peaks more participant-specific information. Dimensions with early peaks appeared to be primarily visual dimensions and those with later peaks more conceptual, suggesting that conceptual representations are more variable across people. Together, these data provide a comprehensive account of how behavior-derived object properties unfold in the human brain and form the basis for the rich nature of object vision.