bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic modulation of histone acetylation mediated by HMGCL activates the FOXM1/β-catenin pathway in glioblastoma
Authors: Sun Yanfei , Mu Guangjing , Zhang Xuehai , Wu Yibo , Wang Shuai , Wang Xu , Xue Zhiwei , Wang Chuanwei , Liu Jilong , Li Wenbo , Zhang Lin , Guo Yunyun , Zhao Feihu , Liu Xuemeng , Xue Zhiyi , Zhang Yan , Ni Shilei , Wang Jian , Li Xingang , Han Mingzhi , Huang Bin
Published: December 2023

Background

Altered branched-chain amino acid (BCAA) metabolism modulates epigenetic modification, such as H3K27ac in cancer, thus providing a link between metabolic reprogramming and epigenetic change, which are prominent hallmarks of glioblastoma multiforme (GBM). Here, we identified mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase (HMGCL), an enzyme involved in leucine degradation, promoting GBM progression and glioma stem cell (GSC) maintenance.

Methods

In silico analysis was performed to identify specific molecules involved in multiple processes. Glioblastoma multiforme cells were infected with knockdown/overexpression lentiviral constructs of HMGCL to assess malignant performance in vitro and in an orthotopic xenograft model. RNA sequencing was used to identify potential downstream molecular targets.

Results

HMGCL, as a gene, increased in GBM and was associated with poor survival in patients. Knockdown of HMGCL suppressed proliferation and invasion in vitro and in vivo. Acetyl-CoA was decreased with HMGCL knockdown, which led to reduced NFAT1 nuclear accumulation and H3K27ac level. RNA sequencing-based transcriptomic profiling revealed FOXM1 as a candidate downstream target, and HMGCL-mediated H3K27ac modification in the FOXM1 promoter induced transcription of the gene. Loss of FOXM1 protein with HMGCL knockdown led to decreased nuclear translocation and thus activity of β-catenin, a known oncogene. Finally, JIB-04, a small molecule confirmed to bind to HMGCL, suppressed GBM tumorigenesis in vitro and in vivo.

Conclusions

Changes in acetyl-CoA levels induced by HMGCL altered H3K27ac modification, which triggers transcription of FOXM1 and β-catenin nuclear translocation. Targeting HMGCL by JIB-04 inhibited tumor growth, indicating that mediators of BCAA metabolism may serve as molecular targets for effective GBM treatment.
Cooperative actin filament nucleation by the Arp2/3 complex and formins maintains the homeostatic cortical array inArabidopsisepidermal cells
Authors: Xu Liyuan , Cao Lingyan , Li Jiejie , Staiger Christopher J
Published: December 2023

Precise control over how and where actin filaments are created leads to the construction of unique cytoskeletal arrays within a common cytoplasm. Actin filament nucleators are key players in this activity and include the conserved actin-related protein 2/3 (Arp2/3) complex as well as a large family of formins. In some eukaryotic cells, these nucleators compete for a common pool of actin monomers and loss of one favors the activity of the other. To test whether this mechanism is conserved, we combined the ability to image single filament dynamics in the homeostatic cortical actin array of living Arabidopsis (Arabidopsis thaliana) epidermal cells with genetic and/or small molecule inhibitor approaches to stably or acutely disrupt nucleator activity. We found that Arp2/3 mutants or acute CK-666 treatment markedly reduced the frequency of side-branched nucleation events as well as overall actin filament abundance. We also confirmed that plant formins contribute to side-branched filament nucleation in vivo. Surprisingly, simultaneous inhibition of both classes of nucleator increased overall actin filament abundance and enhanced the frequency of de novo nucleation events by an unknown mechanism. Collectively, our findings suggest that multiple actin nucleation mechanisms cooperate to generate and maintain the homeostatic cortical array of plant epidermal cells.
Early stage of erythrocyte sedimentation rate test: Fracture of a high-volume-fraction gel
Authors: John Thomas , Kaestner Lars , Wagner Christian , Darras Alexis
Published: December 2023

Erythrocyte sedimentation rate (ESR) is a clinical parameter used as a nonspecific marker for inflammation, and recent studies have shown that it is linked to the collapse of the gel formed by red blood cells (RBCs) at physiological hematocrits (i.e. RBC volume fraction). Previous research has suggested that the observation of a slower initial dynamics is related to the formation of fractures in the gel. Moreover, RBC gels present specific properties due to the anisotropic shape and flexibility of the RBCs. Namely, the onset of the collapse is reached earlier and the settling velocity of the gel increases with increasing attraction between the RBCs, while the gel of spherical particles shows the opposite trend. Here, we report experimental observations of the gel structure during the onset of the collapse. We suggest an equation modeling this initial process as fracturing of the gel. We demonstrate that this equation provides a model for the motion of the interface between blood plasma and the RBC gel, along the whole time span. We also observe that the increase in the attraction between the RBCs modifies the density of fractures in the gel, which explains why the gel displays an earlier onset when the aggregation energy between the RBCs increases. Our work uncovers the detailed physical mechanism underlying the ESR and provides insights into the fracture dynamics of an RBC gel. These results can improve the accuracy of clinical measurements.
Regulation of lipolysis by 14-3-3 proteins on human adipocyte lipid droplets
Authors: Yang Qin , Loureiro Zinger Yang , Desai Anand , DeSouza Tiffany , Li Kaida , Wang Hui , Nicoloro Sarah M , Solivan-Rivera Javier , Corvera Silvia
Published: December 2023

Adipocyte lipid droplets (LDs) play a crucial role in systemic lipid metabolism by storing and releasing lipids to meet the organism's energy needs. Hormonal signals such as catecholamines and insulin act on adipocyte LDs, and impaired responsiveness to these signals can lead to uncontrolled lipolysis, lipotoxicity, and metabolic disease. To investigate the mechanisms that control LD function in human adipocytes, we applied proximity labeling mediated by enhanced ascorbate peroxidase (APEX2) to identify the interactome of PLIN1 in adipocytes differentiated from human mesenchymal progenitor cells. We identified 70 proteins that interact specifically with PLIN1, including PNPLA2 and LIPE, which are the primary effectors of regulated triglyceride hydrolysis, and 4 members of the 14-3-3 protein family (YWHAB, YWHAE, YWHAZ, and YWHAG), which are known to regulate diverse signaling pathways. Functional studies showed that YWHAB is required for maximum cyclic adenosine monophosphate (cAMP)-stimulated lipolysis, as its CRISPR-Cas9-mediated knockout mitigates lipolysis through a mechanism independent of insulin signaling. These findings reveal a new regulatory mechanism operating in human adipocytes that can impact lipolysis and potentially systemic metabolism.
Interplay of two low-barrier hydrogen bonds in long-distance proton-coupled electron transfer for water oxidation
Authors: Saito Keisuke , Nishio Shunya , Ishikita Hiroshi
Published: December 2023

D1-Tyr161 (TyrZ) forms a low-barrier H-bond with D1-His190 and functions as a redox-active group in photosystem II. When oxidized to the radical form (TyrZ-O•), it accepts an electron from the oxygen-evolving Mn4CaO5 cluster, facilitating an increase in the oxidation state (Sn; n = 0–3). In this study, we investigated the mechanism of how TyrZ-O• drives proton-coupled electron transfer during the S2 to S3 transition using a quantum mechanical/molecular mechanical approach. In response to TyrZ-O• formation and subsequent loss of the low-barrier H-bond, the ligand water molecule at the Ca2+ site (W4) reorients away from TyrZ and donates an H-bond to D1-Glu189 at Mn4 of Mn4CaO5 together with an adjacent water molecule. The H-bond donation to the Mn4CaO5 cluster triggers the release of the proton from the lowest pKa site (W1 at Mn4) along the W1…D1-Asp61 low-barrier H-bond, leading to protonation of D1-Asp61. The interplay of the two low-barrier H-bonds, involving the Ca2+ interface and forming the extended Grotthuss-like network [TyrZ…D1-His190]-[Mn4CaO5]-[W1…D1-Asp61], rather than the direct electrostatic interaction, is likely a basis of the apparent long-distance interaction (11.4 Å) between TyrZ-O• formation and D1-Asp61 protonation.
Tree-ring isotopic imprints on time series of reproductive effort indicate warming-induced co-limitation by sink and source processes in stone pine
Authors: Shestakova Tatiana A , Sin Ester , Gordo Javier , Voltas Jordi
Published: December 2023

Increasing evidence indicates that tree growth processes, including reproduction, can be either sink- or source-limited, or simultaneously co-limited by sink and source, depending on the interplay between internal and environmental factors. We tested the hypothesis that the relative strengths of photosynthate supply and demand by stem growth and reproduction create variable competition for substrate that is imprinted in the tree-ring isotopes (C and O) of stone pine (Pinus pinea L.), a masting gymnosperm with large costs of reproduction, under warming-induced drought. Across five representative stands of the Spanish Northern Plateau, we also identified reproductive phases where weather drivers of cone yield (CY) have varied over a 60-year period (1960–2016). We found that these drivers gradually shifted from winter–spring conditions 3 years before seed rain (cone setting) to a combination of 3- and 1-year lagged effects (kernel filling). Additionally, we observed positive regional associations between carbon isotope discrimination (Δ13C) of the year of kernel filling and CY arising at the turn of this century, which progressively offset similarly positive relationships between Δ13C of the year of cone setting and CY found during the first half of the study period. Altogether, these results pinpoint the increasing dependence of reproduction on fresh assimilates and suggest sink and source co-limitation superseding the sink-limited functioning of reproduction dominant before 2000. Under climate warming, it could be expected that drier conditions reinforce the role of source limitation on reproduction and, hence, on regeneration, forest structure and economic profit of the nutlike seeds of the species.
Original Research: Predictors of COVID-19 Vaccine Hesitancy Among Asian Indians in the United States: A Cross-Sectional Descriptive Study
Authors: Albuquerque Lydia Honorata , Luckose Anne B. , Joseph Maya , Mathews Nisha , Devarayasamudram Sujayalakshmi , Mahon Emily
Published: December 2023

Background:

Although COVID-19 is a highly infectious disease, vaccine hesitancy remains a primary barrier to attaining full population inoculation. Numerous factors related to vaccine hesitancy have been identified. The aim of this study was to explore associations between select demographic variables and COVID-19 vaccine hesitancy among Asian Indians in the United States.

Methods:

The study used a cross-sectional, descriptive, correlational design. The sample consisted of 363 Asian Indians living in the United States who were 18 years of age or older and were literate in English. Vaccine hesitancy was assessed using an online survey. Both descriptive and inferential statistical analyses were conducted. Inferential tests included t tests, regression analyses, and analysis of variance (ANOVA) tests.

Results:

As participant age increased, there was a statistically significant proportionate increase in the total vaccine hesitancy score (P = 0.01). There were also statistically significant differences in the vaccine hesitancy scores of participants with no more than a high school degree compared to those with associate or bachelor's degrees, although this finding was based on just six participants. Although most participants had already been vaccinated, many identified reasons for feeling some degree of vaccine hesitancy.

Conclusions:

The reasons for vaccine hesitancy vary by individual and are often complex. The results of this study will help guide public health agencies and health care personnel in developing vaccination strategies tailored to the specific requirements of Asian Indians in the United States, which could reduce vaccine hesitancy in this population.
Intra-accumbal orexinergic system contributes to the stress-induced antinociceptive behaviors in the animal model of acute pain in rats
Authors: Nikoohemmat Mohammad , Farmani Danial , Moteshakereh Seyed Mohammadmisagh , Salehi Sakineh , Rezaee Laleh , Haghparast Abbas
Published: December 2023

Stress and pain are interleaved at numerous levels - influencing each other. Stress can increase the nociception threshold in animals, long-known as stress-induced analgesia (SIA). Orexin is known as a neuropeptide that modulates pain. The effect of stress on the mesolimbic system in the modulation of pain is known. The role of the intra-accumbal orexin receptors in the modulation of acute pain by forced swim stress (FSS) is unclear. In this study, 117 adult male albino Wistar rats (270–300 g) were used. The animals were unilaterally implanted with cannulae above the NAc. The antagonist of the orexin-1 receptor (OX1r), SB334867, and antagonist of the orexin-2 receptor (OX2r), TCS OX2 29, were microinjected into the NAc in different doses (1, 3, 10, and 30 nmol/0.5 µl DMSO) before exposure to FSS for a 6-min period. The tail-flick test was carried out as an assay nociception of acute pain, and the nociceptive threshold [tail-flick latency (TFL)] was measured for 60-minute. The findings demonstrated that exposure to acute stress could remarkably increase the TFLs and antinociceptive responses. Moreover, intra-accumbal microinjection of SB334867 or TCS OX2 29 blocked the antinociceptive effect of stress in the tail-flick test. The contribution of orexin receptors was almost equally modulating SIA. The present study’s findings suggest that OX1r and OX2r within the NAc modulate stress-induced antinociceptive responses. The intra-accumbal microinjection of orexin receptors antagonists declares inducing antinociceptive responses by FSS in acute pain. Proposedly, intra-accumbla orexinergic receptors have a role in the development of SIA.
Facial Contouring after Permanent Filler Removal with Combined Facelift and Fat Grafting: A Case Series
Authors: Gadallah Ahmed , Etman Adnan Gamal , Mamdouh Abd Elhalim Mohamed
Published: December 2023

Background:

Aesthetic procedures for addressing aging range from simple injection of dermal fillers to facelift surgery. The last few decades have witnessed the development of diverse techniques to minimize facial wrinkles, volumize the face, and restore a youthful appearance. For example, fillers are a group of compounds used for cosmetic and reconstructive purposes, especially related to the face. Therefore, this study aimed to demonstrate specific cases where problematic dermal fillers were evacuated in combination with facelift procedures and fat grafting. It therefore demonstrates means to manage and treat permanent filler complications with a multidisciplinary evidence-based approach to achieve functional and cosmetic outcomes.

Methods:

Between January 2020 and August 2022, 50 patients were subjected to drainage of permanent dermal filler followed by facelift and fat grafting with a minimum 6-month follow-up recorded.

Results:

A total of 50 female patients between 30 and 56 years of age underwent permanent dermal filler removal in conjunction with facelift and fat grafting. The surgery was successful in all cases, but four cases of seroma and four cases of facial mandibular nerve neuropraxia, five cases of scar hypertrophy, two cases of wound infection and one case of pixie ear deformity were encountered during the follow-up.

Conclusion:

In this study, we present the characteristics of combining facelift and fat grafting procedures after surgical drainage of permanent dermal fillers to achieve aesthetically favorable results.
Cannulation Indocyanine Green Method for Strategic Management of Postoperative Arterial Thrombosis after Free Jejunal Flap Transfer
Authors: Fujii Taketo , Karakawa Ryo , Yoshimatsu Hidehiko , Yano Tomoyuki
Published: December 2023

Indocyanine green (ICG) angiography is widely used in reconstructive surgery to confirm the perfusion of the flap. Here, we report a case in which the use of the “cannulation ICG method” was useful for strategic management of postoperative arterial thrombosis after free jejunal flap transfer. A 64-year-old woman underwent cervical esophagectomy followed by a free jejunal transfer. On postoperative day 3, ischemia of the free jejunum was suspected, and takeback was performed. In the reoperation, re-anastomosis of the artery was planned after the removal of arterial thrombus. However, before re-anastomosis, it was unclear whether there was venous thrombus and whether this jejunum flap was salvageable. To resolve these two questions, we performed the cannulation ICG method. In this method, we injected a mixture of 1.0 mL of ICG and 20 mL of blood into the jejunal artery via 24-gauge cannula. We then evaluated the perfusion of the jejunal flap and monitoring jejunum, and the patency of the venous anastomosis site using a near-infrared fluorescence imaging device (LIGHTVISION; Shimadzu Corporation, Kyoto, Japan). In this case, the whole jejunal flap (including the monitoring jejunum) and venous anastomosis site were highlighted. We determined that there were no venous thrombi and that the entire jejunum was salvageable. After the arterial re-anastomosis, ICG angiography showed good perfusion of the whole jejunum. The postoperative course was uneventful, and the free jejunal flap survived completely. The cannulation ICG method may be effective for determining the surgical method for reoperation due to arterial thrombosis after reconstruction of the free jejunum.
Age Matters
Authors: Mitsuhashi Shuji , Azari Jade , Dioguardi Vincent , Bilello Justin , Tang Marshall , Kastenberg David
Published: December 2023

Goals:

This study aims to address gaps in medical knowledge by determining whether adenoma detection rate (ADR) in average-risk screening patients aged 45 to 49 is equivalent to screening patients aged 50 to 54.

Background:

Current guidelines recommend initiating colon cancer screening at age 45, yet our understanding of the effects of ADR in average-risk individuals among 45- to 49-year-olds is still limited.

Study:

A retrospective analysis was conducted on records of average-risk screening colonoscopies performed on patients aged 45 to 54 from January 2018 to August 2022. Exclusions were prior diagnoses of colorectal cancer or adenomatous polyps, inflammatory bowel disease, personal or family history of genetic cancer syndromes, incomplete colonoscopy, and inadequate bowel preparation. The primary outcome was ADR in the age 45 to 49 group compared with the age 50 to 54 group.

Results:

Of the 3199 average-risk screening colonoscopies performed, 879 and 2116 patients were included in the age 45 to 49 and 50 to 54 groups, respectively. Both groups were predominantly female, White ethnicity, never smokers, and obese. ADR was found to be 27% in the age 45 to 49 group compared with 34% in the age 50 to 54 group (odds ratio 0.70, 90% CI: 0.60-0.83, P-value for equivalence=0.81 w/ margin 0.77 to 1.30).

Conclusions:

The study did not demonstrate equivalent ADR between the 2 age groups, with ADR being substantially lower in the age 45 to 49 group (27% vs. 34%). Despite this, the ADR in the 45 to 49 age range surpasses the established benchmark of 25%, supporting the decision to lower the screening age to 45 years. Ongoing national monitoring is essential to comprehensively evaluate the impact of these updated guidelines.
Bone turnover change after randomized switch from tenofovir disoproxil to tenofovir alafenamide fumarate in men with HIV
Authors: Moore Amelia E.B. , Burns James E. , Sally Deirdre , Milinkovic Ana , Krokos Georgios , John Joemon , Rookyard Christopher , Borca Alessandro , Pool Erica R.M. , Tostevin Anna , Harman Alyss , Dulnoan Dwight S. , Gilson Richard , Arenas-Pinto Alejandro , Cook Gary J.R. , Saunders John , Dunn David , Blake Glen M. , Pett Sarah L.
Published: December 2023

Objective:

Bone loss in people with HIV (PWH) is poorly understood. Switching tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) has yielded bone mineral density (BMD) increases. PETRAM (NCT#:03405012) investigated whether BMD and bone turnover changes correlate.

Design:

Open-label, randomized controlled trial.

Setting:

Single-site, outpatient, secondary care.

Participants:

Nonosteoporotic, virologically suppressed, cis-male PWH taking TDF/emtricitabine (FTC)/rilpivirine (RPV) for more than 24 weeks.

Intervention:

Continuing TDF/FTC/RPV versus switching to TAF/FTC/RPV (1 : 1 randomization).

Main outcome measures:

:[18F]NaF-PET/CT for bone turnover (standardized uptake values, SUVmean) and dual-energy x-ray absorptiometry for lumbar spine and total hip BMD.

Results:

Thirty-two men, median age 51 years, 76% white, median duration TDF/FTC/RPV 49 months, were randomized between 31 August 2018 and 09 March 2020. Sixteen TAF:11 TDF were analyzed. Baseline-final scan range was 23–103 (median 55) weeks. LS-SUVmean decreased for both groups (TAF -7.9% [95% confidence interval -14.4, -1.5], TDF -5.3% [-12.1,1.5], P = 0.57). TH-SUVmean showed minimal changes (TAF +0.3% [-12.2,12.8], TDF +2.9% [-11.1,16.9], P = 0.77). LS-BMD changes were slightly more favorable with TAF but failed to reach significance (TAF +1.7% [0.3,3.1], TDF -0.3 [-1.8,1.2], P = 0.06). Bone turnover markers decreased more with TAF ([CTX -35.3% [-45.7, -24.9], P1NP -17.6% [-26.2, -8.5]) than TDF (-11.6% [-28.8, +5.6] and -6.9% [-19.2, +5.4] respectively); statistical significance was only observed for CTX (P = 0.02, P1NP, P = 0.17).

Conclusion:

Contrary to our hypothesis, lumbar spine and total hip regional bone formation (SUVmean) and BMD did not differ postswitch to TAF. However, improved LS-BMD and CTX echo other TAF-switch studies. The lack of difference in SUVmean may be due to inadequate power.
A potential pathway that links intron retention with the physiological recovery by a Japanese herbal medicine
Authors: Okada Norihiro , Oshima Kenshiro , Maruko Akiko , Vu Trieu-Duc , Chiu Ming-Tzu , Nishiyama Mitsue , Yamamoto Masahiro , Nishi Akinori , Kobayashi Yoshinori
Published: December 2023

Our previous experiments with klotho mice (i.e., klotho knockout mice) showed that aberrant intron retention (IR) occurs in a pre-symptomatic state of aging and can be restored to the normal state by administration of Juzentaihoto (JTT), a formula of the Japanese herbal medicine (referred to as kampo; Okada et al., 2021). To explain that this phenomenon is not just a specific example observed in klotho mice, but is due to a universal cause that may be common in a pre-symptomatic state, we re-analyzed the data for genes that were differentially expressed in the klotho liver in response to JTT. Our data showed that AMPK signaling was activated in these mice, resulting in inhibition of anabolic pathways including protein synthesis and activation of catabolic pathways including lipolysis in various organs. These data were consistent with the observation that klotho mice appeared to be in a perpetual state of pseudo-starvation, i.e., based on their overall metabolic profile. The abnormally increased incidence of IR (IncIR) in the liver of klotho mice could be classified into three types according to their transcriptional status, revealing that each of all the three types of IncIR was caused by AMPK activation, a consequence of the pseudo-starvation state exhibited by these mice. Furthermore, we showed that both the transcriptional drift variance and the IR drift variance can be useful for visually assessing recovery from the pseudo-starvation state of klotho mice after administration of JTT. With these data, we propose a novel pathway linking intron retention to changes in the physiological state such as starvation, resulting in the maintenance of cellular homeostasis.
Decreased voluntary alcohol intake and ventral striatal epigenetic and transcriptional remodeling in male Acss2 KO mice
Authors: Egervari Gabor , Donahue Greg , Quijano-Carde Natalia , Hogan Connor , Periandri Erica M , Fleites Vanessa , Alexander Desi C , De Biasi Mariella , Berger Shelley L
Published: December 2023

Metabolic-epigenetic interactions are emerging as key pathways in regulating alcohol-related transcriptional changes in the brain. We previously demonstrated that this is mediated by the metabolic enzyme Acetyl-CoA synthetase 2 (Acss2), which is nuclear and chromatin-bound in neurons. Mice lacking Acss2 fail to deposit alcohol-derived acetate onto histones in the brain and show no conditioned place preference for ethanol reward. Here, we explored the role of this pathway during voluntary alcohol intake. We found that Acss2 KO mice consumed significantly less alcohol during drinking-in-the-dark, and this effect was primarily driven by males. We performed genome-wide transcriptional profiling of 7 key brain regions implicated in alcohol and drug use, and found that, following drinking, Acss2 KO mice exhibited blunted gene expression in the ventral striatum, and similar to the behavioral differences, transcriptional dysregulation was more pronounced in male mice. Further, we found that the gene expression changes were associated with depletion of ventral striatal histone acetylation (H3K27ac) in Acss2 KO mice compared to WT. Taken together, our data suggest that Acss2 plays an important role in orchestrating ventral striatal epigenetic and transcriptional changes during voluntary alcohol drinking, especially in males. Consequently, targeting this pathway could be a promising new therapeutic avenue.
Choosing explanation over performance: Insights from machine learning-based prediction of human intelligence from brain connectivity
Authors: Thiele Jonas Alexander , Faskowitz Joshua , Sporns Olaf , Hilger Kirsten
Published: December 2023

A growing body of research predicts individual cognitive ability levels from brain characteristics including functional brain connectivity. The majority of this research achieves good prediction performance but provides limited insight into neurobiological processes underlying the predicted concepts. The insufficient identification of predictive characteristics may present an important factor critically contributing to this constraint. Here, we encourage to design predictive modelling studies with an emphasis on interpretability to enhance our conceptual understanding of human cognition. As an example, we investigated in a preregistered study which functional brain connections successfully predict general, crystallized, and fluid intelligence in a sample of 806 healthy adults (replication: N = 322). The choice of the predicted intelligence component as well as the task during which connectivity was measured proved crucial for better understanding intelligence at the neural level. Further, intelligence could be predicted not solely from one specific set of brain connections, but from various combinations of connections with system-wide locations. Such partially redundant, system-wide functional characteristics complement intelligence-relevant connectivity of brain regions proposed by established intelligence theories. In sum, our study showcases how future predictive studies on human cognition can enhance explanatory value by prioritizing a systematic evaluation of predictive characteristics over maximizing prediction performance.
A High-Resolution LED Display for Steady State Visual Stimulation: Customized, Affordable, and Open Source
Authors: Otero Monica , Prieur-Coloma Yunier , El-Deredy Wael , Weinstein Alejandro
Published: December 2023

Visually evoked steady-state potentials (SSVEPs) are neural responses elicited by visual stimuli oscillating at specific frequencies. In this study, we introduce a novel LED display system designed specifically for steady-state visual stimulation, offering precise control over visual stimulus parameters, including frequency resolution, luminance, and the ability to control the phase at the end of the stimulation. The LED display provides a personalized, modular, and affordable option for experimental setups. Based on the Teensy 3.2 board, the display utilizes Direct Digital Synthesis and Pulse Width Modulation techniques to control the LEDs. Its performance is validated through four experiments: the first two measure LED light intensities directly, while the last two assess the display’s impact on EEG recordings. The results demonstrate that the display can deliver a stimulus suitable for generating SSVEPs with the desired frequency and phase resolution. We provide comprehensive documentation, including all necessary codes and electrical diagrams, as an open-source resource. This facilitates the replication and adaptation of the system for specific experimental requirements, enhancing its potential for widespread use in the field of neuroscience.
Phosphorylation of MYCN and MAX by PAK family kinases is a novel tumor-suppressor mechanism in neuroblastoma with potential therapeutic implications
Authors: Rozen Esteban J , Wigglesworth Kim , Shohet Jason
Published: December 2023

High-risk Neuroblastoma (HR-NB) is a very aggressive pediatric cancer, responsible of over 15% of all childhood cancer-associated deaths. Despite very aggressive multimodal interventions, less than 50% of HR-NB patients survive, exhibiting serious long-term sequelae from therapy. Therefore, more efficient, and less toxic interventions are urgently needed. Genomic amplification of the MYCN gene is observed in about 50% of all HR-NB cases, and is the most reliable genomic hallmark associated to a bad prognosis. c-MYC is highly expressed in a significant amount of the remaining (non-MYCN-amplified) HR-NB cases. Here, we investigated an endogenous mechanism mediated by the PAK2 kinase and known to phosphorylate and suppress c-MYC transcriptional activity. We uncovered that PAK2 can also phosphorylate MYCN and its obligate transcriptional partner MAX in two conserved Ser/Thr residues, disrupting MYCN:MAX interaction, transcription, and neuroblastoma cell proliferation. We further provide evidence for a potential mechanism by which PAK kinase activity is blunted in MYCN-amplified neuroblastoma tumors and propose an innovative strategy to circumvent such signaling impairment and potentially suppress HR-NB tumor growth.
Parkinson’s Families Project: a UK-wide study of early onset and familial Parkinson’s disease
Authors: Towns Clodagh , Fang Zih-Hua , Tan Manuela M. X. , Jasaityte Simona , Schmaderer Theresa M. , Stafford Eleanor J. , Pollard Miriam , Tilney Russel , Hodgson Megan , Wu Lesley , Labrum Robyn , Hehir Jason , Polke James , Lange Lara M. , Schapira Anthony H. V. , Bhatia Kailash P. ,   Parkinson’s Families Project (PFP) Study Group,   Global Parkinson’s Genetics Program (GP2), Singleton Andrew B. , Blauwendraat Cornelis , Klein Christine , Houlden Henry , Wood Nicholas W. , Jarman Paul R. , Morris Huw R. , Real Raquel
Published: December 2023

The Parkinson’s Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson’s disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset ≤ 45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruited affected and unaffected relatives. We analysed DNA samples with a combination of single nucleotide polymorphism (SNP) array genotyping, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing (WGS). We investigated the association between identified pathogenic mutations and demographic and clinical factors such as age at motor symptom onset, family history, motor symptoms (MDS-UPDRS) and cognitive performance (MoCA). We performed baseline genetic analysis in 718 families, of which 205 had sporadic early-onset PD (sEOPD), 113 had familial early-onset PD (fEOPD), and 400 had late-onset familial PD (fLOPD). 69 (9.6%) of these families carried pathogenic variants in known monogenic PD-related genes. The rate of a molecular diagnosis increased to 28.1% in PD with motor onset ≤ 35 years. We identified pathogenic variants inLRRK2in 4.2% of families, and biallelic pathogenic variants inPRKNin 3.6% of families. We also identified two families withSNCAduplications and three families with a pathogenic repeat expansion inATXN2, as well as single families with pathogenic variants inVCP,PINK1,PNPLA6,PLA2G6,SPG7,GCH1, andRAB32. An additional 73 (10.2%) families were carriers of at least one pathogenic or riskGBA1variant. Most early-onset and familial PD cases do not have a known genetic cause, indicating that there are likely to be further monogenic causes for PD.
“At the end of the day, it is Council’s decision”: Integration of health and equity into urban design and urban planning decisions and policies in Regina Saskatchewan
Authors: Mahani Akram , Lyeo Joonsoo Sean , Fung Agnes , Husack Kelly , Muhajarine Nazeem , Diener Tania , Brown Chelsea
Published: December 2023

While there is a wealth of literature on the impact of urban design on health, our understanding of the factors that influence integration of health into urban design is limited. With the growing recognition of cities playing a leading role in enhancing health equity and population health outcomes, there is a need to examine the perspectives and experiences of municipal actors around health and equity. To address this gap, we interviewed 30 stakeholders engaged with urban design policy- and decision-making at the City of Regina in Saskatchewan, Canada. We found a lack of shared understanding of health among municipal actors. Our findings identified a number of factors that serve as facilitators and barriers to integrating health and equity in urban design policies. Findings from this case study deepen our understanding of these factors and provide recommendations for developing healthy urban design policies. Our findings underscore the importance of adopting an integrated and holistic approach for healthy and equitable urban design. As urbanisation continues to bring a greater share of the world’s population into urban areas, it is imperative that we deepen our understanding of how municipal governance can be leveraged to create environments that are conducive to the wellbeing of their residents.
Neurocognitive features of mild cognitive impairment and distress symptoms in older adults without major depression
Authors: Nantachai Gallayaporn , Maes Michael , Tran-Chi Vinh-Long , Hemrungrojn Solaphat , Tunvirachaisakul Chavit
Published: December 2023

Background

Two distinct symptom dimensions were identified in older adults who did not have major depressive disorder (MDD): a) a dimension associated with mild cognitive dysfunction, and b) a dimension related to distress symptoms of old age (DSOA). It is uncertain whether previous findings regarding the features of amnestic mild cognitive impairment (aMCI) remain valid when patients with MDD are excluded.

Objectives

To examine, in participants without MDD, the neurocognitive characteristics of aMCI and the objective cognitive characteristics of DSOA. Neurocognition was evaluated utilizing the Cambridge Neurological Test Automated Battery (CANTAB) and memory tests.

Results

This research demonstrated that CANTAB tests have the capability to differentiate between aMCI and controls. The One Touch Stockings of Cambridge, probability solved on first choice (OTS_PSFC), Rapid Visual Information Processing, A prime, and the Motor Screening Task, mean latency (MOT_ML), were identified as the significant discriminatory CANTAB tests. 37.6% of the variance in the severity of aMCI was predicted by OTS_PSFC, RVP_A’, word list recognition scores, and education. Psychosocial stressors (adverse childhood experiences, negative life events), subjective feelings of cognitive impairment, and RVP, probability of false alarm, account for 40.0% of the DSOA score.

Discussion

When MDD is ruled out, aMCI is linked to deficits in attention, executive functions, and memory. Psychosocial stressors did not have a statistically significant impact on aMCI or its severity. Enhanced false alarm response bias coupled with heightened psychological stress (including subjective perception of cognitive decline) may contribute to an increase in DSOA among the elderly.

Keys word: depression, mild cognitive impairment, adverse childhood experiences, stress, anxiety
Ethnic and region-specific genetic risk variants of stroke and its comorbid conditions may better define the variations in the burden of stroke and its phenotypic traits
Authors: Sukumaran Rashmi , Nair Achuthsankar S , Banerjee Moinak
Published: December 2023

Burden of stroke differs by region, which could be attributed to differences in comorbid conditions and ethnicity. Genomewide variation acts as a proxy marker for ethnicity, and comorbid conditions. We present an integrated approach to understand this variation by considering prevalence and mortality rates of stroke and its comorbid risk for 204 countries from 2009 to 2019, and GWAS risk variant for all these conditions. Global and regional trend analysis of rates using linear regression, correlation and proportion analysis, signify ethnogeographic differences. Interestingly, the comorbid conditions that act as risk drivers for stroke differed by regions, with more of metabolic risk in America and Europe, in contrast to high SBP in Asian and African regions. GWAS risk loci of stroke and its comorbid conditions indicate distinct population stratification for each of these conditions, signifying for population specific risk. Unique and shared genetic risk variants for stroke, and its comorbid and followed up with ethnic specific variation can help in determining regional risk drivers for stroke. Unique ethnic specific risk variants and their distinct patterns of Linkage Disequilibrium further uncover the drivers for phenotypic variation. Therefore, identifying population and comorbidity specific risk variants might help in defining the threshold for risk, and aid in developing population specific prevention strategies for stroke.
SARS-CoV-2 Humoral Immune Responses in Convalescent Individuals Over 12 Months Reveal Severity-Dependent Antibody Dynamics
Authors: Siles Nadia , Schuler Maisey , Maguire Cole , Amengor Dzifa , Nguyen Annalee , Wilen Rebecca , Rogers Jacob , Bazzi Sam , Caslin Blaine , DiPasquale Christopher , Abigania Melissa , Olson Eric , Creaturo Janelle , Hurley Kerin , Triplett Todd A. , Rousseau Justin F. , Strakowski Stephen M. , Wylie Dennis , Maynard Jennifer , Ehrlich Lauren I. R. , Melamed Esther
Published: December 2023

Background

Understanding the kinetics and longevity of antibody responses to SARS-CoV-2 is critical to informing strategies toward reducing Coronavirus disease 2019 (COVID-19) reinfections, and improving vaccination and therapy approaches.

Methods

We evaluated antibody titers against SARS-CoV-2 nucleocapsid (N), spike (S), and receptor binding domain (RBD) of spike in 98 convalescent participants who experienced asymptomatic, mild, moderate or severe COVID-19 disease and in 17 non-vaccinated, non-infected controls, using four different antibody assays. Participants were sampled longitudinally at 1, 3, 6, and 12 months post-SARS-CoV-2 positive PCR test.

Findings

Increasing acute COVID-19 disease severity correlated with higher anti-N and anti-RBD antibody titers throughout 12 months post-infection. Anti-N and anti-RBD titers declined over time in all participants, with the exception of increased anti-RBD titers post-vaccination, and the decay rates were faster in hospitalized compared to non-hospitalized participants. <50% of participants retained anti-N titers above control levels at 12 months, with non-hospitalized participants falling below control levels sooner. Nearly all hospitalized and non-hospitalized participants maintained anti-RBD titers above controls for up to 12 months, suggesting longevity of protection against severe reinfections. Nonetheless, by 6 months, few participants retained >50% of their 1-month anti-N or anti-RBD titers. Vaccine-induced increases in anti-RBD titers were greater in non-hospitalized relative to hospitalized participants. Early convalescent antibody titers correlated with age, but no association was observed between Post-Acute Sequelae of SARS-CoV-2 infection (PASC) status or acute steroid treatment and convalescent antibody titers.

Interpretation

Hospitalized participants developed higher anti-SARS-CoV-2 antibody titers relative to non-hospitalized participants, a difference that persisted throughout 12 months, despite the faster decline in titers in hospitalized participants. In both groups, while anti-N titers fell below control levels for at least half of the participants, anti-RBD titers remained above control levels for almost all participants over 12 months, demonstrating generation of long-lived antibody responses known to correlate with protection from severe disease across COVID-19 severities. Overall, our findings contribute to the evolving understanding of COVID-19 antibody dynamics.

Funding

Austin Public Health, NIAAA, Babson Diagnostics, Dell Medical School Startup.
Bronchoscopy in children with diffuse alveolar hemorrhage under general anesthesia with spontaneous respiration by face mask ventilation: an analysis of thirty-eight procedures
Authors: Yang Ruimin , Wei Qing , Chen Xun , Liu Jing , Li Yan , Liu Jingchen
Published: December 2023

Purpose

To improve the management level of general anesthesia during bronchoscopy in the children with diffuse alveolar hemorrhage (DAH).

Methods

A retrospective study was conducted in the children with DAH who had performed bronchoscopy under general anesthesia with spontaneous respiration by face mask ventilation initially from June 2021 to June 2022 in our hospital.

Results

1. Thirty-four children who had underwent 38 bronchoscopy procedures were included. 2. General anesthesia induction was performed by bolus of propofol intravenous in all the procedures. For maintaining anesthesia, 31 procedures (81.6%) received both propofol and remifentanil intravenously infusion and the rest 7 procedures (18.4%) received propofol intravenously infusion only. An intravenous bolus of ketamine or propofol was given as an anesthetic adjuvant in 21 procedures (55.3%). Thirty-five procedures (92.1%) were successfully completed under non-tracheal intubation ventilation, whereas the rest 3 procedures (7.9%) needed change to tracheal intubation ventilation. 3. Respiratory depression was found in 7 procedures (18.4%), laryngospasm was found in 2 procedure (2.6%) and bronchospasm was found in 17 procedures (44.7%). Sixteen procedures (42.1%) developed intraoperative hypoxemia. The incidence of intraoperative hypoxemia in the procedures at the active phage of disease was significantly higher compared to those at the remission phage of the disease (P<0.05). Sixteen procedures (42.1%) developed intraoperative hypercapnia. Two procedures (5.3%) were complicated by severe pulmonary hemorrhage.

Conclusions

General anesthesia with spontaneous respiration by face mask ventilation is feasible and relatively safe for the children with DAH undergoing bronchoscopy, whereas the anesthetic protocol still needs to be improved.
Do Networks facilitate innovation, learning and sharing? An evaluation of the Quality-of-Care Network (QCN) in Bangladesh, Ethiopia, Malawi, and Uganda
Authors: Mwandira Kondwani , Lemma Seblewengel , Dube Albert , Akter Kohenour , Tufa Asebe Amenu , Kyamulabi Agnes , Seruwagi Gloria , Nakidde Catherine , Mwaba Kasonde , Djellouli Nehla , Makwenda Charles , Colbourn Tim , Shawar Yusra Ribhi
Published: December 2023

The Quality-of-Care Network (QCN), launched by WHO and partners, links global and national actors across several countries to improve maternal and newborn health. We examine if QCN facilitated learning, sharing and innovations within and between network countries.

We evaluated the QCN in Bangladesh, Ethiopia, Malawi and Uganda. We conducted a total 227 qualitative interviews with QCN actors iteratively across a 3-year period from October 2019 to March 2022. We also reviewed all accessible QCN documents.

Sharing and learning opportunities were evident through a number of virtual and in-person platforms such as meetings, conferences, webinars, and websites. Conferences and webinars have been hosted on online resource libraries such as the quality-of-care network website. These provided access to materials on strategies and approaches shared by different countries and actors. Innovations were also evident in some countries like Ethiopia. Innovative software applications aimed at boosting the capacity of service providers were developed and these were adopted by countries such as Bangladesh. Locally, there had been strengthening of learning collaborative meetings, coaching and mentorship. Regular meetings such as Stakeholder Coordination Meetings and Learning Collaborative Sessions provided an opportunity for stakeholders to strategize, as well as share and learn approaches within the network.

The network has promoted coordination among stakeholders. Similar approaches to sharing and learning such as Learning Collaborative Sessions were evident across the study countries. Innovations were not as apparent across countries and most of the learning and sharing approaches were similar to those from broader, pre-existing maternal health approaches, adopted from an era preceding the QCN. There was evidence that the introduction of the QCN improved the functionality and visibility of learning and sharing platforms.
The role of veterinary diagnostic laboratories during COVID-19 response in the United States
Authors: Clements Nia , Diel Diego G. , Elvinger François , Koretzky Gary , Siler Julie , Warnick Lorin D.
Published: December 2023

Robust testing capacity was necessary for public health agencies to respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the coronavirus disease 19 (COVID-19) pandemic. As the nation faced the need for robust testing capacity, it became necessary to use all possible resources. In many cases, veterinary diagnostic laboratories rose to meet this demand because these facilities routinely perform high throughput diagnostic testing of large animal populations and are typically familiar with pathogens of high pandemic concern. In this study, we evaluated the impact of veterinary diagnostic laboratories in the United States on SARS-CoV-2 testing. Results of surveys, semi-structured interviews, and analysis of publicly available information showed that veterinary diagnostic laboratories had a substantial impact on human health through population-level testing in the COVID-19 response, supporting timely and informed public health interventions. This success was not without significant hurdles, as many participating veterinary diagnostic laboratories experienced restriction in their response due to difficulties obtaining the Clinical Laboratory Improvement Amendments (CLIA) certification required to conduct human diagnostic testing. Our results point out the importance of reducing hurdles before the next major public health emergency to enhance access to testing resources overall and to ultimately improve population health.