bluuebunny/crossref_metadata_2025 huggingface dataset:
IGF2BP2 promotes ovarian cancer growth and metastasis by upregulating CKAP2L protein expression in an m6A‐dependent manner
Authors: Shi Yaqian , Xiong Xueyou , Sun Yu , Geng Zhe , Chen Xiyi , Cui Xin , Lv Juan , Ge Lili , Jia Xuemei , Xu Juan
Published: September 2023

Ovarian cancer (OC) is the second leading cause of gynecological cancer‐related death in women worldwide. N6‐methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNA. Human insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2), an m6A reader, can enhance mRNA stability and promote translation by recognizing m6A modifications. Its tumor‐promoting effects have been demonstrated in several cancers. However, the roles of m6A modification and IGF2BP2 in OC remain unclear. Here, by using methylated RNA immunoprecipitation sequencing, we demonstrated that there is widespread dysregulation of m6A modification in OC tissues. The m6A modification and the mRNA and protein levels of IGF2BP2 were significantly elevated in OC. Overexpression of IGF2BP2 facilitated OC cell proliferation, migration, and invasion in vitro and accelerated tumor growth and metastasis in vivo. While IGF2BP2‐knockdown showed the opposite effect. Mechanistically, we identified cytoskeleton‐associated protein 2‐like (CKAP2L) as a target of IGF2BP2. IGF2BP2 promoted CKAP2L translation dependent on m6A modification, rather than affecting mRNA and protein stability. Overexpression of CKAP2L rescued the tumor‐suppressive effect of IGF2BP2 knockdown in OC cells. In conclusion, this study revealed the potential role of IGF2BP2 in tumor progression, at least partially via promoting the translation of CKAP2L in an m6A‐dependent manner.
A genome‐wide transposon mutagenesis screening identifies LppB as a key factor associated with Mycoplasma bovis colonization and invasion into host cells
Authors: Lan Shimei , Li Zhangcheng , Hao Huafang , Liu Shuang , Huang Zhicheng , Bai Yutong , Li Yanzhao , Yan Xinmin , Gao Pengcheng , Chen Shengli , Chu Yuefeng
Published: September 2023

Mycoplasma spp., the smallest self‐replicating and genome‐reduced organisms, have raised a great concern in both the medical and veterinary fields due to their pathogenicity. The molecular determinants of these wall‐less bacterium efficiently use their limited genes to ensure successful infection of the host remain unclear. In the present study, we used the ruminant pathogen Mycoplasma bovis as a model to identify the key factors for colonization and invasion into host cells. We constructed a nonredundant fluorescent transposon mutant library of M. bovis using a modified transposon plasmid, and identified 34 novel adhesion‐related genes based on a high‐throughput screening approach. Among them, the ΔLppB mutant exhibited the most apparent decrease in adhesion to embryonic bovine lung (EBL) cells. The surface‐localized lipoprotein LppB, which is highly conserved in Mycoplasma species, was then confirmed as a key factor for M. bovis adhesion with great immunogenicity. LppB interacted with various components (fibronectin, vitronectin, collagen IV, and laminin) of host extracellular matrix (ECM) and promoted plasminogen activation through tPA to degrade ECM. The 439–502 amino acid region of LppB is a critical domain, and F465 and Y493 are important residues for the plasminogen activation activity. We further revealed LppB as a key factor facilitating internalization through clathrin‐ and lipid raft‐mediated endocytosis, which helps the Mycoplasma invade the host cells. Our study indicates that LppB plays a key role in Mycoplasma infection and is a potential new therapeutic and vaccine target for Mycoplasma species.
Mitochondrial DNA – novel mechanisms of kidney damage and potential biomarker
Authors: Malik Afshan N.
Published: September 2023

Purpose of review

MtDNA copy number (CN), a putative noninvasive biomarker of mitochondrial dysfunction, is associated with renal disease. The purpose of this review is to describe studies which measured human blood mtDNA-CN in the context of chronic kidney disease (CKD), and to evaluate its potential as a clinical biomarker of kidney disease.

Recent findings

Following on from small scale cross-sectional studies implicating mtDNA-CN changes in diabetic kidney disease, recent large scale population studies provide compelling evidence of the association of mtDNA-CN and risk of renal disease in the general population and poor outcomes in CKD patients.

The kidney has high bioenergetic needs, renal cells are rich in mitochondrial content containing 100s to 1000s of mtDNA molecular per cell. MtDNA has emerged as both a potential mediator, and a putative biomarker of renal disease. Damage to mtDNA can result in bioenergetic deficit, and reduced MtDNA levels in the blood have been shown to correlate with CKD. Furthermore, leakage of mtDNA outside of mitochondria into the cytosol/periphery can directly cause inflammation and is implicated in acute kidney injury (AKI). Recent large-scale population studies show the association of mtDNA-CN and renal disease and provide a strong basis for the future evaluation of circulating DNA-CN in longitudinal studies to determine its utility as a clinical biomarker for monitoring renal function.
PET/CT imaging fibroblast activation protein in initial colorectal cancer: compared to 18F-FDG PET/CT
Authors: Dong Ye , Sun Penghui , Wu Hubing , Zhong Jinmei , Cao Min , Tang Ganghua , Zhou Wenlan
Published: September 2023

Objective

In this study, the potential advantage of FAPI over 18F-labelled deoxyglucose (18F-FDG) in evaluation of the initial staging colorectal cancer (CRC) was investigated.

Materials and methods

Thirty-two patients with histopathologically confirmed primary CRC were included in our study. They all underwent both 18F-FDG and FAPI PET/CT. Lesion detectability and tracer uptakes, mainly quantified by maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR), were compared for paired lesions between both modalities using the Wilcoxon signed-rank test and paired t-test.

Results

Thirty-five CRC lesions in 32 patients were diagnosed. The sensitivity of FAPI PET/CT in diagnosis of the CRC lesions was 100% while 93.8% of 18F-FDG PET/CT. FAPI and 18F-FDG had a similar uptake in CRC lesion (mean SUVmax: 14.3 ± 8.6 vs. 15.4 ± 9.8, P = 0.604), but lesions contained mucus and/or signet-ring cell carcinoma seemed to have a trend of higher FAPI uptake although there was no statistical difference (mean SUVmax: 12.7 ± 5.6 vs. 8.5 ± 4.1, P = 0.152) and higher TBR (13.4 ± 6.2 vs. 4.9 ± 2.2, P = 0.004) than those of 18F-FDG. For regional lymph node metastases, both FAPI and FDG PET/CTs showed high sensitivity (7/8 vs. 7/8), specificity (7/8 vs. 6/8) and accuracy (14/16 vs. 13/16) (all P > 0.05). For distant metastasis, FAPI PET/CT depicted more positive lesions in distant lymph node (46 vs. 26), liver (13 vs. 7) and peritoneum (107 vs. 45) than 18F-FDG PET/CT. FAPI PET/CT also had a higher peritoneal cancer index score (median 11 vs 4; P < 0.001) than 18F-FDG PET/CT in evaluation of peritoneal metastases.

Conclusion

FAPI PET/CT showed high sensitivity in detection of primary CRC and superiority to 18F-FDG PET/CT in detection of metastases to distant lymph node, liver and peritoneum.
Identifying and troubleshooting the pitfalls of ictal/interictal brain perfusion SPECT studies
Authors: Rogeau Antoine , Lilburn David M.L. , Kaplar Zoltan , Anderson Cameron , Scott Catherine J. , Chowdhury Fahmida A. , Fraioli Francesco , Bomanji Jamshed B.
Published: September 2023

Epilepsy is a prevalent condition, and surgical intervention can benefit patients with refractory seizures. Single photon emission computed tomography (SPECT) using 99mTc-HMPAO or 99mTc-ECD provides assessment of regional cerebral blood flow and is the primary non-invasive approach for imaging brain perfusion in ictal and interictal states. Ictal/interictal SPECT is valuable in localising epileptogenic foci, particularly when MRI and electroencephalography are negative. However, to obtain accurate images reflecting brain perfusion in both states, meticulous preparation of the patient, timely radiotracer injection and close coordination between neurology and nuclear medicine teams are essential. Tracers also have inherent limitations, and patients may present with coexisting brain pathologies for which coregistration of SPECT images with MRI is recommended to improve diagnostic accuracy. Inconclusive SPECT findings may require repeating the exam or considering additional investigations. A comprehensive approach, considering various factors, is crucial for accurate interpretation of SPECT studies in presurgical epilepsy evaluations. This article provides a summary of the organisation and key challenges involved in conducting ictal/interictal SPECT studies, covering the entire process from a patient’s hospital arrival to the integration of results within their presurgical pathway and using our experience of 182 patients over 10 years.
Clinical Outcomes of Children With COVID-19 by SARS-CoV-2 Strain
Authors: Klingensmith Lauren M. , Goel Swati , Kampalath Vinay N. , Cohn Keri A.
Published: September 2023

Objective

We sought to investigate the disease outcomes and predictors of severe outcomes among children infected with the Delta variant of SARS-CoV-2 compared with pre-Delta strains.

Methods

Single-center retrospective cohort study in an emergency department located within an urban academic children's hospital. Patients included children (0–18 years) who tested positive for SARS-CoV-2. Main outcomes measured include need for hospital admission or COVID-directed therapies.

Results

There was a trend toward decreased hospital admission and no significant difference in the severity of outcomes in the Delta cohort relative to the pre-Delta cohort. The Delta cohort had lower odds of hospital admission (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.51–1.23), but the result was not statistically significant. Logistic regression analyses showed that overall, age 1 to 4 years (OR, 2.35; 95% CI, 1.23–4.57) and public insurance (OR, 1.80, 95% CI, 1.08–3.01) were predictors of hospital admission. Within the Delta cohort, the presence of any comorbidity increased the odds of admission (OR, 2.52; 95% CI, 1.09–6.04). Black children had lower odds of admission than white children (overall OR, 0.53; 95% CI, 0.31–0.90; pre-Delta OR, 0.50; 95% CI, 0.26–0.95).

Conclusions

The severity of measured disease outcomes was similar in pediatric patients when comparing children infected with the pre-Delta and Delta variants of SARS-CoV-2, even among children with comorbidities once adjusting for acuity.

Ongoing research is essential to determine disease severity and risk for children with comorbidities because SARS-CoV-2 continues to mutate, including with Omicron subvariants.
Seize the Opportunity
Authors: Shakir Rashida M. , Doshi Samir , Blakeslee Samantha , Jessee Morgan
Published: September 2023

Objectives

Our objective was to increase human immunodeficiency virus (HIV) screening in adolescents presenting to our community pediatric emergency department with symptoms suggestive of a sexually transmitted infection (STI) and who were being tested for gonorrhea and chlamydia. Specifically, we aimed to increase the monthly average proportion of adolescents concurrently screened for HIV in this target group from 11% to 50% in 6 months.

Methods

We identified barriers to HIV screening, focusing on physician-related challenges and adolescents' concerns about confidentiality. We designed interventions targeting these barriers and implemented them in plan-do-study-act cycles beginning in February 2020. We educated physicians and nurses about screening recommendations, emphasized a physician-conducted private interview during which confidential contact information could be obtained, and assured confidentiality on after visit summaries by removing STI results. We also provided regular feedback to physicians on the screening rate. In addition, we implemented an electronic health record quick order set and a documentation tool. Using a statistical process control chart, we measured the average monthly proportion of adolescents in the target group who were offered HIV screening or tested for HIV before and after interventions.

Results

A total of 140 adolescents in the target group presented to our pediatric emergency department from February 2020 through December 2021. After plan-do-study-act cycles, the average monthly screening rate increased to 80%.

Conclusions

Raising physician awareness of HIV screening recommendations and the importance of conducting a private interview improved screening rates. Assuring adolescent minors of confidentiality in a private interview, removing STI results from the after visit summary, and obtaining confidential contact information were important measures to overcome confidentiality barriers.
Virtual Coaching and the Reduction of Radial Head Subluxation
Authors: Istasy Paul , Lynch Tim P. , Van Aarsen Kristine , Helleman Krista E. , Edmonds Marcia L.
Published: September 2023

Objectives

After the establishment of the virtual pediatric emergency medicine clinic at our institution, we noted that several physicians independently began to instruct caregivers virtually on reducing a radial head subluxation. We thus conducted a case series to investigate the number, success, and follow-ups for the virtual reduction of radial head subluxation.

Methods

The electronic medical records at our institution were searched from the inception of the virtual clinic in May 2020 until August 2022 (inclusive), for visits and discharge diagnosis containing the word “elbow” or “arm.”

Results

Fourteen charts were retrieved; however, 2 were excluded because they were not a suspected radial head subluxation. A virtual reduction was attempted for eight (66.7%) of the 12 patients. In 6 of 8 patients (75.0%), the reduction was deemed successful, and for 2 patients (25.0%), it was deemed unsuccessful. Of the latter, one was found to have a nondisplaced radial neck fracture. All 4 patients (33.3%) for whom a virtual reduction was not attempted were referred to the emergency department.

Conclusions

Virtual video coaching of pulled elbow reduction was completed at our institution with overall good success rate. All the physicians involved noted the essential need and benefits of video conferencing for successfully reducing radial head subluxation. We note that a pediatric population may be more amenable to video-based appointments than other populations due to their caregivers' familiarity with digital technology. Finally, as nonphysician models of healthcare delivery for virtual urgent care visits expand, we propose a checklist based on our experience to ensure patient safety.
Protein appetite as an integrator in the obesity system: the protein leverage hypothesis
Authors: Raubenheimer David , Simpson Stephen J.
Published: September 2023

Despite the large volume and extensive range of obesity research, there is substantial disagreement on the causes and effective preventative strategies. We suggest the field will benefit from greater emphasis on integrative approaches that examine how various potential contributors interact, rather than regarding them as competing explanations. We demonstrate the application of nutritional geometry, a multi-nutrient integrative framework developed in the ecological sciences, to obesity research. Such studies have shown that humans, like many other species, regulate protein intake more strongly than other dietary components, and consequently if dietary protein is diluted there is a compensatory increase in food intake—a process called protein leverage. The protein leverage hypothesis (PLH) proposes that the dilution of protein in modern food supplies by fat and carbohydrate-rich highly processed foods has resulted in increased energy intake through protein leverage. We present evidence for the PLH from a variety of sources (mechanistic, experimental and observational), and show that this mechanism is compatible with many other findings and theories in obesity research.

This article is part of a discussion meeting issue ‘Causes of obesity: theories, conjectures and evidence (Part II)’.
The provisioned primate: patterns of obesity across lemurs, monkeys, apes and humans
Authors: Pontzer Herman
Published: September 2023

Non-human primates are potentially informative but underutilized species for investigating obesity. I examined patterns of obesity across the Primate order, calculating the ratio of body mass in captivity to that in the wild. This index, relative body mass, for
n
= 40 non-human primates (mean ± s.d.: females: 1.28 ± 0.30, range 0.67–1.78, males: 1.24 ± 0.28, range 0.70–1.97) overlapped with a reference value for humans (women: 1.52, men: 1.44). Among non-human primates, relative body mass was unrelated to dietary niche, and was marginally greater among female cohorts of terrestrial species. Males and females had similar relative body masses, but species with greater sexual size dimorphism (male/female mass) in wild populations had comparatively larger female body mass in captivity. Provisioned populations in wild and free-ranging settings had similar relative body mass to those in research facilities and zoos. Compared to the wild, captive diets are unlikely to be low in protein or fat, or high in carbohydrate, suggesting these macronutrients are not driving overeating in captive populations. Several primate species, including chimpanzees, a sister-species to humans, had relative body masses similar to humans. Humans are not unique in the propensity to overweight and obesity.

This article is part of a discussion meeting issue ‘Causes of obesity: theories, conjectures and evidence (Part II)’.
Reflections on the Teaching Symposium at the Microbiology Society Annual Conference 2023
Authors: Lacey Melissa M , Jones Kirsty L , Gostić Monika , Easton Victoria , Efthimiou Georgios , Kelly Bridget G , Graham Alison I
Published: September 2023

The Microbiology Society Education and Outreach Network (EON) recently hosted the Teaching Symposium at the Microbiology Society Annual Conference, sponsored by Access Microbiology. The presence of the Symposium as an established parallel session within the wider Annual Conference reflects the importance of high-quality, contemporary microbiology education and outreach delivered in an enthusiastic and inclusive manner.  At the 2023 Symposium, a variety of pedagogical research projects in higher education learning, teaching and assessment, as well as public engagement projects, were showcased through flash talks, offered talks, invited talks and posters. The event was attended by up to 70 delegates. Several themes were noted throughout the day: engaging with GenZ, active learning, art in science, and engaging with non-HE audiences. Inclusivity was a key driver in the organisation of the Symposium; the room was set up to encourage discussion and participants could ask questions using an online platform as well as speaking in the room. We now encourage all speakers to consider publishing their work as a peer-reviewed article for further dissemination and impact.
A Coxsackievirus B1-mediated nonlytic Extracellular Vesicle-to-cell mechanism of virus transmission and its possible control through modulation of EV release
Authors: Jorfi Samireh , Ansa-Addo Ephraim Abrokwa , Mariniello Katia , Warde Purva , bin Senian Ahmad Asyraf , Stratton Dan , Bax Bridget E. , Levene Michelle , Lange Sigrun , Inal Jameel Malhador
Published: September 2023

Like most non-enveloped viruses, CVB1 mainly uses cell lysis to spread. Details of a nonlytic virus transmission remain unclear. Extracellular Vesicles (EVs) transfer biomolecules between cells. We show that CVB1 entry into HeLa cells results in apoptosis and release of CVB1-induced ‘medium-sized’ EVs (CVB1i-mEVs). These mEVs (100–300 nm) harbour CVB1 as shown by immunoblotting with anti-CVB1-antibody; viral capsids were detected by transmission electron microscopy and RT-PCR revealed CVB1 RNA. The percentage of mEVs released from CVB1-infected HeLa cells harbouring virus was estimated from TEM at 34 %. Inhibition of CVB1i-mEV production, with calpeptin or siRNA knockdown of CAPNS1 in HeLa cells limited spread of CVB1 suggesting these vesicles disseminate CVB1 virions to new host cells by a nonlytic EV-to-cell mechanism. This was confirmed by detecting CVB1 virions inside HeLa cells after co-culture with CVB1i-mEVs; EV release may also prevent apoptosis of infected cells whilst spreading apoptosis to secondary sites of infection.
Exact solution of a three-stage model of stochastic gene expression including cell-cycle dynamics
Authors: Wang Yiling , Yu Zhenhua , Grima Ramon , Cao Zhixing
Published: September 2023

The classical three-stage model of stochastic gene expression predicts the statistics of single cell mRNA and protein number fluctuations as a function of the rates of promoter switching, transcription, translation, degradation and dilution. While this model is easily simulated, its analytical solution remains an unsolved problem. Here we modify this model to explicitly include cell-cycle dynamics and then derive an exact solution for the time-dependent joint distribution of mRNA and protein numbers. We show large differences between this model and the classical model which captures cell-cycle effects implicitly via effective first-order dilution reactions. In particular we find that the Fano factor of protein numbers calculated from a population snapshot measurement are underestimated by the classical model whereas the correlation between mRNA and protein can be either over-or underestimated, depending on the timescales of mRNA degradation and promoter switching relative to the mean cell-cycle duration time.
ALK signalling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition
Authors: Borenäs Marcus , Umapathy Ganesh , Lind Dan E. , Lai Wei-Yun , Guan Jikui , Johansson Joel , Jennische Eva , Schmidt Alexander , Kurhe Yeshwant , Gabre Jonatan L. , Aniszewska Agata , Strömberg Anneli , Bemark Mats , Hall Michael N. , Van den Eynden Jimmy , Hallberg Bengt , Palmer Ruth H.
Published: September 2023

High-risk neuroblastoma (NB) is a significant clinical challenge. MYCN and ALK, which are often involved in high-risk NB, lead to increased replication stress in cancer cells, suggesting therapeutic strategies. We previously identified an ATR/ALK inhibitor (ATRi/ALKi) combination as such a strategy in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signalling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to a 14-day ALKi/ATRi combination treatment that resulted in a robust and sustained response. Finally, we show that the remarkable response to the 14-day combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumour cells to a neuronal/Schwann cell lineage identity. Our results identify a unique ability of ATR inhibition to trigger neuroblastoma differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.
Advances in genomic characterization ofUrochloa humidicola: exploring polyploid inheritance and apomixis
Authors: da Costa Lima Moraes Aline , Mollinari Marcelo , Ferreira Rebecca Caroline Ulbricht , Aono Alexandre , de Castro Lara Letícia Aparecida , Pessoa-Filho Marco , Barrios Sanzio Carvalho Lima , Garcia Antonio Augusto Franco , do Valle Cacilda Borges , de Souza Anete Pereira , Vigna Bianca Baccili Zanotto
Published: September 2023

Tropical forage grasses are an important food source for animal feeding, withUrochloa humidicola, also known as Koronivia grass, being one of the main pasture grasses for poorly drained soils in the tropics. However, genetic and genomic resources for this species are lacking due to its genomic complexity, including high heterozygosity, evidence of segmental allopolyploidy, and reproduction by apomixis. These complexities hinder the application of marker-assisted selection (MAS) in breeding programs. Here, we developed the highest-density linkage map currently available for the hexaploid tropical forage grassU. humidicola. This map was constructed using a biparental F1 population generated from a cross between the female parent H031 (CIAT 26146), the only known sexual genotype for the species, and the apomictic male parent H016 (BRS cv. Tupi). The linkage analysis included 4,873 single nucleotide polymorphism (SNP) markers with allele dosage information. It allowed mapping of the apospory locus and phenotype to linkage group 3, in a region syntenic with chromosome 3 ofUrochloa ruziziensisand chromosome 1 ofSetaria italica. We also identified hexaploid haplotypes for all individuals, assessed the meiotic configuration, and estimated the level of preferential pairing in parents during the meiotic process, which revealed the autopolyploid origin of sexual H031 in contrast to H016, which presented allopolyploid behavior in preferential pairing analysis. These results provide new information regarding the genetic organization, mode of reproduction, and allopolyploid origin ofU. humidicola, potential SNPs markers associated to apomixes for MAS and resources for research on polyploids and tropical forage grasses.

Key message

We present the highest-density genetic map for the hexaploidUrochloa humidicola. SNP markers expose genetic organization, reproduction, and species origin, aiding polyploid and tropical forage research.
Changes in pro inflammatory and regulatory immune responses during controlled human schistosome infection and the development of clinical symptoms
Authors: Houlder Emma L. , Stam Koen A. , Koopman Jan Pieter R. , König Marion H. , Langenberg Marijke C.C. , Hoogerwerf Marie-Astrid , Niewold Paula , Sonnet Friederike , Janse Jacqueline J. , Partal Miriam Casacuberta , Sijtsma Jeroen C. , de Bes-Roeleveld Laura H. M. , Kruize Yvonne C.M. , Yazdanbakhsh Maria , Roestenberg Meta
Published: September 2023

Schistosomiasis is a prevalent helminthiasis, affecting over 230 million people worldwide, with varied, stage specific morbidity. Whilst the Th2 and regulatory immune responses in chronic infection have been relatively well studied, we have little understanding of human immune responses during acute infection. This is despite the initial infective stages being proposed as crucial targets for much-needed vaccine development. Here, we comprehensively map immune responses in male and female single-sex controlled humanSchistosoma mansoniinfection. Using unbiased, high dimensional techniques we show that human immune responses to male and female single-sex infection are comparable. An early Th1-biased inflammatory response was observed at week 4 post infection, which was particularly apparent in individuals experiencing symptoms of acute schistosomiasis. This included expansion of HLA-DR+effector memory T cells, CD38+monocytes and an increase in serum IFNγ. By week 8 post infection these inflammatory responses were followed by an expansion of Th2 and of regulatory cell subsets, including IL-10 producing CD4-CD8-T cells, CD11c+atypical memory B cells and serum IL-10. This study provides immunological insight into the clinical manifestations of acute schistosomiasis, as well as critical context through which to understand the development of immune responses observed in natural infection.

One sentence summary

Controlled human schistosome infection reveals cellular and cytokine responses to schistosome infection, with early inflammatory responses in symptomatic individuals at week 4 and a balanced Th1, Th2 and regulatory response in all participants by week 8.
Improving emotion control in social anxiety by targeting rhythmic brain activity
Authors: Meijer Sjoerd , Bramson Bob , Toni Ivan , Roelofs Karin
Published: September 2023

Social avoidance is a hallmark of social anxiety disorder. Difficulties in controlling avoidance behavior are the core maintaining factor of this impairing condition, hampering the efficacy of existing therapies. This preregistered study tested a physiologically-grounded non-invasive enhancement of control over social approach and avoidance behavior in socially anxious individuals. Their prefrontal and sensorimotor areas received dual-site phase-coupled electrical stimulation, to enhance inter-regional theta-gamma phase-amplitude coupling, a mechanism known to support emotion control in non-anxious individuals. We measured behavioral and fMRI-BOLD responses during in-phase, anti-phase, and sham stimulations, while participants performed a social approach-avoidance task, involving either automatic or controlled emotional actions. In-phase (vs. anti-phase) stimulation selectively enhanced control over approach-avoidance actions, and modulated neural responses in the same prefrontal region where stimulation-reactivity increased as a function of trait anxiety. These findings illustrate how human neurophysiological connectivity can be leveraged to improve control over social avoidance, opening the way for mechanistically grounded clinical interventions of persistent avoidance in anxiety disorders.

Teaser

Emotion control in social anxiety can be boosted by targeting rhythmic brain activity between prefrontal and sensorimotor cortex
The entire brain, more or less, is at work: ‘Language regions’ are artefacts of averaging
Authors: Aliko Sarah , Wang Bangjie , Small Steven L , Skipper Jeremy I
Published: September 2023

Models of the neurobiology of language suggest that a small number of anatomically fixed brain regions are responsible for language functioning. This observation derives from centuries of examining brain injury causing aphasia and is supported by decades of neuroimaging studies. The latter rely on thresholded measures of central tendency applied to activity patterns resulting from heterogeneous stimuli. We hypothesised that these methods obscure the whole brain distribution of regions supporting language. Specifically, cortical ‘language regions’ and the corresponding ‘language network’ consist of input regions and connectivity hubs. The latter primarily coordinate peripheral regions whose activity is variable, making them likely to be averaged out following thresholding. We tested these hypotheses in two studies using neuroimaging meta-analyses and functional magnetic resonance imaging during film watching. Both converged to suggest that averaging over heterogeneous words is localised to regions historically associated with language but distributed throughout most of the brain when not averaging over the sensorimotor properties of those words. The localised word regions are composed of highly central hubs. The film data shows that these hubs are not fixed. Rather, they are spatiotemporally dynamic, making connections with 44% of peripheral sensorimotor regions at any moment, and only appear in the aggregate over time. Results suggest that ‘language regions’ are an artefact of indiscriminately averaging across heterogeneous language representations and linguistic processes. Rather, these regions are mostly dynamic connectivity hubs coordinating whole-brain distributions of networks for processing the complexities of real-world language use, explaining why damage to them results in aphasia.
Environmental factors and cultural drift influence song evolution in New World Sparrows
Authors: Provost Kaiya L , Yang Jiaying , Carstens Bryan C
Published: September 2023

Variation in bird song is often assumed to be determined by sexual selection, rather than natural selection. However, most investigations to date have drawn their conclusions from a handful of species due to the challenges with manually processing sound data. Here, we use deep machine learning to investigate nearly all species of New World Sparrows. We leverage existing data to identify the processes that structure variation in bird song and to determine how this variation corresponds to patterns in genes and traits. Song variation in ~40% of species can be explained by environment, geography, and time. Across a community and global scale, the action of natural selection on the evolution of song is at least as impactful as it is on other genetically-determined traits.
A Cross-Sectional Evaluation of Health Resource Use in Patients with Functional Neurological Disorders Referred to a Tertiary Neuroscience Centre
Authors: O’Mahony Brian , Nelson-Sice R. , Nielsen Glenn , Hunter Rachel , Cope Sarah , Agrawal Niruj , Edwards Mark , Yogarajah Mahinda
Published: September 2023

Introduction

Functional Neurological Disorder (FND) is a common cause of referral to neurology services. FND has been shown to lead to significant healthcare resource use, and is associated with significant disability, comorbidity, and distress. This leads to substantial direct, indirect, and intangible costs to the patient and society.

Methods

We recruited consecutive patients with FND referred to a tertiary FND specialist clinic. We assessed health and social care resource use, in the 6 months preceding their consultation through a modified version of the Client Service Receipt Inventory (CSRI) in the form of a postal questionnaire. The total cost was estimated by combining the number and frequency of health resource use with standard national unit costs. We also assessed indirect costs such as informal care and loss of income.

Results

We collected data on 118 subjects. Patients with comorbid anxiety or depression had higher costs in the preceding 6 months, as did patients who had a longer duration of FND symptoms. Indirect costs were larger than the already substantial direct costs, and a large proportion of FND patients were receiving government support.

Conclusion

This study highlights the high cost of FND to both patients and health systems. Adequate reform of the patient pathway and re-organization of services to make diagnoses, and initiate treatment more quickly, would likely reduce these costs.
How Large Language Models Perform on the United States Medical Licensing Examination: A Systematic Review
Authors: Brin Dana , Sorin Vera , Konen Eli , Nadkarni Girish , Glicksberg Benjamin S , Klang Eyal
Published: September 2023

ABSTRACT

Objective

The United States Medical Licensing Examination (USMLE) assesses physicians’ competency and passing is a requirement to practice medicine in the U.S. With the emergence of large language models (LLMs) like ChatGPT and GPT-4, understanding their performance on these exams illuminates their potential in medical education and healthcare.

Materials and Methods

A literature search following the 2020 PRISMA guidelines was conducted, focusing on studies using official USMLE questions and publicly available LLMs.

Results

Three relevant studies were found, with GPT-4 showcasing the highest accuracy rates of 80-90% on the USMLE. Open-ended prompts typically outperformed multiple-choice ones, with 5-shot prompting slightly edging out zero-shot.

Conclusion

LLMs, especially GPT-4, display proficiency in tackling USMLE-standard questions. While the USMLE is a structured evaluation tool, it may not fully capture the expansive capabilities and limitations of LLMs in medical scenarios. As AI integrates further into healthcare, ongoing assessments against trusted benchmarks are essential.
Self-reported bruxism in patients with post-traumatic stress disorder
Authors: de Oliveira Solis Ana Cristina , Corchs Felipe , Duran Érica Panzani , Silva Cláudio , Del Real Natalia , Araújo Álvaro Cabral , Wang Yuan-Pang , Lotufo-Neto Francisco
Published: September 2023

Objective

The present study aimed to investigate the association between self-reported awake/sleep bruxism, and orofacial pain with post-traumatic stress disorder (PTSD).

Methods

Participants were recruited from a university-based Trauma Ambulatory. The diagnosis of PTSD was established through a clinical interview and the Structured Clinical Interview (SCID-I/P). Thirty-eight PTSD patients and 38 controls completed the Research Diagnostic Criteria for Temporomandibular Disorders Axis-II to categorize awake/sleep bruxism and orofacial pain. Following this, we performed a short clinical examination of the temporomandibular joint and extraoral muscles.

Results

Adjusted logistic regression analysis showed that awake bruxism was associated with PTSD (OR = 3.38, 95% CI = 1.01-11.27,p= 0.047). Sleep bruxism was not associated with any covariate included in the model. In a Poisson regression model, PTSD (IRR = 3.01, 95% CI = 1.38-6.55,p= 0.005) and the muscle pain/ discomfort (IRR = 5.12, 95% CI = 2.80-9.36,p< 0.001) were significant predictors for current orofacial pain.

Conclusions

PTSD was associated with self-reported awake bruxism and low-intensity orofacial pain. These conditions were frequent outcomes in patients previously exposed to traumatic events.
Psychiatric, cognitive, psychosocial, and neurological outcomes of chimeric antigen receptor T-cell therapy: protocol for a prospective study
Authors: Kuznetsova Valeriya , Oza Harsh , Rosenfeld Hannah , Sales Carmela , van der Linde Samantha , Roos Izanne , Roberts Stefanie , D’Aprano Fiore , Loi Samantha M , Dowling Mark , Dickinson Michael , Kalincik Tomas , Harrison Simon J , Anderson Mary Ann , Malpas Charles B
Published: September 2023

Background

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common side-effect of chimeric antigen receptor T-cell (CAR-T) therapy, with symptoms ranging from mild to occasionally life-threatening. The psychiatric, cognitive, psychosocial, and neurological sequalae of ICANS are diverse and not well-specified, posing a challenge for diagnosis and management. The recovery trajectory of the syndrome is uncertain. Psychiatric, cognitive, psychosocial, and neurological status is rarely examined in this population pre-therapy, adding a layer of complexity to specifying symptoms pertinent solely to CAR-T treatment.

Aims

The aim is to investigate psychiatric, cognitive, psychosocial, and neurological outcomes in patients after CAR-T therapy, particularly among those who develop ICANS. The project will establish a comprehensive pre-treatment baseline and will longitudinally monitor for therapy-associated change.

Methods

A prospective longitudinal study of all adult patients in a single Australian haematology service undergoing CAR-T therapy. Neuropsychological and neurological examinations occur prior to CAR-T, and patients are reviewed during the acute post-treatment period, 28 days, 6 months, and 12 months post-infusion. Data will be sourced from objective psychometric measures, clinical examinations, self-report questionnaires, and accounts of subjective cognitive complaint to capture a broad spectrum of dysfunction and its daily functional impact.

Conclusions

We present a protocol of a research study that will describe the neurocognitive features specific to ICANS, characterise the underlying syndrome, identify predictors of differential post-infusion outcomes, and contribute to optimising the overall management of CAR-T patients. The protocol will serve as the basis of guidance regarding clinical and paraclinical follow-up of patients undergoing CAR-T cell therapy.
White matter lesions as a prognostic marker of recurrence in cryptogenic stroke with high-risk patent foramen ovale
Authors: Niiyama Shunichi , Ueno Yuji , Kurita Naohide , Nakajima Sho , Kijima Chikage , Hira Kenichiro , Miyamoto Nobukazu , Watanabe Masao , Yamashiro Kazuo , Urabe Takao , Hattori Nobutaka
Published: September 2023

Introduction

Atrial septal aneurysms increase the risk of stroke recurrence in cryptogenic stroke patients with a patent foramen ovale. Factors related to stroke recurrence according to the patent foramen ovale risk stratification have not been fully evaluated.

Methods

Data from a multicenter observational registry of ischemic stroke patients undergoing transesophageal echocardiography, with a comprehensive database including clinical characteristics and long-term prognosis, were used for this study. Patients were classified into three groups: high-risk patent foramen ovale group, large shunt patent foramen ovale (≥20 microbubbles) or patent foramen ovale with atrial septal aneurysm; right-to-left shunt group, right-to-left shunt including patent foramen ovale with <20 microbubbles or without atrial septal aneurysm; and negative right-to-left shunt group. Among stroke subtype, factors related to stroke recurrence were investigated according to the risk stratification of patent foramen ovale in cryptogenic stroke.

Results

In total, 586 patients (185 females; 65.5 ± 13.2 years) were analyzed. In cryptogenic stroke (329 patients) with median follow-up of 4.2 (interquartile range, 1.0– 6.1) years, 55 patients had stroke recurrence. The negative right-to-left shunt, right-to-left shunt, and high-risk patent foramen ovale groups included 179, 90, and 60 patients, in which stroke recurrence occurred in 5.3%, 2.5%, and 4.6% per person-year, respectively. In patients with high-risk patent foramen ovale, the NIH stroke scale score (hazard ratio 1.257, 95% CI 1.034-1.530,P=0.022) and periventricular hyperintensity (hazard ratio 3.369, 95% CI 1.103-10.294,P=0.035) were predictive markers for stroke recurrence on multivariate Cox Hazards analysis, but no factors were related to stroke recurrence in the right-to-left shunt and negative right-to-left shunt groups.

Conclusion

High-risk patent foramen ovale is an important embolic source in cryptogenic stroke. Periventricular hyperintensity was shown to predict recurrent stroke in patients with a high-risk patent foramen ovale. In such cases, percutaneous patent foramen ovale closure might be effective at <60 years of age.
Electrochemical detection of myeloperoxidase (MPO) in blood plasma with surface-modified electroless nickel immersion gold (ENIG) printed circuit board (PCB) electrodes
Authors: Nandeshwar Ruchira , Tallur Siddharth
Published: September 2023

Printed circuit board (PCB) based biosensors have often utilized hard gold electroplating, that nullifies the cost advantages of this technology as compared to screen printed electrodes. Electroless nickel immersion gold (ENIG) is a popular gold deposition process widely used in PCB manufacturing, but vulnerable to pinhole defects and large surface roughness, which compromises biosensor performance. In this work, we present a method to address these challenges through electrodeposition of methylene blue (MB) to cover surface defects and improve electroactivity of ENIG PCB electrodes. We also demonstrate a process to realize in situ synthesis of gold nanoparticles (AuNPs) using acid-functionalized multi-walled carbon nanotubes (MWCNTs) as scaffold, that are used to immobilize antibody for the target molecule (myeloperoxidase: MPO, early warning biomarker for cardiovascular diseases) through a modified cysteamine/gluteraldehyde based process. The processing steps on the electrode surface are developed in a manner that do not compromise the integrity of the electrode, resulting in repeatable and reliable performance of the sensors. Further, we demonstrate a cost-effective microfluidic packaging process to integrate a capillary pump driven microfluidic channel on the PCB electrode for seamless introduction of samples for testing. We demonstrate the ability of the sensor to distinguish clinically abnormal concentrations of MPO from normal concentrations through extensive characterization using spiked serum and blood plasma samples, with a limit of detection of 0.202 ng/mL.
Transcriptionally active chromatin loops contain both ‘active’ and ‘inactive’ histone modifications that exhibit exclusivity at the level of nucleosome clusters
Authors: Koestler Stefan A. , Ball Madeleine L. , Muresan Leila , Dinakaran Vineet , White Robert
Published: September 2023

Chromatin state is thought to impart regulatory function to the underlying DNA sequence. This can be established through histone modifications, and chromatin organisation, but exactly how these factors relate to one another to regulate gene expression is unclear. In this study, we have used super-resolution microscopy to image the Y loops ofDrosophila melanogasterprimary spermatocytes, which are enormous transcriptionally active chromatin fibres, each representing single transcription units that are individually resolvable in the nuclear interior. We previously found that the Y loops consist of regular clusters of nucleosomes, with an estimated median of 54 nucleosomes per cluster with wide variation. In this study, we report that the histone modifications H3K4me3, H3K27me3, and H3K36me3 are also clustered along the Y loops, with H3K4me3 more associated with diffuse chromatin compared to H3K27me3. These histone modifications form domains that can be stretches of Y loop chromatin micrometres long, or can be in short alternating domains. The different histone modifications are associated with different sizes of chromatin clusters and unique morphologies. Strikingly, a single chromatin cluster almost always only contains only one type of the histone modifications that were labelled, suggesting exclusivity, and therefore regulation at the level of individual chromatin clusters. The active mark H3K36me3 is more associated with actively elongating RNA polymerase II than H3K27me3, with polymerase often appearing on what are assumed to be looping regions on the periphery of chromatin clusters. These results provide a foundation for understanding the relationship between chromatin state, chromatin organisation, and transcription regulation – with potential implications for pause-release dynamics, splicing complex organisation and chromatin dynamics during polymerase progression along a gene.
Optimizing Predictive Metrics for Human Reading Behavior
Authors: Sun Kun
Published: September 2023

Expectation and memory have been found to play crucial roles in human language comprehension. Currently, the effects of both expectation and memory can be estimated using computational methods. Computational metrics of surprisal and semantic relevance, which represent expectation and memory respectively, have been developed to accurately predict and explain language comprehension and processing. However, their efficacy is hindered by their inadequate integration of contextual information. Drawing inspiration from the attention mechanism in transformers and human forgetting mechanism, this study introduces an attention-aware method that thoroughly incorporates contextual information, updating surprisal and semantic relevance into attention-aware metrics respectively. Furthermore, by employing the quantum superposition principle, the study proposes an enhanced approach for integrating and encoding diverse information sources based on the two attention-aware metrics. Metrics that are both attention-aware and enhanced can integrate information from expectation and memory, showing superior effectiveness compared to existing metrics. This leads to more accurate predictions of eye movements during the reading of naturalistic discourse in 13 languages. The proposed approaches are fairly capable of facilitating simulation and evaluation of existing reading models and language processing theories. The metrics computed by the proposed approaches are highly interpretable and exhibit cross-language generalizations in predicting language comprehension. The innovative computational methods proposed in this study hold the great potential to enhance our understanding of human working memory mechanisms, human reading behavior and cognitive modeling in language processing. Moreover, they have the capacity to revolutionize ongoing research in computational cognition for language processing, offering valuable insights for computational neuroscience, quantum cognition and optimizing the design of AI systems.