bluuebunny/crossref_metadata_2025 huggingface dataset:
It only takes seconds for a human monoclonal autoantibody to inhibit N-methyl-D-aspartate receptors
Authors: Yang Shang , Heckmann Johanna , Taha Abdulla , Gao Shiqiang , Steinke Stephan , Hust Michael , Prüß Harald , Furukawa Hiro , Geis Christian , Heckmann Manfred , Yu-Strzelczyk Jing
Published: June 2024

Transfer of autoantibodies targeting ionotropic N-methyl-D-aspartate receptors in autoimmune encephalitis patients into mice leads to typical disease signs. Long-term effects of the pathogenic antibodies consist of immunoglobulin G-induced crosslinking and receptor internalization. We focused on the direct and immediate impact of a specific pathogenic patient-derived monoclonal autoantibody (immunoglobulin G #003-102) on receptor function.

We performed cell-attached recordings in cells transfected with the GluN1 and GluN2A subunit of the N-methyl-D-aspartate receptor. Immunoglobulin G #003-102 binds to the amino-terminal domain of the glycine-binding GluN1 subunit. It reduced simultaneous receptor openings significantly compared to controls at both low and high glutamate and glycine concentrations. Closer examination of our data in 50-second to 2-second intervals revealed, that Immunoglobulin G #003-102 rapidly decreases the number of open receptors. However, antigen-binding fragments of immunoglobulin G #003-102 did not reduce the receptor openings.

In conclusion, patient-derived immunoglobulin G #003-102 inhibits N-methyl-D-aspartate receptors rapidly and directly before receptor internalization occurs and the entire immunoglobulin G is necessary for this acute inhibitory effect. This suggests an application of the antigen-binding fragment-like constructs of #003-102 as a potential new treatment strategy for shielding the pathogenic epitopes on the N-methyl-D-aspartate receptors.
The correct temporal connectivity of the DG-CA3 circuits involved in declarative memory processes depends on Vangl2-dependent planar cell polarity signaling
Authors: Depret Noémie , Gleizes Marie , Moreau Maïté Marie , Poirault-Chassac Sonia , Quiedeville Anne , Dos Santos Carvalho Steve , Venugopal Vasika , Al Abed Alice Shaam , Barthet Gael , Mulle Christophe , Desmedt Aline , Marighetto Aline , Racca Claudia , Montcouquiol Mireille , Sans Nathalie
Published: June 2024

In the hippocampus, dentate gyrus granule cells connect to CA3 pyramidal cells via their axons, the mossy fibers (Mf). The synaptic terminals of Mfs (Mf boutons, MfBs) form large and complex synapses with thorny excrescences (TE) on the proximal dendrites CA3 pyramidal cells (PCs). MfB/TE synapses have distinctive “detonator” properties due to low intitial release probability and large presynaptic facilitation. The molecular mechanisms shaping the morpho-functional properties of MfB/TE synapses are still poorly understood, though alterations in their morphology are associated with Down syndrome, intellectual disabilities, and Alzheimer’s disease. Here, we identify the core PCP geneVangl2as essential to the morphogenesis and function of MfB/TE synapses. Vangl2 colocalises with the presynaptic heparan sulfate proteoglycan glypican 4 (GPC4) to stabilise the postsynaptic orphan receptor GPR158. Embryonic loss of Vangl2 disrupts the morphology of MfBs and TEs, impairs ultrastructural and molecular organisation, resulting in defective synaptic transmission and plasticity. In adult, the early loss of Vangl2 results in a number of hippocampus-dependent memory deficits including characteristic flexibility of declarative memory, organisation and retention of working/ everyday-like memory. These deficits also lead to abnormal generalisation of memories to salient cues and diminished ability to form detailed contextual memories. Together, these results establish Vangl2 as a key regulator of DG-CA3 connectivity and functions.

Highlights

Vangl2 is a key regulator of MfB/TE synapses morphogenesis and plasticity in CA3

Vangl2-mediated GPC4-GPR158 interaction maintains MfB-TE pre-synaptic morphology and function

Vangl2deletion affects declarative memory in adult mice

Vangl2 function is necessary for contextual learning and its loss leads toa maladaptive fear memory for salient cues
Embodied decisions as active inference
Authors: Priorelli Matteo , Stoianov Ivilin Peev , Pezzulo Giovanni
Published: June 2024

Decision-making is often conceptualized as a serial process, during which sensory evidence is accumulated for the choice alternatives until a certain threshold is reached, at which point a decision is made and an action is executed. Thisdecide-then-actperspective has successfully explained various facets of perceptual and economic decisions in the laboratory, in which action dynamics are usually irrelevant to the choice. However, living organisms often face another class of decisions – calledembodied decisions– that require selecting between potential courses of actions to be executed timely in a dynamic environment, e.g., for a lion, deciding which gazelle to chase and how fast to do so. Studies of embodied decisions reveal two aspects of goal-directed behavior in stark contrast to the serial view. First, that decision and action processes can unfold in parallel; second, that action-related components, such as the motor costs associated with the choice alternatives and required to “change mind” between them, exert a feedback effect on the decision taken. Here, we show that these signatures of embodied decisions emerge naturally in active inference – a framework that simultaneously optimizes perception and action, according to the same (free energy minimization) imperative. We show that optimizing embodied choices requires a continuous feedback loop between motor planning (where beliefs about choice alternatives guide action dynamics) and motor inference (where action dynamics finesse beliefs about choice alternatives). Furthermore, our active inference simulations reveal the normative character of embodied decisions in ecological settings – namely, achieving an effective balance between a high accuracy and a low risk of losing valid opportunities.
Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner
Authors: Staley Hannah A. , Jernigan Janna , Bolen MacKenzie L. , Titus Ann M. , Neighbarger Noelle , Cole Cassandra , Menees Kelly B. , Wallings Rebecca L. , Tansey Malú Gámez
Published: June 2024

Genome-wide association studies have identified a protective mutation in the phospholipase C gamma 2 (PLCG2) gene which confers protection against Alzheimer’s disease (AD)-associated cognitive decline. Therefore, PLCG2, which is primarily expressed in immune cells, has become a target of interest for potential therapeutic intervention. The protective allele, known asP522R, has been shown to be hyper-morphic in microglia, increasing phagocytosis of amyloid-beta (Aβ), and increasing the release of inflammatory cytokines. However, the effect of this protective mutation on peripheral tissue-resident macrophages, and the extent to which sex modifies this effect, has yet to be assessed. Herein, we show that peripheral macrophages carrying theP522Rmutation do indeed show functional differences compared to their wild-type (WT) counterparts, however, these alterations occur in a sex-dependent manner. In macrophages from females, theP522Rmutation increases lysosomal protease activity, cytokine secretion, and gene expression associated with cytokine secretion and apoptosis. In contrast, in macrophages from males, the mutation causes decreased phagocytosis and lysosomal protease activity, modest increases in cytokine secretion, and induction of gene expression associated with negative regulation of the immune response. Taken together, these results suggest that the mutation may be conferring different effects dependent on sex and cell type, and highlight the importance of considering sex as a biological variable when assessing the effects of genetic variants and implications for potential immune system-targeted therapies.
High-gamma and beta bursts in the Left Supramarginal Gyrus can accurately differentiate verbal memory states and performance
Authors: Sawczuk Nicolás , Rubinstein Daniel Y. , Sperling Michael R. , Wendel-Mitoraj Katrina , Djuric Petar , Slezak Diego F. , Kamienkowski Juan , Weiss Shennan A.
Published: June 2024

Revised Abstract

The left supramarginal gyrus (LSMG) may mediate attention to memory, and gauge memory state and performance. We performed a secondary analysis of 142 verbal delayed free recall experiments, in patients with medically-refractory epilepsy with electrode contacts implanted in the LSMG. In 14 of 142 experiments (in 14 of 113 patients), the cross-validated convolutional neural networks (CNNs) that used 1-dimensional(1-D) pairs of convolved high-gamma and beta tensors, derived from the LSMG recordings, could label recalled words with an area under the receiver operating curve (AUROC) of greater than 60% [range: 60-90%]. These 14 patients were distinguished by: 1) higher amplitudes of high-gamma bursts; 2) distinct electrode placement within the LSMG; and 3) superior performance compared with a CNN that used a 1-D tensor of the broadband recordings in the LSMG. In a pilot study of 7 of these patients, we also cross-validated CNNs using paired 1-D convolved high-gamma and beta tensors, from the LSMG, to: a) distinguish word encoding epochs from free recall epochs [AUC 0.6-1]; and distinguish better performance from poor performance during delayed free recall [AUC 0.5-0.86]. These experiments show that bursts of high-gamma and beta generated in the LSMG are biomarkers of verbal memory state and performance.
Intrauterine growth restriction and risk for arterial hypertension in later life. Ribeirao Preto birth cohort study
Authors: Lopes Paulo Cesar , Rocha Paulo Ricardo H. , Bettiol Heloisa , Barbieri Marco Antonio , Coelho Eduardo B.
Published: June 2024

Background

Intrauterine Growth Restriction (IUGR) may contribute to the risk of Arterial Hypertension (AH) in adulthood, but its impact after the 3rd decade of life, where environmental factors are prevalent, is still uncertain.

Methods

1,594 individuals with 38 and 39 years-old were evaluated from an original cohort of 6,824 newborns between 1978 and 1979. Biochemical tests, office BP, and anthropometric measurements were done. Also, questionnaires regarding data on income, habits, education, and information about birth were recorded. Krammer’s criteria defined IURG. Subclinical vascular damage was investigated using Pulse Wave Velocity (PWV).

Results

The IURG group has higher BP [Systolic BP: 123.3±15.6 vs. 121.2± 13.4 (p=0.049); Diastolic BP: 79.1 ± 10.6 mmHg vs. 76.8 ± 9.9 mmHg (p=0.002)] and higher prevalence of HA [56 vs. 49%; OR=1.30 (1.1-1.8), p=0.04] than the control group. There were no differences in PWV and prevalence of early vascular aging (PWV > 2SD of the mean of normal age value) between groups.

Conclusion

IURG was associated with an increase in BP and with a higher risk of hypertension at the end of the third decade of life.
Prediction of future input explains lateral connectivity in primary visual cortex
Authors: Klavinskis-Whiting Sebastian , Fristed Emil , Singer Yosef , Iacaruso M Florencia , King Andrew J , Harper Nicol S
Published: June 2024

Neurons in primary visual cortex (V1) show a remarkable functional specificity in their pre- and postsynaptic partners. Recent work has revealed a variety of wiring biases describing how the short- and long-range connections of V1 neurons relate to their tuning properties. However, it is less clear whether these connectivity rules are based on some underlying principle of cortical organization. Here, we show that the functional specificity of V1 connections emerges naturally in a recurrent neural network optimized to predict upcoming sensory inputs for natural visual stimuli. This temporal prediction model reproduces the complex relationships between the connectivity of V1 neurons and their orientation and direction preferences, the tendency of highly connected neurons to respond more similarly to natural movies, and differences in the functional connectivity of excitatory and inhibitory V1 populations. Together, these findings provide a principled explanation for the functional and anatomical properties of early sensory cortex.
Investigating visuo-tactile mirror properties in Borderline Personality Disorder: a TMS-EEG study
Authors: Agnese Zazio , Miranda Lanza Cora , Antonietta Stango , Giacomo Guidali , Eleonora Marcantoni , Delia Lucarelli , Serena Meloni , Nadia Bolognini , Roberta Rossi , Marta Bortoletto
Published: June 2024

Patients with Borderline Personality Disorder (pw-BPD) are characterized by lower levels of cognitive empathy compared to healthy controls (HCs), indicating difficulties in understanding others’ perspective. A candidate neural mechanism subtending empathic abilities is represented by the Tactile Mirror System (TaMS), which refers to mirror-like mechanisms in the somatosensory cortices. However, little is known about TaMS alterations in BPD, specifically in terms of brain connectivity within this network. Here, we aimed at providing novel insights on TaMS as neurophysiological candidate for BPD empathic deficits, with a special focus on TaMS connectivity by means of the combined use of transcranial magnetic stimulation and electroencephalography (TMS-EEG). Twenty pw-BPD and 20 HCs underwent a thorough investigation: we collected measures of empathic abilities obtained from self-report questionnaires, behavioral performance in a visuo-tactile spatial congruency task, and TMS-evoked potentials (TEPs) as effective connectivity indexes. In the TMS-EEG session, TMS was delivered over the right primary somatosensory cortex (S1) following the presentation of real touches and visual touches, while 74-channel EEG was continuously recorded. In the visuo-tactile spatial congruency task and the TMS-EEG recording, control conditions with visual touches on objects instead of body parts enabled to disentangle the involvement of TaMS from non-specific effects. The study is the first one employing TMS-EEG in pw-BPD and it has been preregistered before data collection. Consistent with previous findings, results show that pw-BPD reported significantly lower levels of cognitive empathy. Moreover, pw-BPD made significantly more errors than controls in the visuo-tactile spatial congruency task during visual touches on human body parts and not on objects. Finally, pw-BPD displayed a different connectivity pattern from S1-TEPs that was not specific for TaMS: they showed a lower P60 component during touch observation, as well as reduced amplitude of later TEPs responses (after ∼100 ms) during real touches. Overall, the present study shows behavioral evidence of TaMS impairment and a more general alteration in the connectivity pattern of the somatosensory network in pw-BPD.
Dynamic functional connectivity is modulated by the amount of p-Tau231 in blood in cognitively intact participants
Authors: Carrasco-Gómez Martín , García-Colomo Alejandra , Nebreda Alberto , Bruña Ricardo , Santos Andrés , Maestú Fernando
Published: June 2024

INTRODUCTION

Electrophysiology and plasma biomarkers are early and non-invasive candidates for Alzheimer’s disease detection. The purpose of this paper is to evaluate changes in dynamic functional connectivity measured with magnetoencephalography, associated with the plasma pathology marker p-tau231 in unimpaired adults.

METHODS

73 individuals were included. Static and dynamic functional connectivity were calculated using leakage corrected amplitude envelope correlation. Each source’s strength entropy across trials was calculated. A data-driven statistical analysis was performed to find the association between functional connectivity and plasma p-tau231 levels. Regression models were used to assess the influence of other variables over the clusters’ connectivity.

RESULTS

Frontotemporal dynamic connectivity positively associated with p-tau231 levels. Linear regression models identified pathological, functional and structural factors that influence dynamic functional connectivity.

DISCUSSION

These results expand previous literature on dynamic functional connectivity in healthy individuals at risk of AD, highlighting its usefulness as an early, non-invasive and more sensitive biomarker.
Fluid flow reconstruction around a free-swimming sperm in 3D
Authors: Ren Xiaomeng , Hernández-Herrera Paul , Montoya Fernando , Darszon Alberto , Corkidi Gabriel , Bloomfield-Gadêlha Hermes
Published: June 2024

We investigate the dynamics and hydrodynamics of a human spermatozoa swimming freely in 3D. We simultaneously track the sperm flagellum and the sperm head orientation in the laboratory frame of reference via high-speed high-resolution 4D (3D+t) microscopy, and extract the flagellar waveform relative to the body frame of reference, as seen from a frame of reference that translates and rotates with the sperm in 3D. Numerical fluid flow reconstructions of sperm motility are performed utilizing the experimental 3D waveforms, with excellent accordance between predicted and observed 3D sperm kinematics. The reconstruction accuracy is validated by directly comparing the three linear and three angular sperm velocities with experimental measurements. Our microhydrodynamic analysis reveals a novel fluid flow pattern, characterized by a pair of vortices that circulate in opposition to each other along the sperm cell. Finally, we show that the observed sperm counter-vortices are not unique to the experimental beat, and can be reproduced by idealised waveform models, thus suggesting a fundamental flow structure for free-swimming sperm propelled by a 3D beating flagellum.
Simulations reveal unique roles for the FXR hinge in the FXR-RXR nuclear receptor heterodimer
Authors: Yu Tracy , Biswas Arumay , Dube Namita , Okafor C. Denise
Published: June 2024

Nuclear receptors are multidomain transcription factors whose full-length quaternary architecture is poorly described and understood. Most nuclear receptors bind DNA as heterodimers or homodimers, which could encompass a variety of arrangements of the individual domains. Only a handful of experimental structures currently exist describing these architectures. Given that domain interactions and protein-DNA interactions within transcriptional complexes are tightly linked to function, understanding the arrangement of nuclear receptor domains on DNA is of utmost importance. Here, we employ modeling and molecular dynamics (MD) simulations to describe the structure of the full-length farnesoid X receptor (FXR) and retinoid X receptor alpha (RXR) heterodimer bound to DNA. Combining over 100 microseconds of atomistic MD simulations with enhanced sampling simulations, we characterize the dynamic behavior of eight FXR-RXR-DNA complexes, showing that these complexes support a range of quaternary architectures. Our simulations reveal critical roles for the hinge in the DNA-bound dimer in facilitating interdomain allostery, mediating DNA binding and driving the dynamic flexibility of the complex. These roles have been hard to appreciate previously due to experimental limitations in studying the flexible hinge. These studies provide a much-needed framework that will enable the field to obtain a complete understanding of nuclear receptor quaternary architectures.
Martini without the twist: Unveiling a mechanically correct microtubule through bottom-up coarse-graining in Martini 3
Authors: Sahoo Abhilash , Hanson Sonya M.
Published: June 2024

Microtubules are essential cytoskeletal filaments involved in cell motility, division, and intracellular transport. These biomolecular assemblies can exhibit complex structural be-haviors influenced by various biophysical factors. However, simulating microtubule systems at the atomistic scale is challenging due to their large spatial scales. Here, we present an approach utilizing the Martini 3 Coarse-Grained (CG) model coupled with an appropriate elastic network to simulate microtubule-based systems accurately. By iteratively optimiz-ing the elastic network parameters, we matched the structural fluctuations of CG hetero-dimer building blocks to their atomistic counterparts. Our efforts culminated in a ∼ 200nm microtubule built with ∼ 6 million interaction-centers that could reproduce experimentally observed mechanical properties. Our aim is to employ these CG simulations to investigate specific biophysical phenomena at a microscopic level. These microscopic perspectives can provide valuable insights into the underlying mechanisms and contribute to our knowledge of microtubule-associated processes in cellular biology. With MARTINI 3 CG simulations, we can bridge the gap between computational efficiency and molecular detail, enabling in-vestigations into these biophysical processes over longer spatio-temporal scales with amino acid-level insights.
CADA-PRO, a patient questionnaire measuring key cognitive, motor, emotional and behavioral Outcomes in CADASIL
Authors: Folco Cécile Di , Jabouley Aude , Reyes Sonia , Machado Carla , Guey Stéphanie , Hervé Dominique , Fernandes Fanny , Agossa Joseph , Chabriat Hugues , Tezenas du Montcel Sophie
Published: June 2024

Background

Cerebral Small Vessel Disease (cSVD) of ischemic type, either sporadic or genetic, as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), can impact the quality of daily life on various cognitive, motor, emotional or behavioral aspects. No instrument has been developed to measure these outcomes from the patient’s perspective. We thus aimed to develop and validate a patient-reported questionnaire.

Methods

In a development study, 79 items were generated by consensus between patients, family representatives and cSVD experts. A first sample of patients allowed assessing the feasibility (missing data, floor and ceiling effect, acceptability), internal consistency, and dimensionality of a first set of items. Thereafter, in a validation study, we tested a reduced version of the item set in a larger sample to assess the feasibility, internal consistency, dimensionality, test-retest reliability, concurrent validity, and sensitivity to change.

Results

The scale was developed in 44 cSVD patients and validated in a second sample of 89 individuals (including 43 patients with CADASIL and 46 with another cSVD). The final CADASIL Patient-Reported Outcome (CADA-PRO) scale comprised 18 items covering four categories of consequences (depression/anxiety, attention/executive functions, motor, daily activities) of the disease. The proportion of missing data was low, no item displayed major floor or ceiling effect. Both the internal consistency and test-retest reliability were good (Cronbach alpha = 0.95, intraclass correlation coefficient = 0.88). In patients with CADASIL, CADA-PRO scores correlated with the modified Rankin scale, Starkstein Apathy Scale (SAS), Hospital Anxiety and Depression scale (HAD), and Trail Making Test times. In patients with other cSVDs, CADA-PRO correlated only with HAD and SAS.

Conclusion

The CADA-PRO is an innovative instrument for measuring patient-reported outcomes in future cSVD trials. Full validation was obtained for its use in CADASIL patients, but further improvement is needed for its application in other cSVDs.
An immune System for the City: A New Paradigm for Surveillance and Control of Disease Vectors
Authors: Levy Michael Z , Tamayo Laura D. , Condori-Pino Carlos E. , Arevalo-Nieto Claudia , Castillo-Neyra Ricardo , Paz-Soldan Valerie A.
Published: June 2024

Vector-borne pathogens continue to emerge, kill and harm humans with unrelenting regularity. Conventional strategies to controlling insect vectors grew out of the military; communication is hierarchical, responses unilateral, and regulation predetermined. We developed an alternative approach, modeled after the adaptive immune system, and compared the approaches through a cluster-randomized trial in the context of an ongoing urban Chagas disease vector control campaign in Arequipa, Peru. We report here early results from a pre-planned interim analysis. In the intervention (immune) arm 23 infested households were detected in 10 separate foci; in the control arm 5 infested households were detected in 1 focus. The immune approach was adaptive and required more effort (1085.2 person days vs 864.2 in the control; Rate ratio 3.66 [1.35 12.38], p-value =0.0062). Vector surveillance approaches modeled after the immune system may be more effective than conventional approaches, especially in cities and other complex civilian environments.
Large language models identify causal genes in complex trait GWAS
Authors: Shringarpure Suyash S. , Wang Wei , Karagounis Sotiris , Wang Xin , Reisetter Anna C. , Auton Adam , Khan Aly A.
Published: June 2024

Identifying underlying causal genes at significant loci from genome-wide association studies (GWAS) remains a challenging task. Literature evidence for disease-gene co-occurrence, whether through automated approaches or human expert annotation, is one way of nominating causal genes at GWAS loci. However, current automated approaches are limited in accuracy and generalizability, and expert annotation is not scalable to hundreds of thousands of significant findings. Here, we demonstrate that large language models (LLMs) can accurately identify genes likely to be causal at loci from GWAS. By evaluating the performance of GPT-3.5 and GPT-4 on datasets of GWAS loci with high-confidence causal gene annotations, we show that these models outperform state-of-the-art methods in identifying putative causal genes. These findings highlight the potential of LLMs to augment existing approaches to causal gene discovery.
Intra-Arrest Percutaneous Stellate Ganglion Block: A Protocol for a Scoping Review
Authors: Vlok Ruan , Shankar Ravi , Cham Jamie , Bridge Bradley , Donaldson Lachlan
Published: June 2024

Introduction

Percutaneous Stellate ganglion blockade (PSGB) is an increasingly recognised technique for the management of refractory ventricular arrhythmias (VA). Both ultrasound guided and landmark based techniques have been used to successfully decrease the burden of VA. The role of intra-arrest PSGB remains unknown, however it may represent a cost-effective point of care intervention that can be performed for shockable cardiac arrest.

Methods

A systematic review of all clinical studies of PSGB performed intra-arrest will be performed across multiple databases. Studies will be included if they described the use of intra-arrest PSGB in humans. Studies will be qualitatively assessed to describe data regarding the PSGB technique, the training of the proceduralist, patient demographics, the context of the arrest and clinical outcomes and complications. This protocol was drafted according to the PRIMSA-P ScR.
Prevalence and associated factors of suicidal ideation among adolescents in rural Bangladesh
Authors: Mumu Rifa Tamanna , Shaikh Md Parvez , Mitra Dipak Kumar
Published: June 2024

Background

Suicide ranks as the fourth most common cause of death globally, which is more pronounced in lower-middle-income countries. LMICs witness 88% of adolescent suicides yearly, with a 14% prevalence of suicidal ideation. A few studies are available based on the suicidal behavior of young adults residing in rural Bangladesh.

Objective

This study seeks to evaluate the prevalence and associated factors of suicidal ideation in 11 to 17-year-old adolescents in a remote subdistrict in Bangladesh.

Method

A cross-sectional study was performed in Lohagara, a rural subdistrict in Narail, in southern Bangladesh from April, 15 to May 14, 2024. 350 subjects were recruited for the study, all of whom were school-going adolescents aged 11 to 17 years. The Bengali-translated versions of the Suicidal Behavior-Revised Questionnaire (SBQ-R) and the Depression, Anxiety, and Stress Scale - 21 Items (DASS-21), as well as another structured questionnaire, were used to collect data from participants. Data analysis was done by STATA version 17.

Result

The prevalence of current suicidal ideation among adolescents is 21% (95% CI: 17% to 25.8%). Smoking, lack of close friends, an unfavorable family environment, and depression were found to be significantly associated with the development of suicidal ideation in adolescents. Unmarried and single relationship status played a protective role in growing young adults’ suicidal thoughts.

Conclusion

The notable prevalence of suicidal ideation in adolescents underscores the need for screening and intervention at an early age to protect them from dreadful consequences. By shedding light on this issue, different health promotional and educational programs, organized in schools and communities may help raise awareness in students, teachers as well as legal guardians. The ultimate goal is to safeguard adolescents from making devastating decisions with adequate counseling, care, and support.
Prevalence and associated factors of antenatal depression in rural Bangladesh
Authors: Mumu Rifa Tamanna , Mitra Dipak Kumar
Published: June 2024

Background

According to the World Health Organization (WHO), approximately 322 million individuals globally were grappling with depressive disorders in 2015. During pregnancy, the risk of experiencing depression is elevated due to certain hormonal changes. Despite the potentially severe consequences of antenatal depression for both the mother and newborn, there have been limited studies conducted on this issue in Bangladesh.

Objective

To find out the prevalence and associated factors of antenatal depression in a rural sub-district in Bangladesh.

Method

A cross-sectional study was performed in Lohagara, a rural subdistrict in Narail, situated in the southern part of Bangladesh between January 08 and 14, 2024. 350 subjects were recruited for the study, who were pregnant at various trimesters and attended antenatal check-ups in a government health complex and a private hospital in Lohagara. The Bengali-translated version of the Edinburgh Postnatal Depression Scale (EPDS) and a structured questionnaire were used for data collection. Data were analyzed in STATA version 14.

Result

The point prevalence of antenatal depression is 39% (38.86%, in 95% CI: 33.9% to 44%). Gestational week (AOR: 0.4, 95% CI: 0.2, 0.8), unintended pregnancy (AOR: 1.7, 95% CI: 1, 3), intimate partner violence (AOR: 3.3, 95% CI: 1.1, 9.7), a history of previous diseases (AOR: 2.4, 95% CI: 1.1, 5.2), and the history of having polygamous husbands (AOR: 13.6, 95% CI: 1.1, 164) are found to be significantly associated with the development of depression in the prenatal period.

Conclusion

In rural Narail, high rates of antenatal depression underscore the importance of increased awareness among healthcare professionals and families. Strategic involvement of stakeholders and policymakers is essential to address issues like intimate partner violence and polygamy. Moreover, there’s a critical need for extra care and counseling for pregnant women with a history of health problems or facing unexpected pregnancies.
Protection of Omicron bivalent vaccine, previous infection, and their induced neutralizing antibodies against symptomatic infection with Omicron XBB.1.16 and EG.5.1
Authors: Yamamoto Shohei , Matsuda Kouki , Maeda Kenji , Mizoue Tetsuya , Horii Kumi , Okudera Kaori , Tan Tomofumi , Oshiro Yusuke , Inamura Natsumi , Nemoto Takashi , Takeuchi Junko S. , Konishi Maki , Sugiyama Haruhito , Aoyanagi Nobuyoshi , Sugiura Wataru , Ohmagari Norio
Published: June 2024

Background

Data are limited on the protective role of the Omicron BA bivalent vaccine, previous infection, and their induced neutralizing antibodies against Omicron XBB.1.16 and EG.5.1 infection.

Methods

We conducted a nested case-control analysis among tertiary hospital staff in Tokyo who had received three or more doses of COVID-19 vaccines and donated blood samples in June 2023 (1 month before Omicron XBB.1.16 and EG.5.1 wave). We identified 206 symptomatic cases between June and September 2023 and selected their controls with 1:1 propensity-score matching. We examined the association of vaccination, previous infection, and preinfection live-virus neutralizing antibody titers against Omicron XBB.1.16 and EG.5.1 with the risk of COVID-19 infection.

Results

Previous infection during Omicron BA- or XBB-dominant phases was associated with a significantly lower infection risk during the XBB.1.16 and EG.5.1 dominant phase than infection-naïve with 70% and 100% protection, respectively, whereas Omicron BA bivalent vaccination showed no association. Preinfection-neutralizing titers against XBB.1.16 and EG.5.1 were 39% (95%CI: 8–60) and 28% (95%CI: 8–44), respectively, lower in cases than in matched controls. Neutralizing activity against XBB.1.16 and EG.5.1. were somewhat detectable in the sera of individuals with previous infection but barely detectable in those who were infection-naïve and received the Omicron bivalent vaccine.

Conclusions

In the era when the Omicron XBB vaccine was unavailable, the Omicron BA bivalent vaccine did not confer the neutralizing activity and protection against Omicron XBB.1.16 and EG.5.1 symptomatic infection. The previous infection afforded neutralizing titers and protection against symptomatic infection with these variants.

Main points

In the era when the Omicron XBB vaccine was unavailable, the Omicron BA bivalent vaccine did not confer the neutralizing activity and protection against Omicron XBB.1.16 and EG.5.1 symptomatic infection. The previous infection afforded neutralizing titers and protection against symptomatic infection with these variants.
Characterizing a Lethal CAG-ACE2 Transgenic Mouse Model for SARS-CoV-2 infection with Using Cas9-Enhanced Nanopore Sequencing
Authors: Smirnov Alexander , Nurislamov Artem , Koncevaya Galina , Serova Irina , Kabirova Evelyn , Chuyko Eduard , Maltceva Ekaterina , Savoskin Maxim , Zadorozhny Daniil , Svyatchenko Victor A. , Protopopova Elena V. , Taranov Oleg S. , Legostaev Stanislav S. , Loktev Valery B. , Serov Oleg , Battulin Nariman
Published: June 2024

The SARS-CoV-2 pandemic has underscored the necessity for functional transgenic animal models for testing. Mouse lines with overexpression of the human receptor ACE2 serve as the primary animal model to study COVID-19 infection. Overexpression ofACE2under a strong ubiquitous promoter facilitates convenient and sensitive testing of COVID-19 pathology. We performed pronuclear microinjections using a 5 kb CAG-ACE2 linear transgene construct and identified three founder lines with 140, 72, and 73 copies, respectively. Two of these lines were further analyzed forACE2expression profiles and sensitivity to SARS-CoV-2 infection. Both lines expressedACE2in all organs analyzed. Embryonic fibroblast cell lines derived from transgenic embryos demonstrated severe cytopathic effects following infection, even at low doses of SARS-CoV-2 (0,1-1.0 TCID50). Infected mice from the two lines began to show COVID-19 symptoms three days post-infection and succumbed between days 4 and 7. Histological examination of lung tissues from terminally ill mice revealed severe pathological alterations. To further characterize the integration site in one of the lines, we applied Nanopore sequencing combined with Cas9 enrichment to examine the internal transgene concatemer structure. Oxford Nanopore sequencing (ONT) is becoming the gold standard for transgene insert characterization, but it is relatively inefficient without targeted region enrichment. We digested genomic DNA with Cas9 and gRNA against theACE2transgene to create ends suitable for ONT adapter ligation. ONT data analysis revealed that most of the transgene copies were arranged in a head-to-tail configuration, with palindromic junctions being rare. We also detected occasional plasmid backbone fragments within the concatemer, likely co-purified during transgene gel extraction, which is a common occurrence in pronuclear microinjections.
Microbial aerotrophy enables continuous primary production in diverse cave ecosystems
Authors: Bay Sean , Ni Gaofeng , Lappan Rachael , Leung Bob , Wong Wei Wen , Holland Sophie , Athukorala Nadeesha , Sand Knudsen Kalinka , Fan Ziqi , Kerou Melina , Jain Surbhi , Schmidt Oliver , Eate Vera , Clarke David , Jirapanjawat Thanavit , Tveit Alexander , Featonby Tim , White Susan , White Nicholas , McGeoch Melodie A. , Singleton Caitlin M , Cook Perran L. M. , Chown Steven L. , Greening Chris
Published: June 2024

Most aerated cave ecosystems are assumed to be oligotrophic given they receive minimal inputs of light energy. Diverse microorganisms have nevertheless been detected within caves, though it remains unclear what strategies enable them to meet their energy and carbon needs. Here we determined the processes and mediators of primary production in aerated limestone and basalt caves through paired metagenomic and biogeochemical profiling. Based on 1458 metagenome-assembled genomes, over half of microbial cells in caves encode enzymes to use atmospheric trace gases as energy and carbon sources. The most abundant microbes in these systems are chemosynthetic primary producers, notably the novel gammaproteobacterial methanotrophic order Ca. Methylocavales and two uncultivated actinobacterial genera predicted to grow on atmospheric hydrogen, carbon dioxide, and carbon monoxide. In situ and ex situ biogeochemical and isotopic measurements consistently confirmed that these gases are rapidly consumed at rates sufficient to meet community-wide energy needs and drive continual primary production. Conventional chemolithoautotrophs, which use trace lithic compounds such as ammonium and sulfide, are also enriched and active alongside these trace gas scavengers. These results indicate that caves are unique in both their microbial composition and the biogeochemical processes that sustain them. Based on these findings, we propose caves are the first known ecosystems where atmospheric trace gases primarily sustain growth rather than survival and define this process as "aerotrophy". Cave aerotrophy may be a hidden process supporting global biogeochemistry.
Discarded diversity: Novel megaphages, auxiliary metabolic genes, and virally encoded CRISPR-Cas systems in landfills
Authors: George Nikhil A. , Zhou Zhichao , Anantharaman Karthik , Hug Laura A.
Published: June 2024

Background

Viruses are the most abundant microbial entity on the planet, impacting microbial community structure and ecosystem services. Despite outnumbering Bacteria and Archaea by an order of magnitude, viruses have been comparatively underrepresented in reference databases. Metagenomic examinations have illustrated that viruses of Bacteria and Archaea have been specifically understudied in engineered environments. Here we employed metagenomic and computational biology methods to examine the diversity, host interactions, and genetic systems of viruses predicted from 27 samples taken from three municipal landfills across North America.

Results

We identified numerous viruses that are not represented in reference databases, including the third largest bacteriophage genome identified to date (∼678 kbp), and note a cosmopolitan diversity of viruses in landfills that are distinct from viromes in other systems. Host-virus interactions were examined via host CRISPR spacer to viral protospacer mapping which captured hyper-targeted viral populations and six viral populations predicted to infect across multiple phyla. Virally-encoded auxiliary metabolic genes (AMGs) were identified with the potential to augment hosts’ methane, sulfur, and contaminant degradation metabolisms, including AMGs not previously reported in literature. CRISPR arrays and CRISPR-Cas systems were identified from predicted viral genomes, including the two largest bacteriophage genomes to contain these genetic features. Some virally encoded Cas effector proteins appear distinct relative to previously reported Cas systems and are interesting targets for potential genome editing tools.

Conclusions

Our observations indicate landfills, as heterogeneous contaminated sites with unique selective pressures, are key locations for diverse viruses and atypical virus-host dynamics.
The Associations of Mental Disorders in Children With Parents’ Subsequent Mental Disorders: A Nationwide Cohort Study From Finland and Denmark
Authors: Hakulinen Christian , Gutvilig Mai , Niemi Ripsa , Momen Natalie C. , Pulkki-Råback Laura , Böckerman Petri , Plana-Ripoll Oleguer , Komulainen Kaisla , Elovainio Marko
Published: June 2024

Background

Intergenerational transmission of mental disorders has been well established, but it is unclear whether exposure to a child’s mental disorder increases parents’ subsequent risk of mental disorders.

Aims

We examined the association of mental disorders in children with their parents’ subsequent mental disorders.

Methods

In this population based-cohort study, we included all persons with children born in Finland or Denmark in 1990–2010. Information of mental disorder was acquired from national registers. The follow-up period began when the parent’s eldest child was 5 years old (for codes F10–F60 ICD-10) or 1 year old (for codes F70–F98 of the ICD-10) and ended on December 31st, 2019, or when the parent received a mental disorder diagnosis, died, or emigrated from Finland or Denmark. The association of mental disorders in children with their parents’ subsequent mental disorders was examined using Cox proportional hazards models.

Results

The study cohort included 1 651 723 parents. In total, 248 328 women and 250 763 men had at least one child who was diagnosed with a mental disorder. The risk of a parent receiving a mental disorder diagnosis was higher among those who had a child with a mental disorder compared to those who did not. For both parents, the hazard ratios were greatest in the first six months after the child’s diagnosis (HR between 2.04-2.54), followed by a subtle decline in the risk (after two years, HR between 1.33-1.77).

Conclusion

Mental disorders in children were associated with a greater risk of subsequent mental disorders among their parents. Additional support is needed for parents whose children have been recently diagnosed with a mental disorder.
Functional brain connectivity in early adolescence after hypothermia-treated neonatal hypoxic-ischemic encephalopathy
Authors: Håkansson Gustaf , Grossmann Katarina Robertsson , Ådén Ulrika , Blennow Mats , Fransson Peter
Published: June 2024

Aim

Neonatal hypoxic-ischemic encephalopathy (HIE) injures the infant brain during the basic formation of the developing functional connectome. This study aimed to investigate long-term changes in the functional connectivity (FC) networks of the adolescent brain following neonatal HIE treated with therapeutic hypothermia (TH).

Method

This prospective, population-based cohort study included all infants (n=66) with TH-treated neonatal HIE in Stockholm during 2007-2009 and a control group (n=43) of children with normal neonatal course. Assessment with resting-state functional magnetic resonance imaging (fMRI) was performed at Karolinska Institutet, Stockholm at age 9-12 years.

Results

fMRI data met quality criteria for 35 children in the HIE-cohort (mean [SD] age at MRI: 11.2 [0.74] years, 46% male) and 30 children in the control group (mean [SD] age at MRI: 10.1 [0.78] years, 53% male). Clinical neurologic symptoms were present in 40% of children in the HIE-cohort. Non-parametric statistical analysis failed to detect any significant (p<0.001) alterations of FC networks in the HIE-cohort, nor between children in the HIE-cohort with or without neurological sequelae.

Interpretation

HT-treated HIE could not be associated with persistent alteration of the functional connectome. This indicates a notable resilience of the functional architecture of the brain against this type of early brain injury.
Multi-polygenic prediction of frailty highlights chronic pain and educational attainment as key risk and protective factors
Authors: Flint J P , Welstead M , Cox S R , Russ T C , Marshall A , Luciano M
Published: June 2024

Frailty is a complex trait. Twin studies and recent Genome-Wide Association Studies have demonstrated a strong genetic basis of frailty but there remains a lack of genetic studies exploring genetic prediction of Frailty. Previous work has shown that a single polygenic predictor – represented by a Frailty polygenic score - predicts Frailty, measured via the frailty index, in independent samples within the United Kingdom. We extended this work, using a multi-polygenic score (MPS) approach to increase predictive power. Predictor variables - twenty-six polygenic scores (PGS) were modelled in regularised Elastic net regression models, with repeated cross-validation, to estimate joint prediction of the polygenic scores and order the predictions by their contributing strength to Frailty in two independent cohorts aged 65+ - the English Longitudinal Study of Ageing (ELSA) and Lothian Birth Cohort 1936 (LBC1936). Results showed that the MPS explained 3.6% and 4.7% of variance compared to the best single-score prediction of 2.6% and 2.2% of variance in ELSA and LBC1936 respectively. The strongest polygenic predictors of worsening frailty came from PGS for Chronic pain, Frailty and Waist circumference; whilst PGS for Parental Death, Educational attainment, and Rheumatoid Arthritis were found to be protective to frailty. Results from the predictors remaining in the final model were then validated using the longitudinal LBC1936, with equivalent PGS scores from the same GWAS summary statistics. Thus, this MPS approach provides new evidence for the genetic contributions to frailty in later life and sheds light on the complex structure of the Frailty Index measurement.
A machine learning-based prediction of tau load and distribution in Alzheimer’s disease using plasma, MRI and clinical variables
Authors: Karlsson Linda , Vogel Jacob , Arvidsson Ida , Åström Kalle , Strandberg Olof , Seidlitz Jakob , Bethlehem Richard A. I. , Stomrud Erik , Ossenkoppele Rik , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Palmqvist Sebastian , Smith Ruben , Janelidze Shorena , La Joie Renaud , Rabinovici Gil D. , Binette Alexa Pichet , Mattsson-Carlgren Niklas , Hansson Oskar
Published: June 2024

Tau positron emission tomography (PET) is a reliable neuroimaging technique for assessing regional load of tau pathology in the brain, commonly used in Alzheimer’s disease (AD) research and clinical trials. However, its routine clinical use is limited by cost and accessibility barriers. Here we explore using machine learning (ML) models to predict clinically useful tau-PET composites from low-cost and non-invasive features, e.g., basic clinical variables, plasma biomarkers, and structural magnetic resonance imaging (MRI). Results demonstrated that models including plasma biomarkers yielded the most accurate predictions of tau-PET burden (best model: R-squared=0.66-0.68), with especially high contribution from plasma P-tau217. In contrast, MRI variables stood out as best predictors (best model: R-squared=0.28-0.42) of asymmetric tau load between the two hemispheres (an example of clinically relevant spatial information). The models showed high generalizability to external test cohorts with data collected at multiple sites. Based on these results, we also propose a proof-of-concept two-step classification workflow, demonstrating how the ML models can be translated to a clinical setting. This study uncovers current potential in predicting tau-PET information from scalable cost-effective variables, which could improve diagnosis and prognosis of AD.