bluuebunny/crossref_metadata_2025 huggingface dataset:
The UFMylation pathway is impaired in Alzheimer’s disease
Authors: Yan Tingxiang , Heckman Michael G. , Craver Emily C. , Liu Chia-Chen , Rawlinson Bailey D. , Wang Xue , Murray Melissa E. , Dickson Dennis W. , Ertekin-Taner Nilufer , Lou Zhenkun , Bu Guojun , Springer Wolfdieter , Fiesel Fabienne C.
Published: May 2024

Background

Alzheimer’s disease (AD) is characterized by the presence of neurofibrillary tangles made of hyperphosphorylated tau and senile plaques composed of beta-amyloid. These pathognomonic deposits have been implicated in the pathogenesis, although the molecular mechanisms and consequences remain undetermined. UFM1 is an important, but understudied ubiquitin-like protein that is covalently attached to substrates. This UFMylation has recently been identified as major modifier of tau aggregation upon seeding in experimental models. However, potential alterations of the UFM1 pathway in human AD brain have not been investigated yet.

Methods

Here we used frontal and temporal cortex samples from individuals with or without AD to measure the protein levels of the UFMylation pathway in human brain. We used multivariable regression analyses followed by Bonferroni correction for multiple testing to analyze associations of the UFMylation pathway with neuropathological characteristics, primary biochemical measurements of tau and additional biochemical markers from the same cases. We further studied associations of the UFMylation cascade with cellular stress pathways using Spearman correlations with bulk RNAseq expression data and functionally validated these interactions using gene-edited neurons that were generated by CRISPR-Cas9.

Results

Compared to controls, human AD brain had increased protein levels of UFM1. Our data further indicates that this increase mainly reflects conjugated UFM1 indicating hyperUFMylation in AD. UFMylation was strongly correlated with pathological tau in both AD-affected brain regions. In addition, we found that the levels of conjugated UFM1 were negatively correlated with soluble levels of the deUFMylation enzyme UFSP2. Functional analysis of UFM1 and/or UFSP2 knockout neurons revealed that the DNA damage response as well as the unfolded protein response are perturbed by changes in neuronal UFM1 signaling.

Conclusions

There are marked changes in the UFMylation pathway in human AD brain. These changes are significantly associated with pathological tau, supporting the idea that the UFMylation cascade might indeed act as a modifier of tau pathology in human brain. Our study further nominates UFSP2 as an attractive target to reduce the hyperUFMylation observed in AD brain but also underscores the critical need to identify risks and benefits of manipulating the UFMylation pathway as potential therapeutic avenue for AD.
Feedback control of recurrent dynamics constrains learning timescales during motor adaptation
Authors: Gurnani Harsha , Liu Weixuan , Brunton Bingni W.
Published: May 2024

Latent dynamical models of the primary motor cortex (M1) have revealed fundamental neural computations underlying motor control; however, such models often overlook the impact of sensory feedback, which can continually update cortical dynamics and correct for external perturbations. This suggests a critical need to model the interaction between sensory feedback and intrinsic dynamics. Such models would also benefit the design of brain-computer interfaces (BCIs) that decode neural activity in real time, where both user learning and proficient control require feedback. Here we investigate the flexible feedback modulation of cortical dynamics and demonstrate its impact on BCI task performance and short-term learning. By training recurrent network models with real-time sensory feedback on a simple 2D reaching task, analogous to BCI cursor control, we show how previously reported M1 activity patterns can be reinterpreted as arising from feedback-driven dynamics. Next, by incorporating adaptive controllers upstream of M1, we make a testable prediction that short-term learning for a new BCI decoder is facilitated by plasticity of inputs to M1, including remapping of sensory feedback, beyond the plasticity of recurrent connections within M1. This input-driven dynamical structure also determines the speed of adaptation and learning outcomes, and explains a continuous form of learning variability. Thus, our work highlights the need to model input-dependent latent dynamics for motor control and clarifies how constraints on learning arise from both the statistical characteristics and the underlying dynamical structure of neural activity.
Angiogenesis in the mature mouse cortex is governed in a region specific and Notch1 dependent manner
Authors: Raudales Alejandra , Schager Ben , Hancock Dominique , Sharma Sorabh S. , Narayana Kamal , Reeson Patrick , Cheema Manjinder , Körbelin Jakob , Brown Craig E.
Published: May 2024

Cerebral angiogenesis is well appreciated in development and after injury, but the extent to which it occurs across cortical regions in normal adult mice and underlying mechanisms, is incompletely understood. Usingin vivoimaging, we show that angiogenesis in anterior-medial cortical regions (retrosplenial and sensorimotor cortex), was exceptionally rare. By contrast, angiogenesis was significantly elevated in posterior-lateral regions such as visual cortex, primarily within 200µm of the cortical surface. There were no regional differences in vessel pruning or sex effects except for the length and depth of new capillaries. To understand mechanisms, we surveyed gene expression and found Notch related genes were enriched in ultra-stable retrosplenial versus visual cortex. Using endothelial specific knockdown of Notch1, cerebral angiogenesis was significantly increased along with genes implicated in angiogenesis (Apln, Angpt2, Cdkn1a). Our study shows that angiogenesis is regionally dependent and manipulations of Notch1 signaling could unlock the angiogenic potential of the mature vasculature.
Lumped Parameter Simulations of Cervical Lymphatic Vessels: Dynamics of Murine Cerebrospinal Fluid Efflux from the Skull
Authors: Kim Daehyun , Tithof Jeffrey
Published: May 2024

Background

Growing evidence suggests that for rodents, a substantial fraction of cerebrospinal fluid (CSF) drains by crossing the cribriform plate into the nasopharengeal lymphatics, eventually reaching the cervical lymphatic vessels (CLVs). Disruption of this drainage pathway is associated with various neurological disorders.

Methods

We employ a lumped parameter method to numerically model CSF drainage across the cribriform plate to CLVs. Our model uses intracranial pressure as an inlet pressure and central venous blood pressure as an outlet pressure. The model incorporates initial lymphatic vessels (modeling those in the nasal region) that absorb the CSF and collecting lymphatic vessels (modeling CLVs) to transport the CSF against an adverse pressure gradient. To determine unknown parameters such as wall stiffness and valve properties, we utilize a Monte Carlo approach and validate our simulation against recentin vivoexperimental measurements.

Results

Our parameter analysis reveals the physical characteristics of CLVs. Our results suggest that the stiffness of the vessel wall and the closing state of the valve are crucial for maintaining the vessel size and volume flow rate observedin vivo. We find that a decreased contraction amplitude and frequency leads to a reduction in volume flow rate, and we test the effects of varying the different pressures acting on the CLVs. Finally, we provide evidence that branching of initial lymphatic vessels may deviate from Murray’s law to reduce sensitivity to elevated intracranial pressure.

Conclusions

This is the first numerical study of CSF drainage through CLVs. Our comprehensive parameter analysis offers guidance for future numerical modeling of CLVs. This study also provides a foundation for understanding physiology of CSF drainage, helping guide future experimental studies aimed at identifying causal mechanisms of reduction in CLV transport and potential therapeutic approaches to enhance flow.
A microglia-containing cerebral organoid model to study early life immune challenges
Authors: Buonfiglioli Alice , Kübler Raphael , Missall Roy , Jong Renske De , Chan Stephanie , Haage Verena , Wendt Stefan , Lin Ada J. , Mattei Daniele , Graziani Mara , Latour Brooke , Gigase Frederieke , Nygaard Haakon B. , De Jager Philip L. , De Witte Lot D.
Published: May 2024

Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.
A connectomics-driven analysis reveals novel characterization of border regions in mouse visual cortex
Authors: Tumma Neehal , Kong Linghao , Sawmya Shashata , Wang Tony T. , Shavit Nir
Published: May 2024

Leveraging retinotopic maps to parcellate the visual cortex into its respective sub-regions has long been a canonical approach to characterizing the functional organization of visual areas in the mouse brain. However, with the advent of extensive connectomics datasets like MICrONS, we can now perform more granular analyses on biological neural networks, enabling us to better characterize the structural and functional profile of the visual cortex. In this work, we propose a statistical framework for analyzing the MICrONS dataset, focusing our efforts on the network encompassed by the retinotopically-induced V1, RL, and AL visual areas. In particular, we bridge the gap between connectomics and retinotopy by identifying several structural and functional differences between these regions. Most notably, by placing our attention on thebordersbetween these regions, we demonstrate how connectomics, in some ways, supersedes retinotopy, providing evidence for two major findings. One, by comparing the V1-RL and RL-AL border regions, we show that not all borders in the visual cortex are the same with respect to structure and function. Two, we propose a novel interpretation for the V1-RL border region in particular, motivating it as a subnetwork that possesses heightened synaptic connectivity and more synchronous neural activity. Going one step further, we analyze structure and function in tandem by measuring information flow along synapses, demonstrating that the V1-RL border serves as a bridge for communication between the V1 and RL visual areas, offering justification as to why it presents itself uniquely with respect to both structure and function.
Testing the application of plasma glucocorticoids and their ratios as biomarkers of acute and chronic stress in rescued wild koala patients: a pilot study
Authors: Pan Liang-Yu , Pahuja Harsh , Portas Tim , Narayan Edward
Published: May 2024

Koalas(Phascolarctos cinereus)are one of the most iconic marsupial species endemic to Australia. However, their population is declining due to threats including habitat loss, disease, dog attacks, and vehicle collisions. These threats also serve as acute or chronic stressors that impact koala welfare and conservation. Cortisol is widely used as a biomarker to study stress in koalas. However, plasma cortisol concentration is less studied due to its limited ability to assess chronic stress and welfare concerns. Dehydroepiandrosterone sulphate (DHEAS) and dihydrotestosterone (DHT) are biomarkers that could potentially detect chronic stress due to their antagonising and inhibitory effects on cortisol. In this study, we used plasma cortisol and the ratio of DHEAS and DHT to cortisol to assess stress in rescued koalas (n = 10) admitted to RSPCA Queensland. Although no significant differences were found between koalas across all biomarkers and the ratios failed to detect chronic stressors, similar trends were found consistently, suggesting the potential use of the biomarkers to assess stress. Across all biomarkers, the highest medians were found in koalas with Chlamydia-related reproductive disease and oxalate nephrosis and the lowest medians were found in koalas with Chlamydia-related conjunctivitis. Higher medians were also found consistently in females (n = 3) and adult koalas. In addition, insignificant negative correlations were found across all biomarkers between age, weight, and body conditioning scores, except for the positive correlation between weight and cortisol and cortisol:DHT. Overall, the consistency of trends and the insignificant differences found across biomarkers in our study suggested that using a single biomarker to assess chronic stress is insufficient, especially for hospital-based studies limited by sample population. Thus, this pilot study provides first step towards developing a koala-specific allostatic load index based on multiple stress biomarkers to understand chronic stress in rescued koalas.

Lay summary

Stress in koalas can be challenging for their welfare and conservation. In this study, we tested plasma glucocorticoids and their ratios as biomarkers of acute and chronic stress. Our finding showed ratios of DHEAS and DHT to cortisol are comparable across stress parameters and animal demographic characteristics. This study serves as a foundational framework for developing a stress index based on multiple biomarkers that could be useful tool for koala welfare.
A cortical locus for modulation of arousal states
Authors: Chintalacheruvu Nithik , Kalelkar Anagha , Boutin Jöel , Breton-Provencher Vincent , Huda Rafiq
Published: May 2024

Fluctuations in global arousal are key determinants of spontaneous cortical activity and function. Several subcortical structures, including neuromodulatory nuclei like the locus coeruleus (LC), are involved in the regulation of arousal. However, much less is known about the role of cortical circuits that provide top-down inputs to arousal-related subcortical structures. Here, we investigated the role of a major subdivision of the prefrontal cortex, the anterior cingulate cortex (ACC), in arousal modulation. Pupil size, facial movements, heart rate, and locomotion were used as non-invasive measures of arousal and behavioral state. We designed a closed loop optogenetic system based on machine vision and found that real time inhibition of ACC activity during pupil dilations suppresses ongoing arousal events. In contrast, inhibiting activity in a control cortical region had no effect on arousal. Fiber photometry recordings showed that ACC activity scales with the magnitude of spontaneously occurring pupil dilations/face movements independently of locomotion. Moreover, optogenetic ACC activation increases arousal independently of locomotion. In addition to modulating global arousal, ACC responses to salient sensory stimuli scaled with the size of evoked pupil dilations. Consistent with a role in sustaining saliency-linked arousal events, pupil responses to sensory stimuli were suppressed with ACC inactivation. Finally, our results comparing arousal-related ACC and norepinephrinergic LC neuron activity support a role for the LC in initiation of arousal events which are modulated in real time by the ACC. Collectively, our experiments identify the ACC as a key cortical site for sustaining momentary increases in arousal and provide the foundation for understanding cortical-subcortical dynamics underlying the modulation of arousal states.
Complex Chronic Diseases Program: Program Description & Health Outcomes Assessment from a Clinical Data Registry
Authors: Meagher Emily , Magel Tianna , Boulter Travis , Muñoz Carola , Prestley Nicole , Chan Wee-Shian , Bryden Cassandra , Nacul Luis
Published: May 2024

Introduction

The Complex Chronic Diseases Program (CCDP) was funded by the BC Ministry of Health to address gaps in health services provision for Complex Chronic Diseases (CCDs). The Program offers medical interventions and education on self-management for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia (FM), and Chronic Lyme-Like Syndrome (CLLS). The CCDP Data Registry was created in 2017 for monitoring participant outcomes and program evaluation.

Methods

This research outlined the CCDP model of care and analyzed patient-reported questionnaires and clinical data collected longitudinally from consented CCDP Data Registry participants spanning June 2017 through September 2022. T-tests and linear regression modelling were conducted to ascertain changes in symptom presentation across program involvement. These analyses specifically targeted data at the following time points: baseline, 6 months follow-up, and discharge.

Results

Data reported in this study represented 668 eligible participants from the 1-year Program. Demographically, the average age was 49 years old (SD=13), 90% were women (n=557), 54% were diagnosed with ME/CFS and FM (n=360), and 36% reported being on long term illness/disability (n=219). Between baseline and discharge, participants with ME/CFS and FM reported improvements in overall physical and mental health, but no significant improvement in other symptom domains such as sleep, fatigue, and pain. The duration of disease at baseline was only related to sleep quality. The previous, more individualized model of care showed better mental health outcomes at 6-months follow-up.

Discussion

This analysis showed that CCDP patients experienced relatively severe and persistent symptom presentations. Participants involved in the Program experienced some health benefits at discharge, but further research and interventions are needed to optimize health outcomes. The reliance on self-report of symptoms and the absence of a control group without intervention limit the significance of these findings. A Strategic Direction Plan was developed by the CCDP which emphasized improved training, decentralized services, fast-tracking of eligible individuals, and enhanced education for better patient outcomes.
Amd1-skp2 cascade regulates hepatocyte proliferation during liver growth and hepatocellular carcinoma development in zebrafish
Authors: Zhang Ke , Li Botong , Deng Zhiling , Dong Yong , Li Yuanyuan , Chen Bingyu , Zhao Ming , Lu Mao , Liu Xindong , Guo Zhenhua , Huang Sizhou
Published: May 2024

Rapid hepatocyte proliferation is a common characteristic of liver growth in early liver development and hepatocellular carcinoma (HCC). Clarifying the mechanism how liver growth is regulated in development would benefit studying HCC progress. Although many genes have been reported to be involved in liver growth during early development, the mechanism underlying liver growth is far from being elucidated. Here we found that the liver undergoes rapid growth from 2dpf to 5dpf in zebrafish. Comparing the transcriptome for different staged hepatocytes identified 813 hepatocyte enriched genes at 3 dpf. Among them, S-adenosylmethionine decarboxylase proenzyme (AMD1) had not been previously reported to be involved in liver development. Our study further confirmed that amd1 was highly enriched in hepatocytes during liver rapid growth and that amd1 mutation inhibited liver growth mainly by repressing hepatocyte proliferation. Mechanistically, amd1 loss of function downregulated the expression of skp2, and skp2 is required for amd1 to regulate hepatocyte proliferation. Furthermore, the role of Amd1-Skp2 cascade in regulating hepatocyte proliferation was also conserved in a zebrafish HCC model. In conclusion, our study systematically identified some uncharacterized genes possibly being involved in regulating liver growth during zebrafish development, and revealed the role of amd1-skp2 cascade in regulating hepatocyte proliferation during liver growth and HCC progression. This work also provided a database which would benefit elucidating the mechanism how hepatocyte proliferation is regulated during liver growth and HCC progress.
Hippocampal mGluR5 levels are comparable in Alzheimer’s and control brains, and divergently influenced by amyloid and tau in control brain
Authors: Wang Junlong , Savodalli Serena , Kong Yanyan , Maschio Cinzia A. , Konietzko Uwe , Klohs Jan , Razansky Daniel , Rominger Axel , Mu Linjing , Schibli Roger , Hock Christoph , Nitsch Roger M. , Ni Ruiqing
Published: May 2024

Background

Metabotropic glutamate receptor 5 (mGluR5) modulates excitatory glutamatergic synaptic transmission and plays an important role in learning and memory formation and in neurodegeneration and amyloid deposition in Alzheimer’s disease (AD). Conflicting results on the cerebral mGluR5 levels in AD have been reported based onin vivoand postmortem studies. Here, we aimed to assess alterations in hippocampal mGluR5 expression in AD, and the associations between mGluR5 expression and pathologies.

Methods

Immunofluorescence staining for mGluR5 was performed on postmortem brain tissue from 34 AD patients and 31 nondemented controls (NCs) and from aged 3×Tg and arcAβ model mice of AD. Autoradiography was performed on brain tissue slices from arcAβ mice using mGluR5 tracer [18F]PSS232. Analysis of different cellular source of GRM5 RNA in human and mouse brains was performed. Proteomic profiling and pathway analysis were performed on hippocampal tissue from aged 3×Tg mice and wild-type mice.

Results

No differences in hippocampal mGluR5 expression or entorhinal cortical GRM5 RNA levels were detected between the AD and NC groups. Hippocampal mGluR5 levels increased with Braak stage and decreased with amyloid level in the NC group. No correlations were detected between the levels of mGluR5 and amyloid, tau, or Iba1/P2X7R in the hippocampus of AD patients and NC cases.Ex vivoautoradiography revealed comparable cerebral levels of [18F]PSS232 in arcAβ mice compared to nontransgenic mice. GO and KEGG pathway enrichment analyses revealed that the Shank3, Grm5 and glutamatergic pathways were upregulated in hippocampal tissue from aged 3×Tg mice compared to wild-type mice.

Conclusion

This study revealed no difference in hippocampal mGluR5 levels between AD patients and NCs and revealed the divergent influence of amyloid and tau pathologies on hippocampal mGluR5 levels in NCs. Species differences were observed in the GRM5 RNA level as well as at the cellular location.

Graphical abstract
AlphaFold3, a secret sauce for predicting mutational effects on protein-protein interactions
Authors: Lu Wei , Zhang Jixian , Rao Jiahua , Zhang Zhongyue , Zheng Shuangjia
Published: May 2024

AlphaFold3 has set the new state-of-the-art in predicting protein-protein complex structures. However, the complete picture of biomolecular interactions cannot be fully captured by static structures alone. In the field of protein engineering and antibody discovery, the connection from structure to function is often mediated by binding energy. This work benchmarks AlphaFold3 against SKEMPI, a commonly used binding energy dataset. We demonstrate that AlphaFold3 learns unique information and synergizes with force field, profile-based, and other deep learning methods in predicting the mutational effects on protein-protein interactions. We hypothesize that AlphaFold3 captures a more global effect of mutations by learning a smoother energy landscape, but it lacks the modeling of full atomic details that are better addressed by force field methods, which possess a more rugged energy landscape. Integrating both approaches could be an interesting future direction. All of our benchmark results are openly available athttps://github.com/luwei0917/AlphaFold3_PPI.
lncRNA ADEPTR loss-of-function elicits sex-specific behavioral and spine deficits
Authors: Chanda Kaushik , Carter Jackson P. , Nishizono Hirofumi , Raveendra Bindu L , Brantley Alicia , Grinman Eddie , Espadas Isabel , Lozano-Villada Sebastien , Wingfield Jenna , Wagner Grace , Peterson Amy , Yasuda Ryohei , Puthanveettil Sathyanarayanan V
Published: May 2024

Activity-dependent changes in neuronal connections are fundamental to learning and long-term memory storage. However, the precise contribution of long noncoding RNAs (lncRNAs) to these modifications remains unclear. In this study, we assessed the role of the lncRNA ADEPTR, a cAMP-modulated lncRNA localized in dendrites, which is crucial for synapse morphology. By generating two different mouse models—one with a deletion of ADEPTR (L-ADEPTR) and one with a deletion of its protein interaction region (S-ADEPTR)—we investigated the sex-specific impacts of ADEPTR loss of function on learning, memory, dendritic arborization, and synapse morphology. Our behavioral analyses revealed a reduction in anxiety in adult male mice, while learning and memory remained unaffected in both models. Systematic evaluations of neuronal morphology across various developmental stages (∼3-day-old postnatal neuronal cultures and postnatal 14- and 42-day-old male and female mice) uncovered substantial deficits in neuronal architecture in both S- and L-ADEPTR male and female neuronal cultures. At postnatal day 42, in contrast to their male counterparts, L-ADEPTR female mice exhibited a significant deficiency in thin spines. Additionally, we found that the expression of plasticity-related gene BDNF, and immediate early gene cFOS were enhanced in both the cortex and hippocampus of adult male and female S- and L-ADEPTR mice, suggesting the activation of a compensatory mechanism protecting against learning and memory deficits. Collectively, these observations underscore the sex-specific role of lncRNA ADEPTR in shaping neuronal morphology and anxiety behavior.
A Wireless Network of Implantable Microstimulators for Addressable and Patterned Electrical Brain Stimulation
Authors: Lee J. , Lee A. H. , Leung V. , Larson L. , Nurmikko A.
Published: May 2024

Transmitting meaningful information into brain circuits by electronic means is a challenge facing brain-computer interfaces. A key goal is to find an approach to inject spatially structured local current stimuli across swaths of sensory areas of the cortex. Here, we introduce a fully wireless approach to multipoint patterned electrical microstimulation by a spatially distributed epicortically implanted network of silicon microchips to target specific areas of the cortex. Each sub-millimeter-sized microchip harvests energy from an external radio-frequency source and converts this into biphasic current injected focally into tissue by a pair of integrated microwires. The amplitude, period, and repetition rate of injected current from each chip are controlled across the implant network by implementing a pre-scheduled, collision-free bitmap wireless communication protocol featuring sub-millisecond latency. As an in vivo demonstration, a network of 30 wireless stimulators was chronically implanted into motor and sensory areas of the cortex in a freely moving rat for three months. We explored the effects of patterned intracortical electrical stimulation on trained animal behavior at average RF powers well below safety limits.
Protocol for the Development of Artificial Intelligence Models for the Reduction of Surgical Complications Based on Intraoperative Video - Surg_Cloud project
Authors: Soares Antonio Sampaio , Bano Sophia , Castro Laura T , Rocha Ricardo , Alves Paulo , Mira Paulo , Costa João , Chand Manish , Stoyanov Danail
Published: May 2024

Introduction

Complications following abdominal surgery have a very significant negative impact on the patient and the health care system. Despite the spread of minimally invasive surgery, there is no automated way to use intraoperative video to predict complications. New developments in data storage capacity and artificial intelligence algorithm creation now allow for this opportunity.

Methods

Development of deep learning algorithms through supervised learning based on the Clavien-Dindo scale to categorise postoperative outcomes in minimally invasive abdominal surgery. An open-source dataset will be built, which will not only include intraoperative variables but also data related to patient outcomes, making it more generalisable and useful to the scientific community. This dataset will be shared under a non-commercial use license to promote scientific collaboration and innovation.

Expected Results

The planned outputs include the publication of a research protocol, main results, and the open-source dataset. Through this initiative, the project seeks to significantly advance the field of artificial intelligence-assisted surgery, contributing to safer and more effective practice.
Psychopharmacoepidemiological trends in the Portuguese territory during the pandemic and post-pandemic periods (2019–2022)
Authors: Belchior David , Madeira Luís , Henriques Rui
Published: May 2024

The increasing prevalence of mental health disorders has been matched with growing psychotropic drug consumption rates around the world. Assessing psychopharmacoepidemiological trends and their determinants is essential to guide medical care delivery and public health policies. However, nation-wide studies on up-to-date consumption patterns are scarce and generally disregard important pharmacological, medical, sociodemographic, and economic covariates. Previous studies on the Portuguese case, a case known for critically high consumption rates of benzodiazepines and antidepressants, are limited to the COVID-19 pre-pandemic period. This study uses the full (electronic) dispensation registry of antidepressants, benzodiazepines and zolpidem, antipsychotics and mood stabilisers in Portugal during the years of 2019 to 2022 with the goal of identifying relevant prescription and consumption patterns prior to, during and after the COVID-19 pandemic. Our findings show a consumption growth trend in antidepressants (7.41% yearly DIDs,P= 0.0215) accelerated since 2020, confirmed by the growing number of users (over 15% of the population), overtaking benzodiazepines and zolpidem as the class with most active users. The total annual expenditure has increased 14M€ between 2020 and 2022 (nearly 2M€ in public copayment), notwithstanding price drops in diverse antipsychotic drugs.
High plasma D-dimer levels correlate with ictal infarction and poor outcomes in spontaneous subarachnoid hemorrhage
Authors: Kobata Hitoshi , Sugie Akira , Tucker Adam , Sarapuddin Gemmalynn , Kimura Hitomi , Takeshita Hitoshi , Morihara Munenori , Kawakami Makiko
Published: May 2024

Structured Abstract

BACKGROUND

Early brain injury (EBI) is the leading cause of poor outcomes in patients with spontaneous subarachnoid hemorrhage (sSAH). Plasma D-dimer levels and acute cerebral ischemia have been highlighted as relevant findings in EBI; however, their correlation has not been substantially investigated.

METHODS

This retrospective, single-center cohort study was conducted at a tertiary emergency medical center from January 2004 to June 2022. Consecutive patients with sSAH who presented within 12 h of SAH ictus and underwent magnetic resonance imaging within 3 days were included. We assessed the correlation of plasma D-dimer levels with acute ischemic lesions detected on the diffusion-weighted images (DWI) and the clinical characteristics of patients.

RESULTS

Among 402 eligible patients (mean age, 63.5 years; 62.7% women; median time from onset to arrival, 45.5 min), 140 (34.8%) had acute ischemic lesions. Higher plasma D-dimer levels linearly correlated with worse neurological grades, more severe SAH on initial CT, acute ischemic lesions, and poor outcomes, except for patients with neurogenic stunned myocardium. In the multivariate analysis, acute ischemic lesions were significantly associated with worse neurological grades, higher plasma D-dimer levels, bilateral loss of light reaction, and advanced age. The receiver operating characteristic curve analysis showed D-dimer levels as excellent predictors for acute ischemic lesions (area under the curve [AUC], 0.897; cut-off value, 5.7 µg/mL; p <0.0001) and unfavorable outcomes (AUC, 0.786; cut-off value, 4.0 µg/mL; p <0.0001).

CONCLUSIONS

High plasma D-dimer levels correlated with the appearance of acute ischemic lesions on DWI and were dose-dependently associated with worse neurological grades, more severe hemorrhage, and worse outcomes. Plasma D-dimer levels provide a valuable perspective on various issues in the acute phase of sSAH.
Deep Learning Detection of Subtle Torsional Eye Movements: Preliminary Results
Authors: Mukunda Krishna , Ye Tianyi , Luo Yi , Zoitou Asimina , Kwon Kyungmin (Esther) , Singh Richa , Woo JiWon , Sivakumar Nikita , Greenstein Joseph L. , Taylor Casey Overby , Kheradmand Amir , Green Kemar Earl
Published: May 2024

The control of torsional eye position is a key component of ocular motor function. Ocular torsion can be affected by pathologies that involve ocular motor pathways, spanning from the vestibular labyrinth of the inner ears to various regions of the brainstem and cerebellum. Timely and accurate diagnosis enables efficient interventions and management of each case which are crucial for patients with dizziness, vertical double vision, or imbalance. Such detailed evaluation of eye movements may not be possible in all frontline clinical settings, particularly for detecting torsional abnormalities. These abnormalities are often more challenging to identify at the bedside compared to horizontal or vertical eye movements. To address these challenges, we used a dataset of torsional eye movements recorded with video-oculography (VOG) to develop deep learning models for detecting ocular torsion. Our models achieve 0.9308 AUROC and 86.79 % accuracy, leveraging ocular features particularly pertinent to tracking torsional eye position.
Perirhinal and postrhinal cortices are necessary for retrieving latently-acquired stimulus associations
Authors: Peng Xiangyuan , Burwell Rebecca D.
Published: May 2024

The perirhinal and postrhinal cortices reside in the parahippocampal region of the medial temporal lobe. They receive and process sensory information from cortical and subcortical sources and support hippocampal functions via direct connectivity and indirectly via the entorhinal cortex. Previous studies using the sensory preconditioning paradigm have shown that the perirhinal and postrhinal cortices are necessary for associating cues during preconditioning and retrieving the associations during conditioning. However, the question of whether these regions are also required for stimulus association retrieval during re-exposure to the preconditioning cue had not been addressed. Using a chemogenetic approach, we temporarily suppressed the perirhinal or postrhinal cortex in adult male rats during the preconditioning cue test phase. Both suppression groups showed impaired sensory preconditioning compared to sham surgery controls, as indicated by significantly reduced preferential responding. Implications of our findings are discussed in relation to the importance of the PER and POR in context processing and episodic-like memory in animal models.

Significance statement

Although Pavlovian conditioning between two stimuli is widely used in neuroscience, associative learning in the real-world is often too complex to be modeled by first-order conditioning alone. Proper responding may require integrating multiple associations via common elements, i.e. higher-order conditioning, the neural basis of which is not well understood. Whereas existing research indicates the perirhinal and postrhinal cortices in the medial temporal lobe contribute to certain forms of sensory preconditioning (SPC, a type of higher-order conditioning), we suggest their contributions lie in the encoding and retrieving latently acquired associations, processes which are central to all forms of SPC. We argue this interpretation also captures perirhinal and postrhinal contributions to contextual and episodic memory, hence offering a unifying explanation regarding the contributions of these cortices across multiple paradigms.
“Value” emerges from imperfect memory
Authors: Ramírez-Ruiz Jorge , Ebitz R. Becket
Published: May 2024

Whereas computational models of value-based decision-making generally assume that past rewards are perfectly remembered, biological brains regularly forget, fail to encode, or misremember past events. Here, we ask how realistic memory retrieval errors would affect decision-making. We build a simple decision-making model that systematically misremembers the timing of past rewards but performs no other value computations. We call these agents “Imperfect Memory Programs” (IMPs) and their single free parameter optimizes the trade-off between the magnitude of error and the complexity of imperfect recall. Surprisingly, we found that IMPs perform better than a simple agent with perfect memory in multiple classic decision-making tasks. IMPs also generated multiple behavioral signatures of value-based decision-making without ever calculating value. These results suggest that mnemonic errors (1) can improve, rather than impair decision-making, and (2) provide a plausible alternative explanation for some behavioral correlates of “value”.
Pregnant women as a sentinel population for genomic surveillance of malaria in the Democratic Republic of Congo
Authors: Onyamboko Marie , Wasakul Varanya , Bakomba Sarah Benie , Kayembe Daddy Kalala , Nzambiwishe Bejos Kifakiou , Ekombolo Pascal Epe , Badjanga Benjamen Basara , Maindombe Jean-Robert Moke , Ngavuka Jephte Ndundu , Lwadi Brunette Nsunda , Drury Eleanor , Ariani Cristina , Goncalves Sonia , Chamsukhee Vanapol , Waithira Naomi , Verschuuren Tess D. , Lee Sue J. , Miotto Olivo , Fanello Caterina
Published: May 2024

Genomic surveillance is a valuable tool for detecting changes in the drug susceptibility of malaria parasites, allowing early modification of treatment strategies. However, implementation can be costly and problematic to set up in fragile and high-burden countries, especially when targeting cohorts of children. To address these challenges, we investigated whether in the Democratic Republic of Congo pregnant women attending antenatal care (ANC) services could act as a surrogate sentinel population. Between 2021 and 2023, we conducted a study in Kinshasa, targeting 4,001 pregnant women attending ANCs, and 2,794 children living in the same area. Blood samples from malaria-positive cases were genotyped using an amplicon sequencing platform, to allow comparisons ofPlasmodium falciparumgenomes between the two cohorts and estimations of drug-resistance mutations prevalence. Parasite populations sampled from the two cohorts exhibited highly similar allele frequencies at all tested loci, including drug resistance markers potentially under selection. Pregnant women did not have higher frequencies of sulphadoxine-pyrimethamine resistant haplotypes, which undermine preventive treatments, than children, and we did not find anykelch13mutation at significant frequency. Although parasite densities were lower in adults, the complexity of infection was similar to that in children. There was no evidence ofPlasmodium vivaxinfections in the study. A cohort of pregnant women produces highly similar results to those from children, allowing the implementation of simple and efficient genomic surveillance systems integrated into routine ANC activities, while benefitting women with diagnosis and treatment. ClinicalTrials.gov Identifier:NCT05072613.
Central bank digital currencies: a comprehensive systematic literature review on worldwide research emergence and methods used
Authors: Fahad Shah , Bulut Mehmet
Published: May 2024

Purpose

The purpose of this paper is to review the literature on Central Bank Digital Currencies (CBDCs) in light of the increasing demand for digital payments globally. It aims to assess the global research landscape, methodologies and data utilized in CBDC studies as their popularity grows.

Design/methodology/approach

The paper employs a systematic literature review (SLR) framework, utilizing the Scopus database to identify 323 studies related to Central Bank Digital Currency or CBDC. Through a thorough manual screening process, 169 studies were selected for inclusion. The research employs R, Biblioshiny and Excel for data evaluation, classifying the studies into three methodological categories: quantitative, qualitative and mixed approaches. This classification allows for a detailed assessment of the research techniques and data used in the literature on CBDCs.

Findings

The findings include a diverse range of research methodologies and data employed in CBDCs literature, highlighting the growing interest and depth of academic investigation into this area. By categorizing papers according to research technique, the study provides a comprehensive evaluation of the academic landscape regarding CBDC research. It offers valuable insights for researchers, policymakers and stakeholders, contributing to an enhanced understanding of the complexities and opportunities presented by the development and implementation of CBDCs.

Originality/value

This study’s originality lies in its rigorous and transparent methodology for data from CBDC studies, offering a solid framework for future research. By evaluating global research growth within an SLR framework and categorizing studies by research technique, it contributes uniquely to the academic discourse on digital currencies. The paper provides a critical resource for researchers, lawmakers and stakeholders, enriching the knowledge base on CBDCs and supporting informed decision-making in the context of digital financial innovation.
Impact of innovation, entrepreneurial orientation and entrepreneurial leadership on supply chain resilience in handicraft industry: moderating role of supply chain orientation
Authors: Yadav Uma Shankar , Tripathi Ravindra
Published: May 2024

Purpose

The study aims to explore dynamic capabilities such as innovation, entrepreneurial leadership, absorptive capability, and the dimension of entrepreneurial orientation in the handicraft sector to enhance supply chain resilience and innovation during unprecedented times. This study also used innovation as a mediating construct and supply chain orientation as a moderating construct.

Design/methodology/approach

We gathered data from the handicraft sector in the Uttar Pradesh (UP) in India using a pretested questionnaire. We used variance-based partial least squares structural equation modelling (PLS-SEM) to test our research hypotheses.

Findings

Our study indicates that to enhance innovation and improve supply chain resilience, firms should focus on developing dynamic capabilities such as entrepreneurial leadership, absorptive capacity, artificial intelligence (AI), innovativeness, risk-taking ability, and protectiveness. The study highlights the significant role of dynamic capabilities in the handicraft sector during times of crisis, enabling innovation and resilience to risk.

Practical implications

The study highlights the significant role of dynamic capabilities in the handicraft sector during times of crisis, enabling innovation and resilience to risk.

Originality/value

This study provides significant insights into the current understanding of dynamic capability theory and supply chain orientation and expands upon the existing literature in this field. It comprehensively analyses the latest research and advances knowledge in this area.
Does off-farm work induce farmland abandonment? Evidence from China
Authors: Zheng Linyi
Published: May 2024

Purpose

This study investigates whether, how and under what circumstances off-farm work induces farmland abandonment, which is of great importance for developing countries to cope with food security.

Design/methodology/approach

Exploiting large-scale panel data from the newly released Chinese Family Database, this study employs a two-way fixed effects model to empirically estimate the causal relationship between off-farm work and farmland abandonment.

Findings

In the context of large-scale labor migration in rural China, current off-farm work leads to an increase in the probability and area of farmland abandoned due to insufficient agricultural labor. However, off-farm work does not harm farm households in plain areas, or villages with land rental markets, abundant agricultural labor, and agricultural machinery, while it harms others. Moreover, farmers who work off-farm in the local area are less likely to abandon their farmland than those in other areas. Additionally, when the number of off-farm workers in a household exceeds two, the probability and area of farmland abandonment will miraculously decline, as the household will no longer live entirely on agriculture.

Originality/value

This study may fill the gap in clarifying the relationship between off-farm work and farmland abandonment, and identify scenarios where off-farm work may not cause farmland abandonment through multiple dimensions, providing insights into the governance of farmland abandonment during rural-urban transformation in developing countries.
Place-based rural development programs and the labor allocation of farm households
Authors: Liu Jhih-Yun , Lee Brian , Chang Hung-Hao
Published: May 2024

Purpose

Rural development programs are widely used policy instruments mitigating rural-urban economic disparities. Yet, little research has examined their effect on rural labor. This study fills this knowledge gap by quantifying the causal impact of such programs on the labor allocation of farm households in Taiwan.

Design/methodology/approach

A theoretical framework based on the agricultural household model is constructed to guide the empirical specification. A unique dataset compiles administrative data on the program’s subsidies with farm household surveys across seven years. To cope with endogeneity bias, an instrumental variables model is applied. The eligibility rule for a township to participate in the program is used as the instrument.

Findings

We find that the program increases the labor supply of farm household members. These effects are more pronounced for off-farm work, particularly non-heads of farm households. The program’s subsidies supporting culture and promotion-related activities have larger effects. Finally, females benefited more from the program.

Originality/value

We focus on farm households since this group is the target of place-based rural development programs. In addition, we identify the causal impact of place-based development programs on rural labor. Finally, this study is relevant to the literature on intra-household models by demonstrating that place-based rural development programs can affect the labor supply of farm household members.