bluuebunny/crossref_metadata_2025 huggingface dataset:
High-grade Solid Pseudopapillary Neoplasms of the Pancreas
Authors: Honda Shogo , Yamaguchi Hiroshi , Aimono Eriko , Hara Shigeo , Minamiguchi Sachiko , Norose Tomoko , Ohike Nobuyuki , Yamochi Toshiko , Yasuda Masanori , Moriya Takuya , Shiko Yuki , Nishihara Hiroshi , Nagao Toshitaka
Published: January 2024

Pancreatic solid pseudopapillary neoplasm (SPN) is a low-grade malignant neoplasm with a good prognosis. Clinically aggressive SPNs have rarely been reported but have not been analyzed in detail. In this study, we referred to this highly malignant type of SPN as high-grade SPN (HG-SPN) and compared its clinicopathological and genetic characteristics with conventional SPN (C-SPN) using immunohistochemistry and gene panel analyses. Five HG-SPNs and 15 C-SPNs were evaluated in this study. HG-SPNs share many pathologic characteristics: macroscopically, solid/cystic appearances, microscopically, pseudopapillary/pseudorosette pattern (100%), tumor cell loose cohesiveness (100%), thin/delicate vasculature (100%), tumor cell cytoplasmic vacuolization (100%), immunohistochemical positivity for β-catenin (nuclear expression) (100%), CD10 (80%), CD56 (80%), and vimentin (100%). Conversely, HG-SPNs showed distinct malignant features compared with C-SPNs: mean tumor size (11.7 vs. 2.9 cm, P<0.001); true necrosis (100% vs. 0%, P<0.001); high-grade nuclear atypia (100% vs. 0%, P<0.001); lymphatic and/or venous invasion (100% vs. 20%, P=0.004); mean mitotic count (4.38 vs. 0.05/high-power field, P<0.001); and mean Ki-67 labeling index (33.9% vs. 3.4%, P<0.001). All HG-SPN patients died of primary disease 3 to 36 months after surgery, while all C-SPN patients were alive without disease. Genetic studies have shown that all analyzed HG-SPNs have CTNNB1 mutations. Two HG-SPN cases showed RB1 mutations with altered immunohistochemical findings for RB1 and p16. Two HG-SPN cases had TP53 mutation and/or p53 overexpression. In conclusion, HG-SPNs show distinct malignant features and some genetic alterations that differ from C-SPNs, indicating the importance of differentiating between these 2 subtypes.
Interleukin 6 Levels and Disease Activity in Takayasu Arteritis
Authors: Souza Pedreira Ana Luisa , Leite de Castro Flores Marília , Barreto Santiago Mittermayer
Published: January 2024

Background

Various studies have suggested interleukin 6 (IL-6) as a potential biomarker for detecting disease activity in Takayasu arteritis.

Methods

A systematic review and meta-analysis was performed to assess differences in IL-6 levels in patients with active (aTA) and inactive Takayasu arteritis (iTA), as well as healthy controls (HCs), using validated activity scores. Study quality and the risk of bias were assessed using STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) and the Newcastle-Ottawa and Joanna Briggs checklist, respectively. For the meta-analysis, we pooled the raw mean IL-6 levels in each group and then estimated and pooled the crude mean differences between the groups. We applied a random-effects model in all analyses.

Results

Of the 93 eligible articles, 10 were included after removing duplicates and studies that met the exclusion criteria. Overall, 1825 patients with a mean age ranging from 24 to 40.6 years were included. The pooled levels of IL-6 increased depending on disease activity as follows: HCs: 3.08 (95% confidence interval [CI], 0.88–5.28), iTA: 7.21 (3.61–10.82), and aTA: 22.67 (12.44–32.91) pg/mL. Patients with aTA had higher IL-6 levels than HCs (21.52 [95% CI, −0.43 to 43.47]) and those with iTA (16.69 [95% CI, 5.32–28.06]), whereas IL-6 levels were not different between HCs and patients with iTA (3.62 [95% CI, −13.18 to 20.42]).

Conclusions

Interleukin 6 levels are significantly increased in patients with aTA compared with those with iTA and HCs but not in patients with iTA compared with HCs. More studies are needed to establish the IL-6 cutoff value for assessing disease activity.
Chronic Nonbacterial Osteomyelitis Associated With Familial Mediterranean Fever in Children
Authors: Karaçayir Nihal , Tunçez Şerife , Öner Nimet , Çelikel Elif , Bağlan Esra , Gezgin-Yildirim Deniz , Bakkaloğlu Sevcan A.
Published: January 2024

Objective

Chronic nonbacterial osteomyelitis (CNO) is a noninfectious autoinflammatory bone condition that frequently occurs alongside other inflammatory diseases, such as familial Mediterranean fever (FMF). We aimed to determine the demographic, clinical, laboratory, and radiological characteristics of patients diagnosed with both FMF and CNO.

Methods

We reviewed the medical records of pediatric patients with both CNO and FMF at 3 pediatric rheumatology centers in Turkey from December 2008 to 2022. Patients' demographics, laboratory features, imaging findings, and treatment were recorded.

Results

Twelve patients with FMF and CNO were included in the study. Half of them were girls. The mean ages at onset for FMF and CNO symptoms were 80 and 116 months, whereas the ages at diagnosis for FMF and CNO were 100 and 125 months, respectively. Ten patients (83.3%) had M694V mutation on at least 1 allele of the Mediterranean fever (MEFV) gene. The most common sites of osteitis were the long bones (58.3%), pelvis (50%), and clavicles (25%). Ten patients (83%) received nonsteroidal anti-inflammatory drugs; 8 (66%) received disease-modifying antirheumatic drugs; biological therapy was administered to 5 patients (41%), who did not respond to these treatments; and all patients received colchicine.

Conclusion

The increased frequency of FMF in patients with CNO is of interest. Because most patients with CNO and FMF carried a homozygous or combined heterozygous M694V mutation, we speculated that the M694V mutation may play a role in the development of osteitis. Further studies are needed to elucidate the link between FMF and CNO.
Laparoscopic Median Arcuate Ligament Release: Surgical Technique and Clinical Outcomes
Authors: Belluzzi Amanda , Salame Marita , Abi Mosleh Kamal , Rasmussen Todd E. , Kendrick Michael L. , Ghanem Omar M.
Published: January 2024

Background:

Median arcuate ligament syndrome (MALS) is characterized by a constellation of symptoms related to the compression of the celiac artery trunk. Laparoscopic release of the ligament has demonstrated its effectiveness in alleviating these symptoms while showing lower postoperative complication rates, reduced hospital stays, and improved clinical outcomes. This study describes a single institution’s experience with this procedure and reports on the preoperative assessment, surgical technique, and clinical outcomes of patients with MALS.

Methods:

We performed a retrospective chart review of all patients who underwent a primary laparoscopic MAL release (MALR) at a single high-volume academic institution from June 2021 to July 2023. Patient demographics, preoperative assessment, postoperative complications, and resolution of preoperative symptoms data were collected.

Results:

A total of 30 patients underwent laparoscopic MALR, with 76.7% being female and a mean age of 33.4±16.3 years. The most common presenting symptom was postprandial epigastric pain (100%), followed by abdominal pain and nausea (83.3%), among others. The preoperative evaluation for all patients included a duplex mesenteric doppler and CT angiogram during inspiration and expiration and 3D reconstruction. Successful laparoscopic decompression of the celiac artery was achieved in 96.6% of cases, with only one conversion to an open procedure. There was only one reported early (<30 d postoperatively) complication with no subsequent late complications or mortality. None of the patients required reintervention or reoperation. Only 1 patient required postoperative celiac plexus/splanchnic block injection to alleviate pain.

Conclusions:

MALS can be effectively and safely managed using a laparoscopic approach when performed by an experienced minimally invasive surgeon. Further studies with longer follow-ups are needed to confirm the long-term effectiveness of this technique.
Faster refill in an urban emergency medical services system saves lives: A prospective preliminary evaluation of a prehospital advanced resuscitative care bundle
Authors: Broome Jacob M. , Nordham Kristen D. , Piehl Mark , Tatum Danielle , Caputo Sydney , Belding Cameron , De Maio Valerie J. , Taghavi Sharven , Jackson-Weaver Olan , Harris Charlie , McGrew Patrick , Smith Alison , Nichols Emily , Dransfield Thomas , Rayburn David , Marino Megan , Avegno Jennifer , Duchesne Juan
Published: January 2024

INTRODUCTION

Military experience has demonstrated mortality improvement when advanced resuscitative care (ARC) is provided for trauma patients with severe hemorrhage. The benefits of ARC for trauma in civilian emergency medical services (EMS) systems with short transport intervals are still unknown. We hypothesized that ARC implementation in an urban EMS system would reduce in-hospital mortality.

METHODS

This was a prospective analysis of ARC bundle administration between 2021 and 2023 in an urban EMS system with 70,000 annual responses. The ARC bundle consisted of calcium, tranexamic acid, and packed red blood cells via a rapid infuser. Advanced resuscitative care patients were compared with trauma registry controls from 2016 to 2019. Included were patients with a penetrating injury and systolic blood pressure ≤90 mm Hg. Excluded were isolated head trauma or prehospital cardiac arrest. In-hospital mortality was the primary outcome of interest.

RESULTS

A total of 210 patients (ARC, 61; controls, 149) met the criteria. The median age was 32 years, with no difference in demographics, initial systolic blood pressure or heart rate recorded by EMS, or New Injury Severity Score between groups. At hospital arrival, ARC patients had lower median heart rate and shock index than controls (p ≤ 0.03). Fewer patients in the ARC group required prehospital advanced airway placement (p < 0.001). Twenty-four-hour and total in-hospital mortality were lower in the ARC group (p ≤ 0.04). Multivariable regression revealed an independent reduction in in-hospital mortality with ARC (odds ratio, 0.19; 95% confidence interval, 0.05–0.68; p = 0.01).

CONCLUSION

Early ARC in a fast-paced urban EMS system is achievable and may improve physiologic derangements while decreasing patient mortality. Advanced resuscitative care closer to the point of injury warrants consideration.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
ROBOtic Care Outcomes Project (ROBOCOP) for Acute Gallbladder Pathology
Authors: Greenberg Shannon , Assali Marc Abou , Li Yanli , Bossie Hannah , Neighorn Chris , Wu Esther , Mukherjee Kaushik
Published: January 2024

Background

Robotic cholecystectomy is being increasingly used for patients with acute gallbladder disease who present to emergency department, but clinical evidence is limited. We aimed to compare the outcomes of emergent laparoscopic and robotic cholecystectomies in a large real-world database.

Methods

Patients who received emergent laparoscopic or robotic cholecystectomies from 2020 to 2022 were identified from the Intuitive Custom Hospital Analytics database, based on de-identified extraction of electronic health record data from US hospitals. Conversion to open or subtotal cholecystectomy and complications were defined using ICD10 and/or CPT codes. Multivariate logistic regression with inverse probability treatment weighting (IPTW) was performed to compare clinical outcomes of laparoscopic versus robotic approach after balancing covariates. Cost analysis was performed with activity-based costing and adjustment for inflation.

Results

Of 26,786 laparoscopic and 3,151 robotic emergent cholecystectomy patients being included, 64% were female, 60% were ≥ 45 years, and 24% were obese. Approximately 5.5% patients presented with pancreatitis, and 4% each presenting with sepsis and biliary obstruction. After IPTW, distributions of all baseline covariates were balanced. Robotic cholecystectomy decreased odds of conversion to open (OR 0.68 [95%CI 0.49, 0.93, p = 0.035]), but increased odds of subtotal cholecystectomy (OR 1.64 [95% CI 1.03, 2.60, p = 0.037]). Surgical site infection, readmission, length of stay, hospital acquired conditions, bile duct injury or leak, and hospital mortality were similar in both groups. There was no significant difference in hospital cost.

Conclusions

Robotic cholecystectomy has reduced odds of conversion to open and comparable complications, but increased odds of subtotal cholecystectomy compared to laparoscopic cholecystectomy for acute gallbladder diseases. Further work is required to assess the long-term implications of these differences.

Level of Evidence

III, Therapeutic/Care Management Case-Control (Retrospective)
Factors associated with trauma recidivism in young children
Authors: Stephens Caroline Q. , Melhado Caroline G. , Shui Amy M. , Yap Ava , Moses Willieford , Jensen Aaron R. , Newton Christopher
Published: January 2024

BACKGROUND

Trauma recidivism is associated with future trauma-associated morbidity and mortality. Previous evidence suggests that socioeconomic factors predict trauma recidivism in older children (10–18 years); however, risk factors in US children 10 years and younger have not been studied. We sought to determine the factors associated with trauma recidivism in young children 10 years and younger.

METHODS

We conducted a retrospective cohort study of pediatric trauma patients 10 years and younger who presented to a single American College of Surgeons-verified Level I pediatric trauma center from July 1, 2017, to June 30, 2021. All patients were evaluated for prior injury during trauma registry entry. Characteristics at the index injury were collected via chart review. Patients were geocoded to assess Social Vulnerability Index. Logistic regression examined factors associated with recidivism. Best subset selection was used to compare multivariable models and identify the most predictive and parsimonious model. Statistical significance was set at p < 0.05.

RESULTS

Of the 3,518 patients who presented in the study period, 169 (4.8%) experienced a prior injury. Seventy-six percent (n = 128) had one prior injury presentation, 18% (n = 31) had two prior presentations, and 5.9% (n = 10) had three or more. Falls were the most common mechanism in recidivists (63% vs. 52%, p = 0.009). Child physical abuse occurred in 6.5% of patients, and 0.9% experienced penetrating injury. The majority (n = 137 [83%]) were discharged home from the emergency department. There was no significant difference in the frequency of penetrating injury and child physical abuse between recidivists and nonrecidivists. Following logistic regression, the most parsimonious model demonstrated that recidivism was associated with comorbidities, age, falls, injury location, nontransfer, and racialization. No significant associations were found with Social Vulnerability Index and insurance status.

CONCLUSION

Medical comorbidities, young age, injury location, and falls were primarily associated with trauma recidivism. Support for parents of young children and those with special health care needs through injury prevention programs could reduce trauma recidivism in this population.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level III.
Ccr2-dependent monocytes exacerbate intestinal inflammation and modulate gut serotonergic signaling following traumatic brain injury
Authors: El Baassiri Mahmoud G. , Raouf Zachariah , Jang Hee-Seong , Scheese Daniel , Duess Johannes W. , Fulton William B. , Sodhi Chhinder P. , Hackam David J. , Nasr Isam W.
Published: January 2024

BACKGROUND

Traumatic brain injury (TBI) leads to acute gastrointestinal dysfunction and mucosal damage, resulting in feeding intolerance. C-C motif chemokine receptor 2 (Ccr2+) monocytes are crucial immune cells that regulate the gut's inflammatory response via the brain-gut axis. Using Ccr2ko mice, we investigated the intricate interplay between these cells to better elucidate the role of systemic inflammation after TBI.

METHODS

A murine-controlled cortical impact model was used, and results were analyzed on postinjury days 1 and 3. The experimental groups included (1) sham C57Bl/6 wild type (WT), (2) TBI WT, (3) sham Ccr2ko, and (4) TBI Ccr2ko. Mice were euthanized on postinjury days 1 and 3 to harvest the ileum and study intestinal dysfunction and serotonergic signaling using a combination of quantitative real-time polymerase chain reaction, immunohistochemistry, fluorescein isothiocyanate-dextran motility assays, and flow cytometry. Student's t test and one-way analysis of variance were used for statistical analysis, with significance achieved when p < 0.05.

RESULTS

Traumatic brain injury resulted in severe dysfunction and dysmotility of the small intestine in WT mice as established by significant upregulation of inflammatory cytokines iNOS, Lcn2, TNFα, and IL1β and the innate immunity receptor toll-like receptor 4 (Tlr4). This was accompanied by disruption of genes related to serotonin synthesis and degradation. Notably, Ccr2ko mice subjected to TBI showed substantial improvements in intestinal pathology. Traumatic brain injury Ccr2ko groups demonstrated reduced expression of inflammatory mediators (iNOS, Lcn2, IL1β, and Tlr4) and improvement in serotonin synthesis genes, including tryptophan hydroxylase 1 (Tph1) and dopa decarboxylase (Ddc).

CONCLUSION

Our study reveals a critical role for Ccr2+ monocytes in modulating intestinal homeostasis after TBI. Ccr2+ monocytes aggravate intestinal inflammation and alter gut-derived serotonergic signaling. Therefore, targeting Ccr2+ monocyte-dependent responses could provide a better understanding of TBI-induced gut inflammation. Further studies are required to elucidate the impact of these changes on brain neuroinflammation and cognitive outcomes.
Procedural sedation of adult patients in the emergency department: a best practice implementation project
Authors: Pickens Jessica , Garbo Candon
Published: January 2024

Introduction:

The emergency department is a fast-paced and complex health care setting, where critical care is provided to patients of all ages. However, various environmental factors, such as high patient volumes, overburdened staff, and frequent nurse turnover, can hinder the use of evidence-based practices during procedural sedation. Proper patient monitoring is essential to prevent adverse events during procedural sedation.

Objectives:

The goal of this implementation project was to enhance compliance with best practices for patient monitoring during procedural sedation in the emergency department.

Methods:

The project used the JBI Model of Evidence-Based Healthcare and JBI's Getting Research into Practice (GRiP) tool for implementing evidence-based monitoring practices for adult patients during procedural sedation in the emergency department. A baseline audit was conducted to assess current practice against evidence-based recommendations, followed by the implementation of strategies to improve compliance with best practices. The project concluded with a follow-up audit to determine any improvement in practice.

Results:

The baseline audit revealed 81% overall compliance with evidence-based practice. Three barriers were identified, namely, lack of staff education, increased turnover rate of nurses, and the need for nurses to be mobile during procedural sedation. Strategies were implemented to improve compliance with evidence-based practice. The follow-up audit showed an overall improvement of 95% after project implementation.

Conclusions:

The project improved best practices for patient monitoring during procedural sedation in the emergency department. However, more work remains to be done to ensure the sustainability of the best practices, including monitoring of end-tidal capnography and vital sign assessment.
Interactive effects of intrinsic and extrinsic factors on metabolic rate
Authors: Glazier Douglas S. , Gjoni Vojsava
Published: January 2024

Metabolism energizes all biological processes, and its tempo may importantly influence the ecological success and evolutionary fitness of organisms. Therefore, understanding the broad variation in metabolic rate that exists across the living world is a fundamental challenge in biology. To further the development of a more reliable and holistic picture of the causes of this variation, we review several examples of how various intrinsic (biological) and extrinsic (environmental) factors (including body size, cell size, activity level, temperature, predation and other diverse genetic, cellular, morphological, physiological, behavioural and ecological influences) can interactively affect metabolic rate in synergistic or antagonistic ways. Most of the interactive effects that have been documented involve body size, temperature or both, but future research may reveal additional ‘hub factors’. Our review highlights the complex, intimate inter-relationships between physiology and ecology, knowledge of which can shed light on various problems in both disciplines, including variation in physiological adaptations, life histories, ecological niches and various organism-environment interactions in ecosystems. We also discuss theoretical and practical implications of interactive effects on metabolic rate and provide suggestions for future research, including holistic system analyses at various hierarchical levels of organization that focus on interactive proximate (functional) and ultimate (evolutionary) causal networks.

This article is part of the theme issue ‘The evolutionary significance of variation in metabolic rates’.
Heat tolerance in
Drosophila melanogaster
is influenced by oxygen conditions and mutations in cell size control pathways
Authors: Privalova Valeriya , Sobczyk Łukasz , Szlachcic Ewa , Labecka Anna Maria , Czarnoleski Marcin
Published: January 2024

Understanding metabolic performance limitations is key to explaining the past, present and future of life. We investigated whether heat tolerance in actively flying
Drosophila melanogaster
is modified by individual differences in cell size and the amount of oxygen in the environment. We used two mutants with loss-of-function mutations in cell size control associated with the target of rapamycin (TOR)/insulin pathways, showing reduced (mutant
rictor
Δ2
) or increased (mutant
Mnt
1
) cell size in different body tissues compared to controls. Flies were exposed to a steady increase in temperature under normoxia and hypoxia until they collapsed. The upper critical temperature decreased in response to each mutation type as well as under hypoxia. Females, which have larger cells than males, had lower heat tolerance than males. Altogether, mutations in cell cycle control pathways, differences in cell size and differences in oxygen availability affected heat tolerance, but existing theories on the roles of cell size and tissue oxygenation in metabolic performance can only partially explain our results. A better understanding of how the cellular composition of the body affects metabolism may depend on the development of research models that help separate various interfering physiological parameters from the exclusive influence of cell size.

This article is part of the theme issue ‘The evolutionary significance of variation in metabolic rates’.
Individual variation in thermally induced plasticity of metabolic rates: ecological and evolutionary implications for a warming world
Authors: Gvoždík Lumír
Published: January 2024

Energy metabolism is a fundamental property of life providing the energy for all processes and functions within an organism. As it is temperature-dependent, it mediates the effects of changing climate on ectotherm fitness and population dynamics. Though resting metabolic rate is a highly labile trait, part of its variation is individually consistent. Recent findings show that resting metabolic rate contains consistent variation not only in the elevations (intercepts) but also in the slopes of individual thermal dependence curves, challenging the thermal dependence assumption for this trait in several ectotherm taxa. I argue that among-individual variation in thermal metabolic curves represents a previously undetected component of ectotherm response to climate change, potentially affecting their adaptive capacity and population resilience under increasing stochasticity of thermal environment. Future studies need to examine not only the amount of among-individual variation in thermal metabolic curves across phylogenetic contexts but also other aspects concerning its mechanisms and adaptive significance to improve predictions about the impact of climate change on ectotherm population dynamics.

This article is part of the theme issue ‘The evolutionary significance of variation in metabolic rates’.
A historical sequence deletion in a commonly usedBacillus subtilischromosome integration vector generates undetected loss-of-function mutations
Authors: Dierksheide K. Julia , Li Gene-Wei
Published: January 2024

Since the 1980s, chromosome-integration vectors have been used as a core method of engineeringBacillus subtilis. One of the most frequently used vector backbones contains chromosomally derived regions that direct homologous recombination into theamyElocus. Here, we report a gap in the homology region inherited from the originalamyEintegration vector, leading to erroneous recombination in a subset of transformants and a loss-of-function mutation in the downstream gene. Internal to the homology arm that spans the 3′ portion ofamyEand the downstream geneldh, an unintentional 227-bp deletion generates two crossover events. The major event yields the intended genotype, but the minor event, occurring in ∼10% of colonies, results in a truncation ofldh, which encodes lactate dehydrogenase. Although both types of colonies test positive foramyEdisruption by starch plating, the potential defect in fermentative metabolism may be left undetected and confound the results of subsequent experiments.
Deep Learning Analysis on Images of iPSC-derived Motor Neurons Carrying fALS-genetics Reveals Disease-Relevant Phenotypes
Authors: Atmaramani Rahul , Dreossi Tommaso , Ford Kevin , Gan Lin , Mitchell Jana , Tu Shengjiang , Velayutham Jeevaa , Zeng Haoyang , Chickering Michael , Soare Tom , Sivanandan Srinivasan , Conrad Ryan , Bao Yujia , Akle Santiago , Liu Jonathan , Redmond Stephanie , Guo Syuan-Ming , Conrad Patrick , Yi Flora , Atkeson Nick , Xu Difei , McMorrow Aidan , Hergenreder Emiliano , Hari Mukund , Sandakli Ahmed , Mittal Nitya , Zhang Liyuan , Topol Aaron , Hartley Brigham , Lam Elaine , Krauel Eva-Maria , Karaletsos Theofanis , Labow Mark , Hargreaves Richard , Trotter Matthew , Biswas Shameek , Pisco Angela Oliveira , Kaykas Ajamete , Koller Daphne , Sances Samuel
Published: January 2024

Amyotrophic lateral sclerosis (ALS) is a devastating condition with very limited treatment options. It is a heterogeneous disease with complex genetics and unclear etiology, making the discovery of disease-modifying interventions very challenging. To discover novel mechanisms underlying ALS, we leverage a unique platform that combines isogenic, induced pluripotent stem cell (iPSC)-derived models of disease-causing mutations with rich phenotyping via high-content imaging and deep learning models. We introduced eight mutations that cause familial ALS (fALS) into multiple donor iPSC lines, and differentiated them into motor neurons to create multiple isogenic pairs of healthy (wild-type) and sick (mutant) motor neurons. We collected extensive high-content imaging data and used machine learning (ML) to process the images, segment the cells, and learn phenotypes. Self-supervised ML was used to create a concise embedding that captured significant, ALS-relevant biological information in these images. We demonstrate that ML models trained on core cell morphology alone can accurately predict TDP-43 mislocalization, a known phenotypic feature related to ALS. In addition, we were able to impute RNA expression from these image embeddings, in a way that elucidates molecular differences between mutants and wild-type cells. Finally, predictors leveraging these embeddings are able to distinguish between mutant and wild-type both within and across donors, defining cellular, ML-derived disease models for diverse fALS mutations. These disease models are the foundation for a novel screening approach to discover disease-modifying targets for familial ALS.
Information-based rhythmic transcranial magnetic stimulation accelerates learning during auditory working memory training
Authors: Whittaker Heather T. , Khayyat Lina , Fortier-Lavallée Jessica , Laverdière Megan , Bélanger Carole , Zatorre Robert J. , Albouy Philippe
Published: January 2024

Rhythmic transcranial magnetic stimulation (rhTMS) has been shown to enhance auditory working memory manipulation, specifically by boosting theta oscillatory power in the dorsal auditory pathway during task performance. It remains unclear whether these enhancements i) persist beyond the period of stimulation, ii) if they can accelerate learning and iii) if they would accumulate over several days of stimulation. In the present study, we investigated the lasting behavioural and electrophysiological effects of applying rhTMS over the left intraparietal sulcus (IPS) throughout the course of seven sessions of cognitive training on an auditory working memory task. Fourteen neurologically healthy participants took part in the training protocol with an auditory working memory task while being stimulated with either theta (5Hz) rhTMS or sham TMS. Electroencephalography (EEG) was recorded before, throughout five training sessions and after the end of training to assess to effects of rhTMS on behavioural performance and on oscillatory entrainment of the dorsal auditory network. We show that this combined approach enhances theta oscillatory activity within the fronto-parietal network and causes improvements in auditory working memory performance. We show that compared to individuals who received sham stimulation, cognitive training can be accelerated when combined with optimized rhTMS, and that task performance benefits can outlast the training period by up to 3 days. Furthermore, we show that there is increased theta oscillatory power within the recruited dorsal auditory network during training, and that sustained EEG changes can be observed up to 3 days following stimulation. The present study improves our understanding of the causal dynamic interactions supporting auditory working memory. Our results constitute an important proof of concept for the potential translational impact of non-invasive brain stimulation protocols and provide preliminary data for developing optimized rhTMS and training protocols that could be implemented in clinical populations.
Molecular, physiological and functional features underlying cortical thinning related to antipsychotic medication use
Authors: Tuominen Lauri , Armio Reetta-Liina , Hansen Justine Y. , Walta Maija , Koutsouleris Nikolaos , Laurikainen Heikki , Salokangas Raimo K.R. , Misic Bratislav , Hietala Jarmo
Published: January 2024

Use of antipsychotic medication is related to thinning of the cerebral cortex, but the underlying mechanisms of this effect remain largely unknown. Here, we investigated potential mechanisms across multiple levels of description, from molecular and physiological factors to whole-brain functional patterns. We first analyzed a single site discovery sample of patients (N=131) with early psychosis for whom antipsychotic related cortical thinning was estimated based on lifetime exposure to antipsychotics. Findings were replicated using data from a large (N≥2168) ENIGMA meta-analysis. We discovered that antipsychotic related cortical thinning is associated with a number of neurotransmitter systems, most notably the serotonin system, physiological measures, and functional networks and neural oscillatory power distributions typical for regions subserving higher cognition. At the functional level, antipsychotic related cortical thinning affects regions involved in executive function and motivation, but not perception. These results show how molecular, physiological, and large-scale functional patterns underlie antipsychotic related cortical thinning.
A Comparative Machine Learning Study of Connectivity-Based Biomarkers of Schizophrenia
Authors: Shevchenko Victoria , Benn R. Austin , Scholz Robert , Wei Wei , Pallavicini Carla , Klatzmann Ulysse , Alberti Francesco , Satterthwaite Theodore D. , Wassermann Demian , Bazin Pierre-Louis , Margulies Daniel S.
Published: January 2024

Functional connectivity holds promise as a biomarker of psychiatric disorders. Yet, its high dimensionality, combined with small sample sizes in clinical research, increases the risk of overfitting when the aim is prediction. Recently, low-dimensional representations of the connectome such as macroscale cortical gradients and gradient dispersion have been proposed, with studies noting consistent gradient and dispersion differences in psychiatric conditions. However, it is unknown which of these derived measures has the highest predictive capacity and how they compare to raw connectivity. Our study evaluates which connectome features — functional connectivity, gradients, or gradient dispersion — best identify schizophrenia. Figure 1 summarizes this work.

Surprisingly, our findings indicate that functional connectivity outperforms its low-dimensional derivatives such as cortical gradients and gradient dispersion in identifying schizophrenia. Additionally, we demonstrated that the edges which contribute the most to classification performance are the ones connecting primary sensory regions.
Beta-Cell Pyroptosis – A Burning Flame in Type 1 Diabetes?
Authors: Frørup Caroline , Svane Cecilie Amalie Søndergaard , Henriksen Kristine , Kaur Simranjeet , Størling Joachim
Published: January 2024

Immune-mediated destruction of the beta-cells in the pancreatic islets of Langerhans is the underlying cause of type 1 diabetes (T1D). Despite decades of research, the exact mechanisms involved at the beta-cell level during the development of disease remain poorly understood. This includes the mode(s) of beta-cell death and signaling events implicated in exacerbating local islet inflammation and immune cell infiltration, commonly known as insulitis. In disease models, beta-cell apoptosis seems to be the predominant cell death form which has led to the general assumption that beta cells mostly die by apoptosis in T1D. However, apoptosis is an anti-inflammatory programmed cell death mechanism, and this dogma is therefore challenged by the pathogenetic nature of T1D, as a progressive increase in islet inflammation is seen. This infers that other modes of beta-cell death that inherently increase insulitis may predominate. One such mechanism could be the newly characterized form of programmed cell death; pyroptosis (from the Greek “fire–falling”). Pyroptosis is characterized by gasdermin-mediated cell lysis with a bursting release of pro-inflammatory factors. Beta-cell death by pyroptosis in T1D may therefore offer a plausible explanation for the exacerbated paracrine islet inflammation that spreads during the progression of insulitis. Here, we briefly debate the evidence supporting beta-cell pyroptosis in T1D as a central mechanism of islet inflammation and beta-cell demise. The paper intends to challenge the current understanding of beta-cell destruction to move the field forward. Importantly, we present experimental data from human islets and EndoC-βH5 cells that directly support beta-cell pyroptosis as a rational death mechanism in T1D. We suggest a model of beta-cell demise in T1D in which pyroptosis plays a prominent role in concert with other cell death mechanisms. As the role of pyroptosis in disease is still in its infancy, we hope also to inspire researchers working in other disease fields.
Arf GTPase-activating protein ASAP1 specifically binds to 440-kD ankyrin-B
Authors: Li Yubing , Zhao Yipeng , He Yaojun , Zhang Mingjie , Chen Keyu
Published: January 2024

The 440-kD giant ankyrin-B (gAnkB) exclusively localizes to axons and is essential for axon development. However, proteins that specifically bind to gAnkB but not to other isoforms of ankyrins are poorly understood. Here, we discovered that an Arf GTPase-activating protein ASAP1 and ASAP2 specifically binds to a short and disordered sequence unique to gAnkB. Biochemical studies showed that the SH3 domain of ASAP1 binds to a 12-residue, positively charged peptide fragment from gAnkB. The high-resolution structure of the ASAP1-SH3 domain in complex with the gAnkB peptide revealed the mechanism underlying this non-canonical SH3 domain-mediated target recognition. Further structural and bioinformatic analysis revealed additional previously unknown ASAP1-SH3 binding partners including Clasp1 and Clasp2, both of which are well-known microtubule regulators. Among all known ASAP1-SH3 binders including those identified in the current study, gAnkB has the strongest affinity in binding to ASAP1. Our results suggest that ASAP1 may function together with gAnkB in regulating axonal cytoskeletons.
Studies of vegetation and land-use history on Bodmin Moor: pollen investigations from Leskernick
Authors: Waller Martyn
Published: January 2024

Details of pollen investigations that accompanied archaeological excavations (of a Late Neolithic/Early Bronze ritual complex and a Middle to Late Bronze Age settlement) at Leskernick Hill Bodmin Moor, undertaken between 1995 and 1999, are presented. Samples were collected both from a nearby ‘off-site’ location and from a variety of ‘on-site’ contexts. The off-site peat profile contains a major hiatus. The earliest assemblage corresponds to the Late Neolithic/Early Bronze Age and indicates a largely open landscape in which both pasture and arable agriculture were practiced. Sedimentation recommenced during the early Medieval period and the pollen record shows the varying degrees to which grazing and arable agriculture were practiced up until the recent past. These phases do not accord well with historic evidence from the wider area, though other pollen diagrams from the region also record a wetter phase found at Leskernick (and dated here toc. 1400-1600 AD). Evidence obtained during the archaeological excavations suggests the ritual complex was abandoned early and the pollen records indicate this was accompanied by a period of low grazing pressure. Samples from the interiors of huts/houses dated to the Middle Bronze Age are dominated by Poaceae pollen suggesting relatively intense human activity. The assemblages from beneath the boundary walls around the settlement probably cover a considerable time period, in part as a result of rebuilding and the reuse of stone. With highCalluna vulgarisvalues they appear largely to reflect the stony nature of the environment in which the settlement was established.

Preamble

This pre-print details the results of pollen investigations that accompanied archaeological excavations at Leskernick Hill, Bodmin Moor, undertaken between 1995 and 1999. A draft manuscript was prepared for publication in 2005, but the monograph in which it was to be included outlining the excavations, has not been forthcoming. Details of the archaeological/historic features present at Leskernick can be found in Johnson and Rose (1994) and Herringet al. (2008), while Benderet al. (2007) provides information on the work that these investigations formed part of. The 2005 manuscript is reproduced here with a new introduction and revisions incorporating information from the later publications.
Development of an optogenetic gene expression system inLactococcus lactisusing a split photoactivatable T7 RNA polymerase
Authors: Rodrigo-Navarro Aleixandre , Salmeron-Sanchez Manuel
Published: January 2024

Cellular processes can be modulated by physical means, such as light, which offers advantages over chemically inducible systems with respect to spatiotemporal control. Here we introduce an optogenetic gene expression system forLactococcus lactisthat utilizes a split T7 RNA polymerase linked to two variants of the Vivid regulators. Depending on the chosen photoreceptor variant, either ‘Magnets’ or ‘enhanced Magnets’, this system can achieve either high protein expression levels or low basal activity in the absence of light, exhibiting a fold induction close to 30, rapid expression kinetics, and heightened light sensitivity. This system functions effectively in liquid cultures and within cells embedded in hydrogel matrices, highlighting its potential in the development of novel engineered living materials capable of responding to physical stimuli such as light. The optogenetic component of this system is highly customizable, allowing for the adjustment of expression patterns through modifications to the promoters and/or engineered T7 RNA polymerase variants. We anticipate that this system can be broadly adapted to other Gram-positive hosts with minimal modifications required.
Spontaneous activity of striatal projection neurons supports maturation of striatal inputs to substantia nigra dopaminergic neurons
Authors: Kokinovic Bojana , Seja Patricia , Donati Angelica , Ryazantseva Maria , de Kerchove d’Exaerde Alban , Schiffmann Serge N. , Taira Tomi , Molchanova Svetlana M.
Published: January 2024

Spontaneous activity of neurons during early ontogenesis is instrumental for stabilization and refinement of developing neuronal connections. The role of spontaneous activity in synaptic development has been described in detail for cortical-like structures. Yet, very little is known about activity-dependent development of long-range inhibitory projections, such as projections from striatum. Here, we show that striatal projection neurons (SPNs) in dorsal striatum are spontaneously active in P4-P14 mice. Spontaneous activity was detected in both direct-pathway SPNs (dSPNs) and indirect-pathway SPNs (iSPNs). Most of the spontaneously active cells were in striosomes – a chemical compartment in striatum defined by expression of µ-opioid receptor. Higher excitability of both striosomal dSPNs and iSPNs was related to their intrinsic excitability properties (higher action potential half-width and IV slope). Tonic activation of muscarinic M1 receptor maintains the spontaneous activity of striosomal SPNs, the effect being stronger in iSPNs and weaker in dSPNs. To investigate if the neonatal spontaneous activity is needed for the stabilization of SPN long-range projections, we chemogenetically inhibited striosomal SPNs in neonatal animals and studied the efficiency of striatonigral projections in adult animals. Inhibition of striosomal SPNs by chronic CNO administration to P6-14 pups caused a reduction in the functional GABAergic innervation and in the density of gephyrin puncta in dopaminergic neurons of substantia nigra pars compacta of the adult (P52-79) animals. Chronic administration of CNO later in development (P21-29), on the contrary, resulted in higher mIPSC frequency in dopaminergic cells of the adult animals. Thus, the activity-dependent stabilization of striosomal projections has different developmental phases, and the long-term outcome of perturbations in these processes depends on the developmental period when they occur. Taken together, our results demonstrate that spontaneous activity of SPNs is essential for the maturation and stabilization of striatal efferents.
Interpretable deep learning for deconvolutional analysis of neural signals
Authors: Tolooshams Bahareh , Matias Sara , Wu Hao , Temereanca Simona , Uchida Naoshige , Murthy Venkatesh N. , Masset Paul , Ba Demba
Published: January 2024

The widespread adoption of deep learning to build models that capture the dynamics of neural populations is typically based on “black-box” approaches that lack an interpretable link between neural activity and network parameters. Here, we propose to apply algorithm unrolling, a method for interpretable deep learning, to design the architecture of sparse deconvolutional neural networks and obtain a direct interpretation of network weights in relation to stimulus-driven single-neuron activity through a generative model. We characterize our method, referred to as deconvolutional unrolled neural learning (DUNL), and show its versatility by applying it to deconvolve single-trial local signals across multiple brain areas and recording modalities. To exemplify use cases of our decomposition method, we uncover multiplexed salience and reward prediction error signals from midbrain dopamine neurons in an unbiased manner, perform simultaneous event detection and characterization in somatosensory thalamus recordings, and characterize the heterogeneity of neural responses in the piriform cortex and in the striatum during unstructured, naturalistic experiments. Our work leverages the advances in interpretable deep learning to gain a mechanistic understanding of neural activity.
Behavioral screening of conserved RNA-binding proteins reveals CEY-1/YBX RNA-binding protein dysfunction leads to impairments in memory and cognition
Authors: Hayden Ashley N , Brandel Katie L , Merlau Paul R , Vijayakumar Priyadharshini , Leptich Emily J , Pietryk Edward W , Gaytan Elizabeth S , Ni Connie W , Chao Hsiao-Tuan , Rosenfeld Jill A , Arey Rachel N
Published: January 2024

RNA-binding proteins (RBPs) regulate translation and plasticity which are required for memory. RBP dysfunction has been linked to a range of neurological disorders where cognitive impairments are a key symptom. However, of the 2,000 RBPs in the human genome, many are uncharacterized with regards to neurological phenotypes. To address this, we used the model organism C. elegans to assess the role of 20 conserved RBPs in memory. We identified eight previously uncharacterized memory regulators, three of which are in the C. elegans Y-Box (CEY) RBP family. Of these, we determined that cey-1 is the closest ortholog to the mammalian Y-Box (YBX) RBPs. We found that CEY-1 is both necessary in the nervous system for memory ability and sufficient to increase memory. Leveraging human datasets, we found both copy number variation losses and single nucleotide variants in YBX1 and YBX3 in individuals with neurological symptoms. We identified one predicted deleterious YBX3 variant of unknown significance, p.Asn127Tyr, in two individuals with neurological symptoms. Introducing this variant into endogenous cey-1 locus caused memory deficits in the worm. We further generated two humanized worm lines expressing human YBX3 or YBX1 at the cey-1 locus to test evolutionary conservation of YBXs in memory and the potential functional significance of the p.Asn127Tyr variant. Both YBX1/3 can functionally replace cey-1, and introduction of p.Asn127Tyr into the humanized YBX3 locus caused memory deficits. Our study highlights the worm as a model to reveal memory regulators and identifies YBX dysfunction as a potential new source of rare neurological disease.