bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping the Genetic Architecture of the Adaptive Integrated Stress Response inS. cerevisiae
Authors: Baum Rachel , Kim Jinyoung , Muller Ryan Y. , Ingolia Nicholas T.
Published: December 2024

The integrated stress response (ISR) is a conserved eukaryotic signaling pathway that responds to diverse stress stimuli to restore proteostasis. The strength and speed of ISR activation must be tuned properly to allow protein synthesis while maintaining proteostasis. Here, we describe how genetic perturbations change the dynamics of the ISR in budding yeast. We treated ISR dynamics, comprising timecourses of ISR activity across different levels of stress, as a holistic phenotype. We profiled changes in ISR dynamics across thousands of genetic perturbations in parallel using CRISPR interference with barcoded expression reporter sequencing (CiBER-seq). We treated cells with sulfometuron methyl, a titratable inhibitor of branched-amino acid synthesis, and measured expression of an ISR reporter. Perturbations to translation such as depletion of aminoacyl-tRNA synthetases or tRNA biogenesis factors reduced cell growth and caused a strikingly proportionate activation of the ISR activation. In contrast, impaired ribosome biogenesis reduced basal ISR activity and weakened ISR dynamics. Reduced ribosome capacity may lower the demand for amino acids and thereby explain these changes. Our work illustrates how CiBER-seq enables high-throughput measurements of complex and dynamic phenotypes that shed light on adaptive and homeostatic mechanisms.
Modeling the Future Incidence of Preeclampsia under Climate Change and Population Growth Scenarios
Authors: Youssim Iaroslav , Nevo Daniel , Erez Offer , Garfinkel Chaim I. , Okun Barbara S. , Novack Lena , Kloog Itai , Raz Raanan
Published: December 2024

Preeclampsia is a dangerous pregnancy disorder, with evidence suggesting that high ambient temperatures may increase its risk, making future incidence projections crucial for health planning. While temperature-related projections for all-cause mortality exist, disease-specific projections, especially for pregnancy complications, are limited due to data and methodological challenges. Vicedo-Cabrera et al. (2019) pioneered a time-series approach to project health impacts using the attributable fraction (AF) of cases due to climate change. We adjusted this method for preeclampsia, whose risk involves long-term exposures, with delivery as a competing event.

We based our analysis on the exposure-response relationship estimated in our previous study in southern Israel using cause-specific hazard and distributed lag nonlinear models. In the current study, we modeled several demographic and climate scenarios in the region for 2020-2039 and 2040-2059. Scenario-specific AFs were calculated by comparing cumulative preeclampsia incidence with and without corresponding climate change. Finally, annual cases were estimated by applying climate scenario-specific AFs to cases projected under each demographic scenario.

Our models show that climate change alone may increase preeclampsia by 3.2% to 4.3% in 2040-2059 relative to 2000-2019. Fertility trends are modeled to have a larger impact, with a 30% increase in cases by 2020-2039 under a low-fertility scenario. Extreme high-fertility and climate scenarios could result in a 2.3-fold rise in incidence, from 486 cases annually in 2000-2019 to 1,118 by 2040-2059.
Brown Bears activates a Satiety Hormone Cholecystokinin (CCK) pathway in adipose tissue during hibernation
Authors: Henriksen T.I , Engelhard C , Frøbert AM , Schrölkamp M , Friebe A , Overgaard MT , Poulsen SS , Rehfeld JF , Nielsen J , Fröbert O , Scheele C , Feizi A , Nielsen S
Published: December 2024

The brown bear (Ursus arctos) hibernates to survive cold winters without access to food. It builds enormous subcutaneous fat stores during summer and relies on it for energy during winter. Remarkably, the weight loss during winter occurs without muscle loss despite inactivity. Studying brown bear biology can therefore provide insights for improving human health in obesity and weight loss treatments. We here investigate subcutaneous adipose tissue biopsies obtained during summer and winter from free-living brown bears. During winter, a signature of genes involved in food intake and digestion is upregulated. Among these are several regulators of satiety, substrate transport and lipid metabolism. Interestingly, in humans these genes are enriched in distinct metabolic organs including, brain, intestine, stomach, liver and even salivary glands. We focused on the satiety brain/intestinal hormone cholecystokinin (CCK), which we demonstrate is produced in adipocytes, accompanied by an upregulation of the CCK receptor CCKBR. Importantly, CCK was undetectable in the circulation during winter and presence of sensory neurons suggest a neuronal feedback mechanism within the adipose tissue. Using RNA sequencing, we predict additionally 537 secreted proteins to be seasonally regulated, 37 of which could be confirmed with plasma proteomics. In conclusion, we propose that brown bears have developed a strategy of healthy fat burning and satiety regulation through an adipose tissue-contained mechanism which includes digestion factors and satiety mediators to provide safe energy turnover during hibernation-dependent weight loss.
Defining the high-translational readthrough stop codon context
Authors: Smoljanow Daniela , Lebeda Dennis , Hofhuis Julia , Thoms Sven
Published: December 2024

Translational termination is not entirely efficient and competes with elongation, which might result in translational readthrough (TR). TR occurs when a near-cognate tRNA binds to a stop codon, (mis)interpreting it as a sense codon and producing a C-terminal extension of the protein. This process is influenced by the stop codon itself and the surrounding nucleotide sequence, known as the stop codon context (SCC). To investigate the role of these cis-acting elements beyond the high-TR motif UGA CUA G, this study examines specific positions within the SCC, both upstream and downstream of the motif, that contribute to variations in basal and aminoglycoside-induced TR. In particular, we identified a surprisingly large influence of the upstream nucleotide positions -9 and -8 (relative to the stop codon) and positions +11 and +12 on readthrough levels, revealing a complex interplay between nucleotides in the expanded SCC. These findings support our understanding of translational termination and may benefit the development of pharmacological therapy for diseases caused by premature stop codon mutations.
Evolutionary conservation of midline axon guidance activity betweenDrosophilaandTriboliumFrazzled
Authors: Ghosh Piyasi , Wadsworth Benjamin C. , Terry Logan , Evans Timothy A.
Published: December 2024

The regulation of midline crossing of axons is of fundamental importance for the proper development of nervous system connectivity in bilaterian animals. A number of conserved axon guidance signaling pathways coordinate to attract or repel axons at the nervous system midline to ensure the proper regulation of midline crossing. The attractive Netrin-Frazzled/DCC (Net-Fra) signaling pathway is widely conserved among bilaterians, but it is not clear whether the mechanisms by which Net and Fra promote midline crossing are also conserved. InDrosophila, Fra can promote midline crossing via Netrin-dependent and Netrin-independent mechanisms, by acting as a canonical midline attractive receptor and also through a non-canonical pathway to inhibit midline repulsion via transcriptional regulation. To examine the conservation of Fra-dependent axon guidance mechanisms among insects, in this paper we compare the midline attractive roles of the Frazzled receptor in the fruit fly (Drosophila melanogaster) and flour beetle (Tribolium castaneum) using CRISPR/Cas9-mediated gene editing. We replace theDrosophila fragene with sequences encodingDrosophilaFra (DmFra) orTriboliumFra (TcFra) and examine midline crossing of axons in the ventral nerve cord of embryos carrying these modified alleles. We show thatTriboliumFra can fully substitute forDrosophilaFra to promote midline crossing of axons in the embryonic nervous system, suggesting that the mechanisms by which Frazzled regulates midline axon guidance may be evolutionarily conserved within insects.
Energy efficiency and sensitivity benefits in a motion processing adaptive recurrent neural network
Authors: Mohan Vishnu , Rideaux Reuben
Published: December 2024

Motion processing is a key function for the survival of many organisms and is initially implemented in areas V1 and MT of the primate visual cortex. Advances in machine learning approaches have led to the development of motion processing neural networks that have elucidated several aspects of this process. However, it remains unclear how adaptation, a canonical function of sensory processing, influences motion processing. In this study, we developed two recurrent neural networks to study motion processing: MotionNet-R, a baseline model, and AdaptNet, a model that employs adaptive mechanisms inspired by biological systems. Both networks were trained on natural image sequences to estimate motion vectors. We found that both networks developed response properties that resembled those of neurons found in areas V1 and MT, e.g., speed tuning, and AdaptNet recapitulated the motion aftereffect phenomenon (i.e.,the waterfall illusion). We show that the emergent computational properties that implement the phenomenon in AdaptNet confirm previous theoretical hypotheses. Further, we compared the performance of the two networks and found that AdaptNet processed motion more efficiently, operationalized as reduced activation. While AdaptNet incurred reduced accuracy in response to prolonged constant input, it was both more accurate and sensitive in response to changes in motion input. These results are consistent with theoretical explanations of adaptation as neural property that supports metabolic efficiency and increased sensitivity to change in the environment. Our findings provide novel insights into the neural mechanisms underlying motion adaptation and highlight the potential advantages of adaptive neural networks in modelling biological processes.
A molecularly defined brain circuit module for regulating the panic-like defensive state
Authors: Zhao Miao , Zhang Li , Chen Zhenhua , Zhang Shuangfeng , Cheng Xinyu , Huang Meizhu , Li Xiating , Gu Huating , Guan Xuyan , Geng Dandan , Li Yaning , Tu Yiheng , Xie Zhiyong , Zhang Fan , Ma Huijie , Li Dapeng , Wu Qingfeng , Cao Peng
Published: December 2024

Panic is an episode of strong defensive state, characterized by intense fear and severe physical symptoms such as elevated cardiorespiratory activities. How the brain generates panic state remains poorly understood. Here, we developed a robot-based experimental paradigm to evoke panic-like defensive state in mice. When stimulated by the robot, the mice exhibited jumping escapes and elevated cardiorespiratory activities. With this paradigm, we identifiedCbln2-expressing (Cbln2+) neurons in the posterior hypothalamic nucleus (PHN) as a key neuronal population essential for the induction of panic-like defensive state. Activation ofCbln2+ PHN neurons induced behavioral and physical symptoms of panic-like defensive state. These neurons were strongly activated by noxious mechanical stimuli and encode jumping escape vigor. They were synaptically innervated by anxiety-associated brain areas and provoked panic-like defensive state via their projection to the periaqueductal gray. Together, our results reveal a molecularly defined circuit module that regulates the panic-like defensive state in mice.
In VivoPathway Optimization in Yeast viaLoxPsym-Mediated Shuffling of Upstream Activating Sequences
Authors: Ruehmkorff Ciaran , Tafazoli Yazdi Ali , Hochrein Lena
Published: December 2024

The budding yeastSaccharomyces cerevisiaeplays an integral role in the bioeconomy as a powerful host for industrial bio-manufacturing, driving the production of diverse bio-based products. Achieving optimal product yields requires precise fine-tuning of the expression levels of multiple pathway genes, which often relies on cloning-intensive methods. Here, we present PULSE, anin vivopromoter engineering tool based on a streamlined workflow combining FACS-based screening of a randomized DNA library to identify active promoter elements, and their subsequent assembly into synthetic hybrid promoters where each element is flanked byloxPsymsites. Multiple promoter cassettes can be genome-integrated to generate “ready-to-use” platform strains, allowing users to easily place their genes of interest under the control of PULSE promoters. By activating Cre-mediated recombination,loxPsym-flanked promoter elements can be recombined, effectively bringing the target genes under control of a vast set of promoters spanning a wide range of expression levels in one simple step. Applying PULSE on two heterologous pathways, a threefold increase in β-carotene production and improved xylose utilization byS. cerevisiaewas achieved. These results demonstrate the power and efficiency of PULSE as a versatile platform for metabolic engineering, enabling rapid, cloning-free optimization of biosynthetic pathwaysin vivo.
Temporal Dynamics of the Tomato Rhizosphere Microbiome in Response to Synthetic Communities of Plant Growth-Promoting Rhizobacteria
Authors: Nicotra Daniele , Mosca Alexandros , Dimaria Giulio , Tessitori Matilde , Vetukuri Ramesh Raju , Catara Vittoria
Published: December 2024

In sustainable agriculture, the application of microorganisms to soil is a widely adopted strategy aimed at enhancing soil microbiome functionality, restoring fertility, and recovering biodiversity diminished by intensive farming. While introducing individual beneficial microbes often encounters issues with establishment and persistence, multispecies microbial consortia offer a more robust alternative, providing complementary functions that enhance both their resilience and effectiveness. To test this approach, we designed three synthetic bacterial communities (SynComs), each composed of varying combinations of ten bacterial endophytes previously shown to promote plant growth and exert biocontrol effects. The SynComs were designed with ascending levels of richness (4, 6, and 10 members) and diversity (ranging from 3 to 6 bacterial genera). In growth chamber trials with tomatoes, the SynComs not only promoted plant growth but also induced significant shifts in the rhizosphere bacterial communities, primarily affecting less abundant taxa. The SynComs MIX2 and MIX3, which includedPseudomonasspecies, exhibited the greatest impact on both plant growth enhancement and shifts within the resident microbial community. Monitoring of the introduced strains over time demonstrated that most bioinoculants successfully established although at very low concentration in the rhizosphere.
Experimental Murine Periodontitis Increases Salivary Gland IgA‐Producing B Cells Following Oral Dysbiosis
Authors: Nara Mai , Kurosawa Mie , Itsumi Momoe , Morisaki Hirobumi , Fukamachi Haruka , Okahashi Nobuo , Suzuki Noriyuki , Kuwata Hirotaka
Published: December 2024

The oral microbiome is closely involved in the maintenance of host health and the development of systemic diseases. The salivary glands play an essential role in homeostasis in the oral cavity. Here, we investigated the effects of periodontal inflammation on salivary gland function and the oral microbiome. In experimental periodontitis model mice, an increase in IgA⁺ cells in the salivary glands were observed 1 week after treatment. Alteration of the oral microbiome was also induced in this model. Gene expression analysis of the salivary glands showed changes in the expression of genes related to B‐cell maturation and plasma cell differentiation and an increase in the expression of genes related to macrophage activation upon experimental periodontitis induction. Furthermore, the relationship between disruption of oral microflora and salivary gland function was examined using a cohousing model in which experimental periodontitis model mice and untreated mice were reared in the same cage. We found that cohoused normal mice underwent alteration of the oral microbiome, with increases in IgA⁺ cells and macrophages in the salivary glands. In summary, our results suggest that, in the oral cavity, there is a close link between oral bacterial flora and immune cells in the salivary glands. Our results also show that localized inflammation disrupts the homeostasis in the oral cavity, inducing pathological conditions such as dysbiosis. Our study suggests the importance of the interaction among local oral inflammation, salivary gland function, and oral microflora, and provides new insights into the mechanisms by which oral health is maintained.
Medical test and employee's autonomy. Confidentiality of data and non‐discrimination
Authors: Muñiz Javier Fernández‐Costales
Published: December 2024

Monitoring health is one of the basic principles of Occupational Health and Safety. The main objective of this monitoring will be the detection of possible damage to health arising from work. They try to discover the effects that the inherent risks with the work may cause the worker, which will show, given the case, through an alteration of health or the state of organic and functional state, both physically and mentally. Regarding the monitoring of health, there are many and varied issues to be raised concerning the right to personal privacy. Thus, notably, whether there was effective consensus, and whether, in particular, the object and the purpose of the medical examination meant a disregard of the statutory scheme, an excess or even a failure to comply with the terms of the Spanish Constitution. The limits imposed by the law makers to the productive unit will play a key role in identifying the content of the company obligation to monitor health, being in many cases guarantees of constitutional rights. Therefore, the methods of health monitoring and control of workers will always be carried out respecting the privacy and dignity of the worker as well as the confidentiality of all information related to their health.
Relationships between trunk tissue distribution, metabolic risk factors and physical performance in young people—A pilot study
Authors: Ishiguro‐Tanaka Noriko , Kitagawa Funa , Akima Hiroshi
Published: December 2024

The present study examined the relationships between trunk tissue distribution, metabolic risk factors, and physical performance in young Japanese individuals using cross‐sectional and longitudinal analyses. Thirty‐six healthy Japanese men (n = 20, body mass index [BMI]: 20.8 ± 2.0 kg/m2) and women (n = 16, BMI: 19.6 ± 2.0 kg/m2) aged 20–26 years old visited our laboratory twice with an interval of 1 year. The thicknesses of skeletal muscle (MT), subcutaneous adipose tissue (SCAT), and the intra‐abdominal cavity (IAT) were assessed by ultrasound imaging and adjusted by body mass1/3 (BM1/3). Blood properties related to hepatic function or metabolic syndrome, brachial‐ankle pulse wave velocity, hand grip strength, two‐step‐length/height scores, and sit‐and‐reach test scores were also measured. As a result of the cross‐sectional analysis, significant relationships were observed between SCAT/BM1/3 and indices of glucose metabolism (HOMA‐IR and QUICKI) in men (r = 0.513 and ‐0.583), and between IAT/BM1/3 and fasting blood glucose in women (r = 0.524). Longitudinal analyses of women showed that changes (%) in IAT and MT/IAT correlated with % changes in the indices of hepatic function (AST) and glucose metabolism (HOMA‐IR and HOMA‐β) (r = −0.673 to 0.686). Significant correlations were also observed between MT/IAT and walking ability (two‐step‐length/height) in cross‐sectional and longitudinal analyses of men (r = 0.463 and 0.525). In conclusion, the trunk tissue distribution could be used to detect the early symptoms of metabolic risks and declines in physical performance in young men and women.
Sudden unexpected infant death, sudden unexplained death in childhood, and sudden unexpected death in epilepsy
Authors: Sharma Suvasini , Whitney Robyn , Chowdhury Sayoni Roy , Ramachandrannair Rajesh
Published: December 2024

Sudden deaths in infants and children represent a profound and tragic event that continues to challenge researchers despite extensive investigation over several decades. The predominant phenotype, sudden infant death syndrome (SIDS), has evolved into the broader category of sudden unexpected infant death (SUID). In older children, a less understood phenomenon known as sudden unexplained death in childhood (SUDC) has garnered attention. Additionally, sudden unexpected death in epilepsy (SUDEP) constitutes a rare but recognized complication of epilepsy. Recent investigations indicate overlapping clinical, neuropathological, and genetic characteristics among SUID, SUDC, and SUDEP. Common features include death occurring during sleep, discovery in the prone position, hippocampal abnormalities, and genetic variations associated with epilepsy or cardiac arrhythmias. Notably, video recordings in certain examples of SUDC have captured ‘convulsive’ episodes preceding death in children without prior seizure history, suggesting that seizures may contribute more significantly to sudden paediatric deaths than previously presumed. This review explores these shared elements, underscoring their importance in formulating possible preventative measures against these devastating conditions.
Mixed financing strategies for a supply chain with a financially distressed seller: combination of equity financing and debt financing
Authors: Yan Qiang , Wang Chengfu
Published: December 2024

This work discusses a supply chain composed of one third‐party logistics (3PL) firm and one capital‐constrained seller. To cover the seller's ordering and logistics costs, two distinct mixed financing schemes are considered to address the funding needs: (i) equity financing and bank credit financing (EBF) and (ii) equity financing and 3PL firm financing (ELF). We examine how the equity financing ratio influences equilibrium outcomes and derive the financing preference for each member. The results reveal that a large equity financing ratio prompts the seller to buy more. Interestingly, the seller's profit under EBF either monotonically decreases or exhibits a concave relationship with respect to the equity financing ratio. By contrast, the seller's profit under ELF is consistently concave with respect to the equity financing ratio. Additionally, a Pareto zone of the 3PL firm's interest rate exists in which a win–win situation can be achieved. The seller tends to opt for ELF when the sum of the unit transportation fee and ordering cost is high but the equity financing ratio is moderate. Comparatively, the 3PL firm is reluctant to offer financing when both the sum of the unit transportation fee and ordering cost, and the sum of the unit transportation cost and ordering cost are high, while the equity financing ratio is low. Finally, we investigate an endogenous equity financing ratio and further discuss the effect of the seller's initial working capital.
Safety and efficacy of moderate‐intensity statin with ezetimibe in elderly patients with atherosclerotic cardiovascular disease
Authors: Cha Jung‐Joon , Kim Ju Hyeon , Hong Soon Jun , Lim Subin , Joo Hyung Joon , Park Jae Hyoung , Yu Cheol Woong , Lee Pil Hyung , Lee Seung Whan , Lee Cheol Whan , Moon Jae Youn , Lee Jong‐Young , Kim Jung‐Sun , Park Jae Suk , Lim Do‐Sun
Published: December 2024

Background

High‐intensity statin therapy significantly reduces mortality and cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD). However, moderate‐intensity statins are often preferred for elderly patients due to their higher risk of intolerance to high‐intensity statins.

Objective

To compare the incidence of statin‐associated muscle symptoms (SAMS) and the effect on low‐density lipoprotein cholesterol (LDL‐C) levels between elderly ASCVD patients receiving high‐intensity statin monotherapy and those receiving moderate‐intensity statin with ezetimibe in a combination therapy.

Method

In a prospective, multicenter, open‐label trial conducted in South Korea, 561 patients aged 70 years or above with ASCVD were randomly assigned to receive either moderate‐intensity statin with ezetimibe combination therapy (rosuvastatin 5 mg with ezetimibe 10 mg) or high‐intensity statin monotherapy (rosuvastatin 20 mg) over 6 months. The primary endpoint was the incidence of SAMS, and the key secondary endpoint was the achievement of target LDL‐C levels (<70 mg/dL) within 6 months.

Results

The primary endpoint showed a lower incidence of SAMS in the combination therapy group (0.7%) compared to the high‐intensity statin monotherapy group (5.7%, p = 0.005). Both groups achieved similar LDL‐C levels, with 75.4% in the combination therapy group and 68.7% in the monotherapy group reaching target levels.

Conclusion

Moderate‐intensity statin with ezetimibe combination therapy offers a lower risk of SAMS and similar LDL‐C reduction in elderly patients with ASCVD, compared to high‐intensity statin monotherapy.
The Retreat from Marriage and Childbearing in China: Examining the Aspirations of Young Women and Men
Authors: Blair Sampson Lee , Madigan Timothy J.
Published: December 2024

The modernization of China has led to considerable economic and cultural change, and the rates of marriage and fertility have been declining. Despite recent changes in fertility policy, which allow for more births, the resulting pattern has been one of lower fertility. In addition, marriage rates have been declining, while cohabitation and singlehood have increased. Using a sample of young adults, this study examines the respective aspirations for marriage and childbearing of women and men in China. The results show that approximately 16% of females and 18% of males do not aspire to marry. In terms of childbearing, almost one‐third of females do not wish to have any births, while only one‐tenth of males feel likewise. Parental factors are shown to be substantially associated with males' marriage aspirations, while females' aspirations for both marriage and childbearing are strongly linked to their valuation of marriage and parenthood, themselves. The implications of the findings, along with the future of marriage and fertility patterns in China, are discussed within the second demographic transition paradigm.
Comparative efficacy of liberal and restrictive blood transfusion strategies in anemic patients with acute myocardial infarction: A systematic review and meta‐analysis of randomized controlled trials
Authors: Kow Chia Siang , Ramachandram Dinesh Sangarran , Hasan Syed Shahzad , Thiruchelvam Kaeshaelya
Published: December 2024

Introduction

Acute myocardial infarction (AMI) poses a significant global health burden, warranting meticulous management strategies, particularly in patients with concurrent anemia. Blood transfusion strategies play a pivotal role in optimizing oxygen delivery while minimizing transfusion‐related risks. Two contrasting approaches, liberal and restrictive transfusion strategies, have emerged, yet their comparative effectiveness remains uncertain due to conflicting evidence.

Methods

We conducted a systematic review and meta‐analysis focusing on randomized controlled trials (RCTs) comparing liberal versus restrictive transfusion strategies in AMI patients with anemia (hemoglobin levels <10 g/dL). Comprehensive searches were performed across electronic databases up to March 31, 2024. Data extraction, risk of bias assessment using Cochrane's RoB 2 tool, and meta‐analysis were conducted following methodology.

Results

Among 327 initially identified studies, four high‐quality RCTs met the inclusion criteria. These trials encompassed varied sample sizes and patient demographics. Meta‐analysis revealed no significant difference in 30‐day all‐cause mortality nor recurrent MI between liberal and restrictive transfusion strategies. However, combining these outcomes into a composite measure demonstrated a significant reduction favoring liberal transfusion (pooled odds ratio = 0.82; 95% confidence interval = 0.69–0.99).

Conclusion

While liberal transfusion strategies show promise in reducing adverse outcomes, clinical decision‐making should be guided by individual patient factors and preferences. Personalized care remains paramount in determining the most appropriate transfusion approach for AMI patients with anemia. Further research is warranted to elucidate the optimal transfusion strategy in this population.
Electrical stimulation of injured nerves promotes recovery in animals and humans
Authors: Gordon Tessa
Published: December 2024

The frequent poor functional outcomes after delayed surgical repair of injured human peripheral nerves results in progressive downregulation of growth‐associated genes in parallel with reduced neuronal regenerative capacity under each of the experimental conditions of chronic axotomy of neurones that remain without target contact, chronic distal nerve stump denervation, and chronic muscle denervation. Brief (1 h) low‐frequency (20 Hz) electrical stimulation (ES) accelerates the outgrowth of regenerating axons across the surgical site of microsurgical repair of a transected nerve. Exercise programmes also promote nerve regeneration with the combination of ES and exercise being the most effective. An ES conditioning lesion of intact nerve (CES) accelerates both axonal outgrowth and regeneration rate after the surgical repair of a more distal injury to the nerve, in contrast to ES of a repaired injury nerve that accelerates only the axon outgrowth. A CES accelerates both axonal outgrowth and regeneration rate after the surgical repair of a more distal injury to the nerve, in contrast to ES of a repaired injury nerve that accelerates only the axon outgrowth. The loss of contractility of permanently denervated muscles in cauda equinae‐injured patients with accompanying severe loss of muscle mass, disarray of thick and thin contractile filaments, and disorganization of the sarcoplasmic reticulum that controls calcium delivery to the filaments, is alleviated by a 2‐year programme of daily ES of the quadriceps muscle. These findings hold promise for recovery and rehabilitation in patients who suffer injury to the neuromuscular system.

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Key points

Poor functional outcomes after delayed surgical repair of injured human peripheral nerves are replicated by chronic neuronal axotomy, Schwann cell denervation in a nerve autograft, and muscle denervation.

Exponential decline in expression of growth‐associated genes accompanies the same decline in regenerative capacity.

Brief (1 h) low‐frequency (20 Hz) electrical stimulation (ES) that generates action potential conduction to the neuronal soma accelerates the outgrowth of regenerating axons across the surgical repair site of the transected nerve, even after delayed surgery.

The same ES regimen accelerates muscle reinnervation in patients with chronic nerve injury who undergo carpal tunnel syndrome release surgery.

A 2‐year programme of daily ES of permanently denervated quadriceps muscles in cauda equinae‐injured patients reinstated their contractility and organization.
CSF1‐R inhibition attenuates posttraumatic osteoarthritis and quadriceps atrophy following ligament injury
Authors: Keeble Alexander R. , Thomas Nicholas T. , Balawender Peyton J. , Brightwell Camille R. , Gonzalez‐Velez Sara , O'Daniel Madeline G. , Conley Caitlin E. , Stone Austin V. , Johnson Darren L. , Noehren Brian , Jacobs Cale A. , Fry Christopher S. , Owen Allison M.
Published: December 2024

Knee osteoarthritis contributes substantially to worldwide disability. Post‐traumatic osteoarthritis (PTOA) develops secondary to joint injury, such as ligament rupture, and there is increasing evidence suggesting a key role for inflammation in the aetiology of PTOA and associated functional deficits. Colony stimulating factor 1 receptor (CSF1‐R) has been implicated in the pathogenesis of musculoskeletal degeneration following anterior cruciate ligament (ACL) injury. We sought to assess the efficacy of CSF1‐R inhibition to mitigate muscle and joint pathology in a mouse model of PTOA. Four‐month‐old mice were randomized to receive a CSF1‐R inhibitor and studied for 7 or 28 days after joint injury. Additionally, we profiled synovial fluid samples for CSF1‐R from patients with injury to their ACL. Transcriptomic analysis of quadriceps muscle and articular cartilage in CSF1‐R inhibitor‐treated animals at 7 days after injury revealed elevated chondrocyte differentiation within articular cartilage and enhanced metabolic and contractile gene expression within skeletal muscle. At 28 days post‐injury, CSF1‐R inhibition attenuated PTOA severity and mitigated skeletal muscle atrophy. Patient synovial fluid CSF1‐R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA. Our findings support an opportunity for CSF1‐R targeting to mitigate the severity of PTOA and muscle atrophy after joint injury.

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Key points

Posttraumatic osteoarthritis (PTOA) of the knee commonly results from direct injury to the joint, which is characterized by pain, weakness, and disability.

Induction of colony stimulating factor one receptor (CSF1‐R) is positively associated with knee trauma severity, and the initial acute inflammatory state suppresses muscle recovery and degrades articular cartilage.

Skeletal muscle and articular cartilage transcriptomic response following direct joint injury in a murine model of PTOA is rescued by pharmacological inhibition of CSF1‐R.

CSF1‐R inhibition mitigated skeletal muscle atrophy and attenuated PTOA severity and synovitis.

Patient synovial fluid CSF1‐R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA, offering further evidence for CSF1‐R as a therapeutic target across musculoskeletal tissues after injury.
Case Study of an Extreme Heat Wave in Rio de Janeiro on November 2023: Synoptic Conditions and Climatological Trends
Authors: Dereczynski Claudine , Luiz Silva Wanderson , Bazzanela Anna Carolina , Bodstein Airton , Chou Sin Chan
Published: December 2024

This article is a case study to analyze the synoptic and climatological aspects of an heat wave in Rio de Janeiro, located in the Southeast Region of Brazil, during November 2023. This work aims to investigate whether the high temperatures recorded on November 17 and 18, 2023, during a concert of an American singer, could be considered an extreme weather event. On the first day of the concert, the 17th, many people fell ill due to the extreme heat, and a 23-year-old female died, a victim of cardiorespiratory arrest caused by thermal exhaustion. On November 18, 11 meteorological stations recorded a maximum temperature (TX) equal to or over 40 °C, and the highest TX in the city was 43.5 °C. At a station located in the coldest area of the city, the highest TX (39.6ºC) in its entire historical record (1967-2023) was also recorded on the 18th. Such extremely high temperatures occurred during a prefrontal situation and at the end of a heat wave that lasted eight days. Analysis of the diurnal cycle of the air temperature on the 17th and 18th indicated that the minimum temperature (TN) was about 5 to 6 °C above its climatology; the TX was approximately 13 °C above its climatological value, and high temperatures lasted all afternoon. On the 18th, the Heat Index reached 55.1 ºC at 14:00 and 15:00 LT, characterizing a state of medical emergency during seven hours. In terms of climate, in addition to the increase in intensity and frequency of warm extremes over the city, the El Niño phenomenon (EN) was configured in the Pacific Ocean from April 2023 to May 2024, causing a drier and warmer spring in Southeast Brazil. This concert represented a milestone for the city regarding the need for local public policies to regulate massive crowd-gathering events during heat wave episodes. Finally, it is possible to state that the event was extreme, caused by the combination of a heat wave, in a prefrontal situation, during an EN event, and in a context of climate change.
Design of Soluble Compounds for Optical Control of Tetrameric P-Loop Ion Channels
Authors: Gataulina E. D. , Nikolaev M. V. , Tikhonov D. B.
Published: December 2024

The photopharmacology of ion channels is a rapidly developing
area. One reason for paying special attention to the design of photoswitchable
ligands for ion channels is that the channels control fast neurophysiological
processes, and their ability to be rapidly and locally modulated
by light is very important. In the photopharmacology of ion channels,
existing drugs are usually employed to design photochromic analogs
through the incorporation of a photochromic moiety. At present,
photochromic compounds are designed for many channels belong to
the superfamily of so-called P-loop channels. Photoswitchable drugs
differ in their activities, photosensitivity, selectivity, and mechanisms
of action. This paper provides an overview of the available compounds
and the design of their structures.
Thyroid dermopathy and thyroid eye disease associated with hypofunctional autoimmune thyroid disease with high TSI/anti-TSHR antibodies improved with teprotumumab
Authors: Niedzialkowska Ewelina , Pokharel Ashbita , Banka Ajaz
Published: December 2024

Thyroid dermopathy (TD) and thyroid eye disease (TED) are rare clinical entities in patients with hypofunctional autoimmune thyroid disease; however, these can be present in patients with thyroid-stimulating immunoglobulin (TSI)/anti-thyroid-stimulating hormone receptor (TSHR) antibodies. TED is believed to be associated with antibodies stimulating TSHRs and cross-talk with IGF-1 receptor (IGF-1R) pathway, prompting tissue proliferation. Teprotumumab (monoclonal antibody targeting IGF-1R) has been proven to improve symptoms of TED. It is proposed that TD share the same pathophysiology as TED. We present a case of a patient with hypofunctional autoimmune thyroid disease with high TSI/anti-TSHR antibodies who experienced significant improvement of symptoms of both TED and TD after six doses of teprotumumab. We postulate that further studies regarding the efficacy of teprotumumab in patients with TD are needed.
Ranolazine toxicity precipitating seizure in the elderly
Authors: Tracy Evan Paul , Furtado Wilfred , Stanton James , Kingery Justin
Published: December 2024

An 80+ year old woman with stage III chronic kidney disease presented after having an episode of sudden stiffening, shaking and confusion. This was the third such episode that the patient had in the past 4 weeks, and the patient has never had such an episo de previously. Of note, she was prescribed ranolazine for chronic angina 6 weeks prior. She initially started taking 500 mg two times per day which was subsequently increased to 1000 two times per day. Laboratory work up revealed an elevated creatinine of 2.42 compared with baseline of 1.9. Imaging studies revealed no acute findings suggestive of stroke. Electroencephalogram demonstrated seizure activity, and lacosamide 100 mg two times per day was prescribed. During her hospital stay, ranolazine was discontinued and the patient gradually returned to her mental baseline. This case demonstrates ranolazine toxicity that manifests as new-onset epilepsy which is more likely to occur in the elderly and patients with renal dysfunction.
Bickerstaff brainstem encephalitis-Miller-Fisher syndrome (BBE-MFS) overlap with negative anti-GQ1b serology
Authors: Nayak M Vivek , Sharma Harsh , Nagaraju Shreesha , Prabhu M Mukhyaprana
Published: December 2024

Bickerstaff brainstem encephalitis (BBE) and Miller-Fisher syndrome (MFS) are rare post-infectious neurological syndromes, usually involving ‘anti-GQ1b ganglioside’ antibodies. Both syndromes present with ophthalmoplegia and ataxia. However, BBE is differentiated by altered consciousness or pyramidal signs (central nervous system involvement), while MFS has areflexia (peripheral nervous system involvement). Here, we discuss a case of an elderly woman, who, after an initial episode of upper respiratory tract infection, developed bilateral ophthalmoplegia, facial and bulbar palsy, ataxia, depressed consciousness and areflexia. She was diagnosed clinically as a case of BBE-MFS overlap. However, serology was negative for anti-GQ1b antibodies, and brain imaging and cerebrospinal fluid (CSF) analysis were normal. Despite initial clinical deterioration and the need for intubation, she was treated successfully with intravenous immunoglobulin and eventually recovered. This case demonstrates that BBE and MFS can overlap and that early clinical diagnosis becomes essential even if anti-ganglioside antibodies, CSF and imaging studies are negative.
Advanced cutaneous angiosarcoma with aTRIM24::BRAFgene fusion treated with trametinib
Authors: Murphy Patrick , Pankiw Maya , Gibbings Nicole , Zhang Lingxin , Watson Geoffrey
Published: December 2024

A postmenopausal woman presented with a painful, erythematous rash affecting her head and neck. CT imaging revealed diffuse areas of skin thickening affecting her face and neck, and necrotic lymphadenopathy. Additional imaging revealed several osteolytic bone lesions. Biopsy reported a malignant vascular neoplasm, suggestive of angiosarcoma. Molecular analysis reported aTRIM24::BRAFgene fusion. After progression on first-line paclitaxel, the MEK inhibitor trametinib was administered, resulting in an excellent clinical and radiological response. This case reports a novel gene fusion, to our knowledge, the first reported in sarcoma, and highlights the utility and importance of molecular profiling in obtaining access to a treatment that may not otherwise be considered in standard site-specific therapeutic regimens, where therapeutic options may be limited.
Late onset of Pompe’s disease: a rare cause of respiratory failure
Authors: Krogh Charlotte Loumann , Lauritsen Anne Øberg , Hägi-Pedersen Daniel
Published: December 2024

A woman in her 30s was admitted acutely to the emergency department with severe respiratory failure of unknown cause. On arrival, the patient was severely compromised with a reduced Glasgow Coma scale and arterial pCO2 > 14 kPa. She was intubated and taken to the intensive care unit for respiratory support and further investigations.

A detailed patient history revealed multiple admissions in the psychiatric sector with anxiety disorder, as well as numerous admissions to the emergency department with progressive tremors, muscle fatigue and dyspnoea, all of which were interpreted as anxiety attacks. Based on this history, we suspected a neurological disorder in our patient. Following extensive neurological investigation and additional genetic studies, the diagnosis of late-onset Pompe’s disease was confirmed.

Late-onset Pompe’s disease can pose a diagnostic challenge due to its multifaceted presentation with non-specific symptoms. Any patient not responding to treatment should urge clinicians to re-evaluate their differential diagnoses.
Management of atypicalMycobacterium szulgaidigital flexor tenosynovitis
Authors: Arango Sebastian D , Zeitlin Jacob , Kantas Fotios , Miller Andrew J
Published: December 2024

Mycobacterium szulgaiis a rare, atypical pathogen predominantly associated with pulmonary infections but capable of causing suppurative tenosynovitis—a potentially devastating infection of the tendon sheath. This case involves a patient presenting with insidious pain and swelling of the right index finger. After multiple consultations, the patient was indicated for surgical exploration which revealed significant flexor tendon sheath tenosynovitis and inflammation with subsequent cultures growingM. szulgai. The patient was treated with a broad-spectrum antibiotic regimen, adjusted postoperatively based on culture results. Significant improvements in finger mobility and swelling reduction were observed by the 6-week follow-up. This case emphasises the necessity of comprehensive diagnostic evaluation and precise antimicrobial therapy in managing rare mycobacterial infections, contributing valuable insights to the limited literature on non-tuberculous mycobacterial tenosynovitis.
Methaemoglobinemia in paediatrics: a complex diagnostic journey
Authors: Aires Martins Inês , Carvalho Queirós Joana , Cleto Esmeralda , Barbosa Telma
Published: December 2024

Methaemoglobinemia is a potentially life-threatening condition in which the heme iron is oxidised from the ferrous (Fe2+) to the ferric (Fe3+) state, leading to a left shift of the oxygen-dissociation curve and impaired oxygen delivery to the tissues. It can be either acquired through exposure to certain drugs or chemicals or inherited due to genetic mutations affecting enzymes like cytochrome b5 reductase.

We report a case of an adolescent who presented with a persistent cough and unremarkable physical examination, making diagnosis challenging. A low SpO2level that did not improve with supplemental oxygen prompted further testing, leading to the diagnosis of methaemoglobinemia caused by cytochrome b5 reductase deficiency. The case highlights the complexities of diagnosing methaemoglobinemia, especially in the absence of classic symptoms like cyanosis. It underscores the importance of thorough clinical assessment in atypical cases and the need for heightened awareness of rare conditions.
Successful multimodal endobronchial treatment of severe tracheobronchial amyloidosis
Authors: Mullin Monica L , Dunwoody Roisin , Navani Neal , Thakrar Ricky
Published: December 2024

A previously healthy woman in her 40s presented with a 6-month history of increasing cough and breathlessness following COVID-19 infection. She experienced vocal hoarseness and recurrent respiratory infections during this time, requiring several antibiotic courses. She was treated for gastro-oesophageal reflux and trialled on inhaled corticosteroids, without improvement. Further work up included CT scan, demonstrating tracheal thickening, endobronchial narrowing and mucosal abnormalities. Bronchoscopy with biopsies demonstrated amyloidosis. She was referred to a specialist centre with further work up including serum amyloid P component (SAP) scan, echo and bloodwork. She was diagnosed with localised tracheobronchial amyloidosis and referred to interventional respiratory for treatment. Bronchoscopy demonstrated severe narrowing in left main, left upper and lower lobes and to a lesser extent, the right main bronchus. Endobronchial treatment included diode laser therapy, electrocautery and cryorecanalisation. Significant improvement was seen on 3 months post surveillance bronchoscopy. Following this treatment, the patient experienced sustained improvement in breathlessness and cough.
Race against clots: the challenges of managing antithrombin deficiency in the ICU
Authors: Giglio Jimenez Andres , Aravena Paola , Ibañez Valentina , Ferre Andres
Published: December 2024

We present the case of a man in his 50s with a history of recurrent unprovoked venous thromboembolism who developed haemorrhagic shock due to venous intestinal ischaemia. Despite anticoagulation and monitoring of anti-Xa levels, the thrombosis progressed, leading to complete necrosis and perforation of the small bowel wall, persistent septic shock and ultimately death. The clinical course and family history raised suspicion for hereditary antithrombin deficiency, a rare but potentially catastrophic thrombophilia. This case highlights the importance of considering inherited thrombophilia in critically ill patients with progressive thrombosis despite adequate anticoagulation, and the challenges of managing these conditions in the intensive care unit.