bluuebunny/crossref_metadata_2025 huggingface dataset:
The components of arginine and methylarginine metabolism are indicative of altered kidney function in intrauterine growth-restricted neonates
Authors: Kleinebenne Lina , Röhrig Waldemar , Ebach Fabian , Reutter Heiko , Pankraz Alexander , Heuchel Katharina Monika , Müller Andreas , Hilger Alina Christine
Published: August 2024

Background:

Intrauterine fetal growth restriction (IUGR) affects up to 10% of all pregnancies. Severe IUGR is associated with impaired kidney development, reduced nephron endowment, and chronic kidney disease later in life. Currently, no early predictive biomarker exists for detecting altered kidney function in neonates with IUGR. Because nephrons produce key enzymes for the metabolism of arginine and methylarginine components, we quantified and compared the concentrations of arginine and methylarginine metabolites between IUGR and non-IUGR neonates to identify potential biomarkers for the early detection of altered kidney function in IUGR neonates.

Methods:

Seventy-one IUGR and 123 non IUGR neonates were examined. Serum and Urine samples were obtained between 30 h and 5 days of life and between 5 and 70 days of life. Serum concentrations of creatinine, urea, symmetric and asymmetric-dimethylarginine metabolites (SDGV, SDMA, ADGV, and ADMA), guanidino-2-oxo-caproic acid (GOCA), citrulline, homocitrulline, arginine, and homoarginine were quantified using LC-MS/MS and standard clinical laboratory methods. Datasets were compared by Mann—Whitney--Wilcoxon or Chi-square tests for continuous and discrete parameters. P values were corrected for multiple comparisons using the Bonferroni method.

Results:

After Bonferroni correction, we found that serum creatinine, urea, SDGV, ADGV, and GOCA levels were significantly lower in neonates with IUGR. Consequently, the ratios of SDGV/SDMA, ADGV/ADMA, and GOCA/homoarginine were significantly lower in IUGR neonates.

Conclusion:

Our study suggests that arginine and methylarginine are possible early biomarkers for detecting altered kidney function in IUGR neonates.
Association of Federal COVID-19 Funding Distributions With Workforce and Capacity in Health Centers
Authors: Kett Paula , Cole Megan B. , Wright Brad , Frogner Bianca K.
Published: August 2024

Using novel national data, we examined the association between 2020 federal COVID-related funding targeted to health centers (i.e., H8 funding) and health center workforce and operational capacity measures that may be important for preserving patient access to care and staff safety. We assigned health centers to quartiles based on federal funding distribution per patient and used adjusted linear probability models to estimate differences in workforce and operational capacity outcomes across quartiles from April 2020 to June 2022. We found a nearly 6-fold difference in 2020 H8 funding per patient when comparing health centers in the lowest versus highest quartiles. Despite this difference, health centers’ outcomes improved similarly across quartiles over time, with the lowest-funded health centers having the greatest staffing and service capacity challenges. Our findings suggest that COVID-related health center funding may have contributed to stabilization of health centers’ workforce and operations. Amid concerns about staff turnover, sustained investments targeted to supporting workforce retention at health centers can help to ensure ongoing delivery of critical services.
A Mixed-Methods Study to Understand Community Health Worker Integration With Health Care Teams
Authors: McCutcheon Jessica , Cheng Iris , Quinones Selina , Mahabaleshwarkar Rohan , Denizard-Thompson Nancy , Wiseman Kimberly , Taylor Yhenneko , Wise Thomas Sherrie , Palakshappa Deepak
Published: August 2024

Two models employed to integrate community health workers (CHWs) in health care settings are community-clinical linkages and employment within health care. Our objective was to understand the variability in how these models are implemented. We conducted a mixed-methods study across a large health system that included CHW focus groups and electronic health record data on patients referred to the teams. We identified three primary themes in the four focus groups (N = 29) and found differences in the demographics and health care use of the 1,097 patients. Both community- and clinically embedded CHWs reported addressing diverse patient needs; yet, challenges persist in integrating both models.
Hepatic arterial infusion chemotherapy plus targeted therapy and immunotherapy versus systemic chemotherapy for advanced intrahepatic cholangiocarcinoma: a retrospective cohort study
Authors: Zheng Zhikai , Wang Jiongliang , Wu Tianqing , He Minrui , Pan Yangxun , Wang Juncheng , Chen Jinbin , Hu Dandan , Xu Li , Zhang Yaojun , Chen Minshan , Zhou Zhongguo
Published: August 2024

Background:

To improve the prognosis of advanced intrahepatic cholangiocarcinoma (iCCA), the authors retrospectively compared the effect and safety of combined hepatic arterial infusion chemotherapy (HAIC), targeted therapy, and immunotherapy with systemic chemotherapy (SC) in unresectable iCCA patients.

Methods:

The authors retrospectively enrolled 202 advanced iCCA patients treated with SC or targeted therapy, immunotherapy, and FOLFOX-HAIC combined between March 2015 and June 2023 at our institution. Two hundred two patients were divided into two groups based on the therapeutic regimens. Baseline characteristics and prognosis were reviewed and analyzed.

Results:

After 1-to-1 propensity score matching, 76 patients were included in each group. The triple combination therapy group demonstrated longer median overall survival (OS, 20.77 vs. 14.83 months, P=0.047), progression-free survival (PFS, 9.07 vs. 6.23 months, P<0.001), intrahepatic PFS (11.03 vs. 6.73 months, P<0.001), extrahepatic PFS (11.37 vs. 7.13 months, P=0.0064), and a higher objective response rate (35.5% vs. 14.5%, P=0.003) than the SC group. Fever, thrombocytopenia, elevated ALT, elevated AST, hypoalbuminemia, and hyperbilirubinemia were more common adverse events (AEs) in the triple combination therapy group, while fatigue and anemia were more prevalent in the SC group (P<0.05). For grades 3-4 AEs, the rates of elevated ALT were higher in the triple combination group (P=0.028).

Conclusions:

Compared with SC, triple combination therapy comprising HAIC, targeted therapy and immunotherapy appears to be an effective and safe treatment for advanced iCCA.
A machine learning model utilizing Delphian lymph node characteristics to predict contralateral central lymph node metastasis in papillary thyroid carcinoma: a prospective multicenter study
Authors: He Jia-ling , Yan Yu-zhao , Zhang Yan , Li Jin-sui , Wang Fei , You Yi , Liu Wei , Hu Ying , Wang Ming-Hao , Pan Qing-wen , Liang Yan , Ren Ming-shijing , Wu Zi-wei , You Kai , Zhang Yi , Jiang Jun , Tang Peng
Published: August 2024

Background:

This study aimed to use artificial intelligence (AI) to integrate various radiological and clinical pathological data to identify effective predictors of contralateral central lymph node metastasis (CCLNM) in patients with papillary thyroid carcinoma (PTC) and to establish a clinically applicable model to guide the extent of surgery.

Methods:

This prospective cohort study included 603 patients with PTC from three centers. Clinical, pathological, and ultrasonographic data were collected and utilized to develop a machine learning (ML) model for predicting CCLNM. Model development at the internal center utilized logistic regression along with other ML algorithms. Diagnostic efficacy was compared among these methods, leading to the adoption of the final model (random forest). This model was subject to AI interpretation and externally validated at other centers.

Results:

CCLNM was associated with multiple pathological factors. The Delphian lymph node metastasis ratio, ipsilateral central lymph node metastasis number, and presence of ipsilateral central lymph node metastasis were independent risk factors for CCLNM. Following feature selection, a Delphian lymph node-CCLNM (D-CCLNM) model was established using the Random forest algorithm based on five attributes. The D-CCLNM model demonstrated the highest area under the curve (AUC; 0.9273) in the training cohort and exhibited high predictive accuracy, with AUCs of 0.8907 and 0.9247 in the external and validation cohorts, respectively.

Conclusions:

The authors developed a new, effective method that uses ML to predict CCLNM in patients with PTC. This approach integrates data from Delphian lymph nodes and clinical characteristics, offering a foundation for guiding surgical decisions, and is conveniently applicable in clinical settings.
Anomalous left coronary artery from the pulmonary artery in a symptomatic adult: a case report
Authors: KC Sharada , Karki Parag , Khatiwada Abhikanta , Pokhrel Saroj
Published: August 2024

Introduction:

Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly. While only a few of those born with this anomaly survive into adulthood, it becomes an extremely rare diagnosis in adults.

Case presentation:

Here, the authors present a case of ALCAPA in a symptomatic adult female with angina and palpitations that was repeatedly missed on transthoracic echocardiogram.

Clinical discussion:

The adult type of ALCAPA is often missed due to non-specific changes in electrocardiogram, leading to reluctance for angiography. Therefore, identifying abnormal coronaries in echocardiogram is crucial.

Conclusion:

It is essential to consider anomalous coronary arteries as a differential diagnosis in patients with chest pain, despite their rarity. This case report highlights the role of various cardiac imaging modalities in improving the diagnostic yield of ALCAPA.
Using a Patient Portal to Screen Patients for Symptoms After Starting New Medications
Authors: Shah Sonam , Salazar Alejandra , Bennett Samuel , Fathima Aneesha , Kandikatla Renuka , Eguale Tewodros , Mirica Maria , Garabedian Pamela , Volk Lynn A. , Wright Adam , Schiff Gordon D.
Published: August 2024

Objective

Conduct systematic proactive pharmacovigilance screening for symptoms patients experienced after starting new medications using an electronic patient portal. We aimed to design and test the feasibility of the system, measure patient response rates, provide any needed support for patients experiencing potentially drug-related problems, and describe types of symptoms and problems patients report.

Methods

We created an automated daily report of all new prescriptions, excluding likely non-new and various over-the-counter meds, and sent invitations via patient portal inviting patients to inquire if they had started the medication, and if “yes,” inquire if they had they experienced any new symptoms that could be potential adverse drug effects. Reported symptoms were classified by clinical pharmacists using SOC MeDra taxonomy, and patients were offered follow-up and support as desired and needed.

Results

Of 11,724 included prescriptions for 9360 unique patients, 2758 (29.4%) patients responded. Of 2616 unique medication starts, patients reported at least 1 new symptom that represented a potential adverse drug reaction (ADR) in 678/2616 (25.9%). Nearly one-third of those experiencing new symptoms (30.3%) reported 2 or more new symptoms after initiating the drug. GI disorders accounted for 30% of the total reported ADRs.

Conclusions

Systematic portal-based surveillance for potential adverse drug reactions was feasible, had higher response rates than other methods (such as automated interactive phone calling), and uncovered rates of potential ADRs (roughly 1 in 4 patients) consistent with other methods/studies.
Survival and Prognostic Factors After Adrenalectomy for Secondary Malignancy
Authors: Rémond Agathe , Marciniak Camille , Lenne Xavier , Chouraki Vincent , Gobert Mathilde , Baud Gregory , Maillard Laure , Bouriez Damien , Liekens Ellen , Donatini Gianluca , Nominé-Criqui Claire , Ravenet Ambroise , Santucci Nicolas , Kuczma Paulina , Bouviez Nicolas , Tresallet Christophe , Mirallié Eric , Deguelte Sophie , Brunaud Laurent , Guerin Carole , Gronnier Caroline , Lifante Jean-Christophe , Bruandet Amélie , Theis Didier , Cortot Alexis , Scherpereel Arnaud , Hamroun Aghiles , Pattou François , Caiazzo Robert
Published: August 2024

Objective:

To provide a nationwide description of postoperative outcomes and analysis of prognostic factors following adrenalectomy for metastases.

Background:

Adrenal glands are a common site of metastases in many malignancies. Diagnosis of adrenal metastases is on the rise, leading to an increasing number of patient candidates for surgery without consensual management.

Methods:

We conducted a population-based study between January 2012 and December 2022 using the French National Health Data System (SNDS) and the Eurocrine registry (NCT03410394). The first database exhaustively covers all procedures carried out in France, while the second provides more clinical information on procedures and tumor characteristics, based on the experience of 11 specialized centers.

Results:

From the SNDS, we extracted 2515 patients who underwent adrenalectomy for secondary malignancy and 307 from the Eurocrine database. The most common primary malignancies were lung cancer (n=1203, 47.8%) and renal cancer (n=555, 22.1%). One-year survival was 84.3% (n=2120). Thirty-day mortality and morbidity rates were, respectively, 1.3% (n=32) and 29.9% (n=753, including planned intensive care unit - stays). Radiotherapy within the year before adrenalectomy was significantly associated with higher 30-day major complication rates (P=0.039). In the Eurocrine database, the proportion of laparoscopic procedures reached 85.3% without impairing resection completeness (R0: 92.9%). Factors associated with poor overall survival were the presence of extra-adrenal metastases (hazard ratio =0.64; P=0.031) and incomplete resection (≥R1; hazard ratio=0.41; P=0.015).

Conclusions:

The number of patients who can receive local treatment for adrenal metastases is rising, and adrenalectomy is more often minimally invasive and has a low morbidity rate. Subsequent research should evaluate which patients would benefit from adrenal surgery.
Urinary AD7c-NTP is Associated With Cognitive Recovery After Ischemic Stroke
Authors: Wang Yuqin , Tao Huimin , Cao Maohong , Cai Kefu
Published: August 2024

Urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) is regarded as a biomarker for β-amyloid protein deposition in Alzheimer disease (AD). The value of AD7c-NTP in predicting post-stroke cognitive recovery was worth exploring. In total, 224 patients with first-ever stroke were enrolled in this retrospective study. Cognitive assessment was evaluated by Mini-Mental State Examination (MMSE), and cognitive improvement was defined as MMSE scores ≥27 or 4-score elevation at 3-month follow-up after stroke. The AD7c-NTP level was 0.68±0.40 ng/mL in the 135 patients with cognitive improvement, while the AD7c-NTP level was 1.49±0.99 ng/mL in the 89 patients without improvement (P<0.001). Those displaying better cognitive recovery also had younger ages, higher MMSE scores, and lower NIHSS scores on admission. In multivariable logistic regression analysis, AD7c-NTP concentration (OR=9.14, 95% CI: 4.52-18.49, P<0.001), age (OR=1.04, 95% CI: 1.01-1.08, P=0.012), and NIHSS score on admission (OR=1.17, 95% CI: 1.07-1.28, P<0.001) remained the independent risk factors affecting cognitive recovery. The area under the receiver operating characteristics curve for AD7c-NTP in predicting unfavorable cognitive function was 0.80 (sensitivity: 0.73 and specificity: 0.84). Urinary AD7c-NTP is a valuable biomarker associated with post-stroke cognitive recovery. It might be adopted to discriminate coexisting AD pathology from vascular cognitive impairment.
The functions of leg muscles, structures and mechanisms in running
Authors: Usherwood James R.
Published: August 2024

The actions of the major human leg muscles are well established; however, the functions of these muscle actions during steady running remain unclear. Here, leg structures and mechanisms are considered in terms of their functions in meeting the task of a vehicle acting as an effective machine, supporting body weight during translation with low mechanical work demand and in supplying mechanical work economically. Legs are modelled as a sequence of linkages that predict muscle actions and reveal the varying muscle functions within the integrated leg. Work avoidance is achieved with isometric muscles and linkages that promote a sliding of the hip over the ground contact, resulting in an approximately horizontal path of the centre of mass. Economical work supply requires, for muscle with constrained power, shortening over the entire stance duration; this function is achieved by the hamstrings without disrupting the linkages resulting in work avoidance. In late stance, the two functions occur through coactivation of antagonistic muscles, providing one answer to Lombard’s paradox. Quadriceps and hamstring tensions result in opposing moments about both hip and knee joints, but by doing so perform the independent yet complementary roles of work avoidance during translating weight support and economical work supply.
Genetic variation in the brooding brittle-star: a global hybrid polyploid complex?
Authors: Hugall Andrew F. , Byrne Maria , O'Hara Timothy D.
Published: August 2024

The widespread and abundant brooding brittle-star (
Amphipholis squamata
) is a simultaneous hermaphrodite with a complex mitochondrial phylogeography of multiple divergent overlapping mtDNA lineages, high levels of inbreeding or clonality and unusual sperm morphology. We use exon-capture and transcriptome data to show that the nuclear genome comprises multiple (greater than 3) divergent (π > 6%) expressed components occurring across samples characterized by highly divergent (greater than 20%) mitochondrial lineages, and encompassing several other genera, including diploid dioecious species. We report a massive sperm genome size in
A. squamata
, an order of magnitude larger than that present in other brittle-stars, and consistent with our SNP-based measure of greatly elevated ploidy. Similarity of these genetic signatures to well-known animal systems suggests that
A. squamata
(and related taxa) is a hybrid polyploid asexual complex of variable subgenome origins, ploidy and reproductive mode. We discuss enigmatic aspects of
A. squamata
biology in this light. This putative allopolyploid complex would be the first to be reported from the phylum Echinodermata.
The intervals between zero-crossings of non-Gaussian stable random processes
Authors: Hopcraft Keith I. , Slater Daniel , Cao Yufei
Published: August 2024

Properties of the intervals between zero-crossings of non-Gaussian stable random processes are investigated. The classes of process considered are divided into those having short- and long-term memories, characterized by a coherence function that imbues dependence between a random variable measured at different times, which replaces the auto-correlation function, which exists only for the Gaussian case. For exponential coherence functions, all moments of probability densities for the intervals exist and a persistence parameter is determined that characterizes the rate of decay of the exponential tail of the probability densities, together with the full form of the density functions for selected values of the stability index. Results are verified with numerical simulation of a Cauchy process using a method independent of the theoretical development. For power-law coherence functions, the existence of moments of the distribution is conditional upon the indices characterizing the stable process and coherence function. The probability densities of the intervals have power-law tails depending on the product of these indices, with a logarithmic correction for specific combinations of these. An outer-scale or cut-off to power-law coherence functions regains a persistence parameter to the densities and the existence of all moments of the intervals.
Response analysis of the Duffing oscillator in dielectric elastomer transducers
Authors: Xie Yu-Xin , Li Huijiang , Song Xiaotian
Published: August 2024

To elucidate the nonlinear oscillations inherent to dielectric elastomer transducers (DETs), this study delves into the dynamic behaviour exhibited by a one-dimensional asymmetric Duffing oscillator, which may exhibit either hardening or softening stiffness. The investigation utilizes hyperelastic and visco-hyperelastic constitutive models to capture the nonlinear stiffness properties of dielectric elastomers within compliant transducers. The canonical Duffing equation is employed to articulate the oscillator’s motion, complemented by both asymptotic and quantitative analyses of unforced vibrations and harmonic excitation. Our results reveal that the distinctive stiffness characteristics observed in DETs arise from the complex interplay among hyperelasticity, rheology and applied electric fields. Contrary to conventional oscillators, Maxwell stress substantially modifies the nonlinear dynamics of DETs, an aspect that has been quantitatively dissected in this study. Furthermore, the influence of additional system parameters on forced oscillation has also been meticulously evaluated.
The evolutionary consequences of learning under competition
Authors: McNamara John M. , Dall Sasha R. X. , Houston Alasdair I. , Leimar Olof
Published: August 2024

Learning is a taxonomically widespread process by which animals change their behavioural responses to stimuli as a result of experience. In this way, it plays a crucial role in the development of individual behaviour and underpins substantial phenotypic variation within populations. Nevertheless, the impact of learning in social contexts on evolutionary change is not well understood. Here, we develop game theoretical models of competition for resources in small groups (e.g. producer–scrounger and hawk–dove games) in which actions are controlled by reinforcement learning and show that biases in the subjective valuation of different actions readily evolve. Moreover, in many cases, the convergence stable levels of bias exist at fitness minima and therefore lead to disruptive selection on learning rules and, potentially, to the evolution of genetic polymorphisms. Thus, we show how reinforcement learning in social contexts can be a driver of evolutionary diversification. In addition, we consider the evolution of ability in our games, showing that learning can also drive disruptive selection on the ability to perform a task.
Endothelial Immunosuppression in Atherosclerosis : Translational Control by Elavl1/HuR
Authors: Nicholas Sarah-Anne E. , Helming Stephen R. , Ménoret Antoine , Pathoulas Christopher , Xu Maria M. , Hensel Jessica , Kimble Amy L. , Heineman Brent , Jellison Evan R. , Reese Bo , Zhou Beiyan , Rodriguez-Oquendo Annabelle , Vella Anthony T. , Murphy Patrick A.
Published: August 2024

Atherosclerotic plaques are defined by the accumulation of lipids and immune cells beneath the endothelium of the arterial intima. CD8 T cells are among the most abundant immune cell types in plaque, and conditions linked to their activation correlate with increased levels of cardiovascular disease. As lethal effectors of the immune response, CD8 T cell activation is suppressed at multiple levels. These checkpoints are critical in dampening autoimmune responses, and limiting damage in cardiovascular disease.

Endothelial cells are well known for their role in recruiting CD8 T and other hematopoietic cells to low and disturbed flow (LDF) arterial regions that develop plaque, but whether they locally influence CD8 effector functions is unclear. Here, we show that endothelial cells can actively suppress CD8 T cell responses in settings of chronic plaque inflammation, but that this behavior is governed by expression of the RNA-binding protein Embryonic Lethal, Abnormal Vision-Like 1 (Elavl1). In response to immune cell recruitment in plaque, the endothelium dynamically shifts splicing of pre-mRNA and their translation to enhance expression of immune-regulatory proteins including C1q and CD27. This program is immuno-suppressive, and limited by Elavl1. We show this byCdh5(PAC)-CreERT2-mediated deletion of Elavl1 (ECKO), and analysis of changes in translation by Translating Ribosome Affinity Purification (TRAP). In ECKO mice, the translational shift in chronic inflammation is enhanced, leading to increased ribosomal association of C1q components and other critical regulators of immune response and resulting in a ∼70% reduction in plaque CD8 T cells. CITE-seq analysis of the remaining plaque T cells shows that they exhibit lower levels of markers associated with T cell receptor (TCR) signaling, survival, and activation. To understand whether the immunosuppressive mechanism occurred through failed CD8 recruitment or local modulation of T cell responses, we used a novelin vitroco-culture system to show that ECKO endothelial cells suppress CD8 T cell expansion—even in the presence of wild-type myeloid antigen-presenting cells, antigen-specific CD8 T cells, and antigen. Despite the induction of C1q mRNA by T cell co-culture in both wild-type and ECKO endothelial cells, we find C1q protein abundantly expressed only in co-culture with ECKO cells. Together, our data define a novel immune-suppressive transition in the endothelium, reminiscent of the transition of T cells to T-regs, and demonstrate the regulation of this process by Elavl1.
GPSA2: combining landmark-free and landmark-based methods in geometric morphometrics
Authors: Pomidor Benjamin J. , Dean Matt
Published: August 2024

Geometric Morphometrics (GM) revolutionized the way that biologists quantify shape variation among individuals, populations, and species. Traditional GM methods are based on homologous landmarks that can be reliably identified across all specimens in a sample. However, landmark-based studies are limited by the intensive labor required of anatomical experts, and regions of interest are often devoid of landmarks. These limitations inspired the development of many “landmark-free” approaches, but unreliable homology estimation and complicated underlying mathematical bases can make biological interpretation challenging. Here we present GPSA2, a novel method for analyzing surface meshes that combines landmark-based and landmark-free methodology within the familiar framework of Generalized Procrustes Analysis. In a major innovation, our method can incorporate user-defined landmarks into otherwise landmark-free analysis by transforming the landmarks into pointwise shape descriptors that are exploited during iterative homology estimation and superimposition (i.e. “alignment” of objects). GPSA2 also addresses a longstanding issue in morphometrics – the impact of variability in the distribution of sampled points over an object – by introducing a surface area-weighted shape distance metric and superimposition cost function. The improved homology approximation, together with the application of Taubin smoothing and an optional resistant-fit superimposition technique, ensure robust analysis even when a dataset exhibits regions of intense shape variation. We apply GPSA2 to two empirical datasets: 15 primate skulls and 369 mouse bacula. Our analyses show that inclusion of landmarks increases biological accuracy, and that GPSA2 produces summaries of shape variation that are easy to visualize and interpret.
Characterization of aberrant splicing in pediatric central nervous system tumors revealsCLK1as a candidate oncogenic dependency
Authors: Naqvi Ammar S. , Corbett Ryan J. , Seghal Priyanka , Conkrite Karina L. , Rathi Komal S. , Ennis Brian M. , Hayer Katharina E , Zhang Bo , Brown Miguel A. , Miller Daniel P. , Kraya Adam A. , Coleman Kaleem L. , Dybas Joseph M. , Geng Zhuangzhuang , Blackden Christopher , Arif Shehbeel , Chroni Antonia , Lahiri Aditya , Hollawell Madison L. , Storm Phillip B. , Haydar Dalia , Foster Jessica B. , Koptyra Mateusz , Madsen Peter J. , Diskin Sharon J. , Thomas-Tikhonenko Andrei , Resnick Adam C. , Rokita□ Jo Lynne
Published: August 2024

Pediatric brain cancer is the leading cause of disease-related mortality in children, and many aggressive tumors still lack effective treatment strategies. We characterized aberrant alternative splicing across pediatric brain tumors, identifying pediatric high-grade gliomas (HGGs) among the most heterogeneous. Annotating these events with UniProt, we identified 11,940 splice events in 5,368 genes leading to potential protein function changes. We discoveredCDC-like kinase 1(CLK1) is aberrantly spliced to favor exon 4 inclusion, resulting in a gain of two phosphorylation sites and subsequent activation. Inhibition ofCLK1with Cirtuvivint significantly decreased both cell viability and proliferation in the pediatric HGG KNS-42 cell line. Morpholino-mediated depletion ofCLK1exon 4 splicing reduced RNA expression, protein abundance, and cell viability with concurrent differential expression of 78 cancer genes and differential splicing at functional sites in 193 cancer genes. Our findings highlight a dependency of pediatric HGGs onCLK1and represent a promising therapeutic strategy.

Highlights

Splice variation across pediatric CNS tumors from 1,415 patients is heterogeneous

In HGGs, 11,940 splice events in 5,368 genes contain functional sites

CLK1exon 4 inclusion is prevalent in HGGs, driving canonical expression

CLK1splicing impacts cancer genes, phenotypes, and is therapeutically targetable
Understanding Electrical Brain Stimulation via the Reciprocity Theorem
Authors: Ness Torbjørn V. , Koch Christof , Einevoll Gaute T.
Published: August 2024

Electrical stimulation of nervous tissue is grounded in well-established biophysical principles, yet understanding its precise effect on neural activity remains challenging. This represents a major obstacle to both scientific and clinical applications of electrical brain stimulations.

We here show that the reciprocity theorem of electromagnetism can be applied more broadly than previously acknowledged, providing a framework for elucidating the effects of electrical brain stimulation on neurons. Through this perspective, we account for the observed weak frequency-dependence of extracellular stimulation–induced membrane potential changes, and the 1/rfalloff for nearby and 1/r2falloff for distant neurons. We also show that transcranial electrical stimulation at established safety limits (<4 mA) induces somatic membrane potential changes less than 0.1 mV in pyramidal cells, exhibiting weak spatial but strong orientation dependency across human neocortex.
The scope and limits of fine-grained image and category information in the ventral visual pathway
Authors: Badwal Markus W. , Bergmann Johanna , Roth Johannes , Doeller Christian F. , Hebart Martin N.
Published: August 2024

Humans can easily abstract incoming visual information into discrete semantic categories. Previous research employing functional MRI (fMRI) in humans has identified cortical organizing principles that allow not only for coarse-scale distinctions such as animate versus inanimate objects but also more fine-grained distinctions at the level of individual objects. This suggests that fMRI carries rather fine-grained information about individual objects. However, most previous work investigating fine-grained category representations either additionally included coarse-scale category comparisons of objects, which confounds fine-grained and coarse-scale distinctions, or only used a single exemplar of each object, which confounds visual and semantic information. To address these challenges, here we used multisession human fMRI (female and male) paired with a broad yet homogenous stimulus class of 48 terrestrial mammals, with 2 exemplars per mammal. Multivariate decoding and representational similarity analysis (RSA) revealed high image-specific reliability in low- and high-level visual regions, indicating stable representational patterns at the image level. In contrast, analyses across exemplars of the same animal yielded only small effects in the lateral occipital complex (LOC), indicating rather subtle category effects in this region. Variance partitioning with a deep neural network and shape model showed that across exemplar effects in EVC were largely explained by low-level visual appearance, while representations in LOC appeared to also contain higher category-specific information. These results suggest that representations typically measured with fMRI are dominated by image-specific visual or coarse-grained category information but indicate that commonly employed fMRI protocols may reveal subtle yet reliable distinctions between individual objects.

Significance Statement

While it has been suggested that functional MRI (fMRI) responses in ventral visual cortex carry fine-grained information about individual objects, much previous research has confounded fine-grained with coarse-scale category information or only used individual visual exemplars, which potentially confounds semantic and visual object information. Here we address these challenges in a multisession fMRI study where participants viewed a highly homogenous stimulus set of 48 land mammals with 2 exemplars per animal. Our results reveal a strong dominance of image-specific effects and additionally indicate subtle yet reliable category-specific effects in lateral occipital complex, underscoring the capacity of commonly employed fMRI protocols to uncover fine-grained visual information.
Bacterial strain sharing between humans, animals, and the environment among urban households
Authors: Kim Daehyun D. , Swarthout Jenna M. , Worby Colin J. , Chieng Benard , Mboya John , Earl Ashlee M. , Njenga Sammy M. , Pickering Amy J.
Published: August 2024

Identifying bacterial transmission pathways is crucial to inform strategies aimed at curbing the spread of pathogenic and antibiotic-resistant bacteria, especially in rapidly urbanizing low– and middle-income countries. In this study, we assessed bacterial strain-sharing and dissemination of antibiotic resistance across humans, domesticated poultry, canines, household soil, and drinking water in urban informal settlements in Nairobi, Kenya. We collected 321 samples from 50 households and performed Pooling Isolated Colonies-seq (PIC-seq) by sequencing pools of up to fiveEscherichia colicolonies per sample to capture strain diversity, strain-sharing patterns, and overlap of antibiotic-resistant genes (ARGs). Bacterial strains isolated from the household environment carried clinically relevant ARGs, reinforcing the role of the environment in antibiotic resistance dissemination. Strain-sharing rates and resistome similarities across sample types were strongly correlated within households, suggesting clonal spread of bacteria is a main driver of dissemination of ARGs in the domestic urban environment. Within households,E. colistrain-sharing was rare between humans and animals but more frequent between humans and drinking water.E. colicontamination in stored drinking water was also associated with higher strain-sharing between humans in the same household. Our study demonstrates that contaminated drinking water facilitates human to human strain sharing and water treatment can disrupt transmission.
Prenatal Dexamethasone Programs Autonomic Dysregulation in Female Rats
Authors: Madhavpeddi Lakshmi , Martinez Monique , Alvarez Jared , Sharma Arpan , Hu Chengcheng , Tobet Stuart A , Hale Taben M
Published: August 2024

Autonomic dysfunction is associated with cardiovascular and neurological disease, including hypertension, heart failure, anxiety, and stress-related disorders. Prior studies demonstrated that late gestation exposure to dexamethasone (DEX) resulted in female-biased increases in stress-responsive mean arterial pressure (MAP) and heart rate (HR), suggesting a role for glucocorticoid-mediated programming of autonomic dysfunction. The present study investigated the influence of sympathetic (SYM) or parasympathetic (PS) blockade on cardiovascular function in male and female rat offspring of mothers injected with DEXin utero(gestation days [GD]18-21). At 11-12-weeks of age, MAP, HR, and heart rate variability (HRV) were evaluated at baseline and in response to SYM antagonists (α1-adrenoceptor + β1-adrenoceptor), a PS (muscarinic) antagonist, or saline (SAL). To assess stress-responsive function, rats were exposed to acute restraint. Tyrosine hydroxylase was measured in adrenals and left ventricle, and gene expression for the β1adrenergic receptor was measured in left ventricle. Maternal DEX injection reduced basal HRV in male and female offspring. SYM blockade attenuated increases in stress-responsive HR and MAP. PS blockade elevated stress-responsive HR and MAP to a greater extent in Vehicle females. SYM and PS blockade produced equivalent effects on HR and MAP responses in male offspring, regardless of maternal treatment. Based on these findings, we suggest that maternal DEX injection disrupted autonomic regulation of cardiovascular function in females, resulting in a shift toward greater SYM input and less input from PS. Future studies will investigate whether changes in autonomic function are mediated by changes in central autonomic circuitry.

New and Noteworthy

These studies use pharmacological antagonists to characterize the nature of the autonomic dysregulation induced in female offspring exposed to the synthetic glucocorticoid, dexamethasone,in utero. The female offspring of dams injected with dexamethasone in late gestation show a reduction in vulnerability to parasympathetic blockade and an increase in responses to acute restraint stress even in the presence of sympathetic blockade. This suggests that late gestation dexamethasone disrupts the normal development of the autonomic function in females leading to a shift in the sympathovagal balance.
Optic flow density modulates corner-cutting independently of age in a virtual reality steering task
Authors: Giguere Arianna P. , Huxlin Krystel R. , Tadin Duje , Fajen Brett R. , Diaz Gabriel J.
Published: August 2024

There is a critical need to understand how aging visual systems contribute to age-related increases in vehicle accidents. We investigated the potential contribution of age-related detriments in steering based on optic flow, a source of information known to play a role in navigation control. Seventeen younger adults (mean age: 21.1 years) and thirteen older adults (mean age: 57.3 years) performed a virtual reality steering task. The virtual environment depicted movement at 19 m/s along a winding road. Participants were tasked with maintaining a central lane position while experiencing 8 repetitions of each combination of optic flow density (low, medium, high), turn radius (35, 55, 75 meters), and turn direction (left, right), presented in random order. All participants cut corners, but did so less on turns with rotational flow from distant landmarks and without proximal optic flow. The magnitude of this flow-related effect was independent of age, although older adults cut corners more on all turns. An exploratory gaze analysis revealed no age-related differences in gaze behavior. The lack of age-related differences in steering or gaze behavior as a function of optic flow implies that processing of naturalistic optic flow stimuli when steering may be preserved with age.
Whole Exome Sequencing RevealsFCGBPVariant Associated with Spontaneous Intraabdominal Hemorrhage in Severe Acute Pancreatitis
Authors: Tang Qiu-Yi , Hu Yue-Peng , Yang Qi , Zhou Jing , Zhang Jing-Zhu , Yang Jie , Hao Haibin , Li Gang , Li Bai-Qiang , Ke Lu , Tong Zhi-Hui , Liu Yu-Xiu , Yu Evan Yi-Wen , Li Wei-Qin
Published: August 2024

This study sought to identify genetic cause of spontaneous intraabdominal hemorrhage (SIH) in severe acute pancreatitis (SAP) to develop more effective treatment for this life-threatening complication. A four-phase study was conducted, leveraging a large-scale acute pancreatitis (AP) patients (n=600); the first phase involved whole-exome sequencing analyses, and identified specific exonic variant located inFCGBP(i.e., rs1326680184) that was consistently associated with SIH; the second phase performed serum ELISA tests, and revealed thatFCGBPvariant altered FCGBP level and further led to predisposition of SIH; the third phase conducted an i)in-vivoexperiment with aFcgbp-knockdown mouse model, and demonstrated lower expression ofFcgbpled to more severe AP morphology and higher risk of hemorrhage; ii)in-vitroexperiment withFCGBP-knockdown human vascular fibroblasts demonstrated that down-regulatedFCGBPexpression could destabilize the vascular wall, and lead to vascular injury in SAP; the fourth phase comparedFCGBPvariant carriers to non-carriers with clinical characteristics, and foundFCGBPvariant associated with higher risks of poor complications and AP prognosis and enhanced the diagnostic capability as an indicator. These findings provide important insights into the underlying mechanism of SIH in SAP, and facilitate therapeutic development for AP prognosis and critical care in an early phase.

Highlights

Genetic mutation inFCGBPpresents a strong association with predisposition of spontaneous intraabdominal hemorrhage, and provide a novel insight in increasing the severity of acute pancreatitis when knockdown the expression of Fcgbp.

The incorporation ofFCGBPmutation as an indicator enhances the ability of clinical assessment with respect to complications and mortality of acute pancreatitis in an early phase before manifestation.

Our findings highlight the geneFCGBPas a probable pathogenic cause of spontaneous intraabdominal hemorrhage in severe acute pancreatitis patients, which enable a development of effective targeted therapies in improving the prognosis and critical care of severe acute pancreatitis.
Assembling the Challenge of Multimorbidity in Zimbabwe: A Participatory Ethnographic Study
Authors: Dixon Justin , Dhodho Efison , Mundoga Fionah , Webb Karen , Chimberengwa Pugie , Mhlanga Trudy , Nhapi Tatenda , Chinyanga Theonevus Tinashe , Mudavanhu Justice , Nkala Lee , Nyabereka Ronald , Gwati Gwati , Shambira Gerald , Zaranyika Trust , Chandler Clare I.R. , Ferrand Rashida A. , Ndhlovu Chiratidzo Ellen
Published: August 2024

Multimorbidity, increasingly recognised as a global health challenge, has recently emerged on the health agendas of many lower-income countries, including in Africa. Yet with its conceptual origins in the global North, its meaning and possible utility for stakeholders in lower-resources settings remains abstract. This study drew together policymakers, public health practitioners, academics, health informaticians, health professionals, and people living with multimorbidity (PLWMM) in Zimbabwe to understand: What is the transformative potential and possible limitations of elevating multimorbidity as a priority in this setting? To bring these different perspectives into conversation, we used a participatory ethnographic design that involved a health facility survey, participant-observation, in-depth interviews, audio-visual diaries, and participatory workshops. Multimorbidity, we found, was new to many respondents but generally viewed as a meaningful and useful concept. It foregrounded a range of challenges related to the ‘vertical’ organisation and uneven funding of different diseases, while revealing promising opportunities for integration across entrenched silos of knowledge and practice. However, with capacity and momentum to address multimorbidity currently concentrated within the HIV programme, there was concern that multimorbidity could itself become verticalized, undercutting its transformative potential. Participants agreed that responding to multimorbidity requires a decisive shift from vertical, disease-centred programming to restore the comprehensive primary care that undergirded Zimbabwe’s once-renowned health system. It also means building a policy-enabling environment that values generalist (as well as specialist) knowledge, ground-level experience, and inclusive stakeholder engagement. The ‘learning’ health system, we conclude, represents a promising conceptual lens for unifying these imperatives, providing a tangible framework for how knowledge, policy, and practice synergise within more self-reliant, person-centred health systems able to respond to ever-evolving complex health challenges like multimorbidity.
A time-multiplexing approach to shared ventilation
Authors: Yarinsky Jacob Q , Blocker Abby , Alves Pinto Carolyna Yamamoto , Passaglia Christopher L , Pasetto Stefano , Enderling Heiko , Muncey Aaron R
Published: August 2024

Ventilator shortages during the COVID-19 pandemic forced some hospitals to practice and many to consider shared ventilation, where a single ventilator is used to ventilate multiple patients simultaneously. However, the high risk of harm to co-ventilated patients secondary to the inability to treat anatomically different patients or safely adapt to dynamic ventilation requirements has prevented full adoption of multi-patient coventilation. Here, a time-multiplexing approach to shared ventilation is introduced to overcome these safety concerns. A proof-of-concept device consisting of electromechanically coupled ball valves to induce customized resistances and facilitate the delivery of alternating breaths from the ventilator to each patient is presented. The approach successfully ventilated two test lungs, and individualized tidal volume combinations of various magnitudes were produced. Over five hours of co-ventilation, consistency in tidal volume delivery was comparable to independent ventilation. Time-multiplexing was able to facilitate delivery of statistically unique tidal volumes to two test lungs and maintain the consistency of tidal volumes within each test lung while independently ventilated with identical parameters. The ability to adjust each test lung’s inspiratory pressures dynamically and independently was also demonstrated. The time-multiplexing approach has the potential to increase the viability of co-ventilation for ongoing and future ventilator shortages.
ThermoTargetMiner as a proteome integral solubility alteration target database for prospective drugs against lung cancer
Authors: Lyu Hezheng , Gharibi Hassan , Sokolova Bohdana , Voiland Anna , Nilsson Brady , Meng Zhaowei , Gaetani Massimiliano , Saei Amir Ata , Zubarev Roman A.
Published: August 2024

Knowledge of the targets of therapeutic compounds is vital for understanding their action mechanisms and side effects, but such valuable data is seldom available. The multiple complementary techniques needed for comprehensive target characterization must combine data reliability with sufficient analysis throughput. Here, we leveraged the Proteome Integral Solubility Alteration (PISA) assay to comprehensively characterize the targets of 67 approved drugs and candidate compounds against lung cancer. The analysis was performed on two cell lines representing different lung cancer phenotypes and novel targets for 77% of the tested molecules were found. Comparison of the protein solubility shifts in lysate vs. living cells highlighted the targets directly interacting with the compounds. As PISA analysis is now joining the arsenal of fast and reliable target characterization techniques, the presented database, ThermoTargetMiner, will become a useful resource in lung cancer research.