bluuebunny/crossref_metadata_2025 huggingface dataset:
A Retrospective Review on the Effects of Nasoalveolar Molding on Infant Weight Gain and Time to Primary Lip Repair in Unilateral and Bilateral Cleft Lip and Palate
Authors: Ndem Idorenyin E. , Kugar Meredith , Caruso Deanna , Duchesneau Emilie , Agala Chris B. , Mehta Nina , Van Aalst John , Wood Jeyhan S.
Published: May 2024

Background:

In patients with severe cleft deformities, nasoalveolar molding (NAM) can improve long-term lip and nasal symmetry by reducing the size of the cleft, better aligning the alveolus, lip, and nose, and making the primary lip repair more predictable. Despite the increasing number of published studies on modified NAM techniques, the effects of NAM on weight gain and time to primary lip repair remain less studied.

Purpose:

This study aims to evaluate the effect of NAM on feeding, weight gain, growth velocity, and time to primary lip repair in patients with complete unilateral and bilateral cleft lip and palate (BCLP).

Methods:

A retrospective, single-institution review was conducted to identify patients with complete unilateral and BCLP treated between January 2005 and June 2020. The following outcomes were measured: age at the time of lip and palate repairs; weight, height, and BMI on the date of lip repair; and growth velocity. Crude and standardized morbidity ratio-weighted differences in outcome means and 95% confidence intervals were estimated using t tests.

Results:

Seventy-one patients were included in the study, 30 of whom underwent NAM. On average, patients treated with preoperative NAM underwent lip repair later than patients who were not treated with NAM. They also had a greater growth velocity and BMI when compared to their non-NAM counterparts. These differences, however, were not statistically significant.

Conclusion:

This study explores the relationships between the use of NAM and preoperative weight gain, as well as time to lip repair in patients with complete unilateral and BCLP. Additional studies may be needed to better elucidate the effect of NAM on weight gain and the time required for surgical repair of the cleft lip and palate.
Normothermic Machine Perfusion Reduces Transfusion Requirements Even After Static Cold Storage: A 1 y Retrospective Single-center Analysis
Authors: Mathis Simon , Putzer Gabriel , Gasteiger Lukas , Eschertzhuber Stephan , Schneeberger Stefan , Cardini Benno , Hell Tobias , Martini Judith
Published: May 2024

Background.

Normothermic machine perfusion (NMP) of liver grafts has been shown to reduce intraoperative catecholamine consumption and the need for allogenic blood products after reperfusion compared with organs undergoing classical static cold storage (SCS). This study aimed to investigate the effects of an NMP phase after SCS (NMP after SCS) of liver grafts in terms of postreperfusion hemodynamics and transfusion requirements.

Methods.

Eighteen recipients of NMP after SCS grafts were matched according to recipient age, donor age, and model for end-stage liver disease score in a 1:2 ratio with recipients of an SCS graft. Postreperfusion hemodynamics and the need for catecholamines, blood products, and clotting factors were compared.

Results.

After reperfusion of the organ, patients in the NMP after SCS group showed significantly reduced transfusion requirements for packed red blood cells and platelet concentrates compared with patients of the SCS group (P < 0.001 and P = 0.018, respectively). In addition, patients in the NMP after SCS group received less fibrinogen concentrate (NMP after SCS group 0 [0–1.5] g versus SCS group 2 [0–4] g; P = 0.0163). No differences in postreperfusion hemodynamics could be detected between groups.

Conclusions.

This retrospective analysis shows that NMP reduces postreperfusion requirements of red blood cells, platelet concentrates, and fibrinogen concentrate even if installed after a phase of organ SCS, because it may be practiced on most centers where NMP is available.
Expanding Access to High KDPI Kidney Transplant for Recipients Aged 60 y and Older: Cost Utility and Survival
Authors: Bamforth Ryan J. , Trachtenberg Aaron , Ho Julie , Wiebe Chris , Ferguson Thomas W. , Rigatto Claudio , Forget Evelyn , Dodd Nancy , Tangri Navdeep
Published: May 2024

Background.

Modern organ allocation systems are tasked with equitably maximizing the utility of transplanted organs. Increasing the use of deceased donor organs at risk of discard may be a cost-effective strategy to improve overall transplant benefit. We determined the survival implications and cost utility of increasing the use of marginal kidneys in an older adult Canadian population of patients with end-stage kidney disease.

Methods.

We constructed a cost-utility model with microsimulation from the perspective of the Canadian single-payer health system for incident transplant waitlisted patients aged 60 y and older. A kidney donor profile index score of ≥86 was considered a marginal kidney. Donor- and recipient-level characteristics encompassed in the kidney donor profile index and estimated posttransplant survival scores were used to derive survival posttransplant. Patients were followed up for 10 y from the date of waitlist initiation. Our analysis compared the routine use of marginal kidneys (marginal kidney scenario) with the current practice of limited use (status quo scenario).

Results.

The 10-y mean cost and quality-adjusted life-years per patient in the marginal kidney scenario were estimated at $379 485.33 (SD: $156 872.49) and 4.77 (SD: 1.87). In the status quo scenario, the mean cost and quality-adjusted life-years per patient were $402 937.68 (SD: $168 508.85) and 4.37 (SD: 1.87); thus, the intervention was considered dominant. At 10 y, 62.8% and 57.0% of the respective cohorts in the marginal kidney and status quo scenarios remained alive.

Conclusions.

Increasing the use of marginal kidneys in patients with end-stage kidney disease aged 60 y and older may offer cost savings, improved quality of life, and greater patient survival in comparison with usual care.
Similar enzymatic functions in distinct bioluminescence systems: evolutionary recruitment of sulfotransferases in ostracod light organs
Authors: Lau Emily S. , Goodheart Jessica A. , Anderson Nolan T. , Liu Vannie L. , Mukherjee Arnab , Oakley Todd H.
Published: May 2024

Genes from ancient families are sometimes involved in the convergent evolutionary origins of similar traits, even across vast phylogenetic distances. Sulfotransferases are an ancient family of enzymes that transfer sulfate from a donor to a wide variety of substrates, including probable roles in some bioluminescence systems. Here, we demonstrate multiple sulfotransferases, highly expressed in light organs of the bioluminescent ostracod
Vargula tsujii
, transfer sulfate
in vitro
to the luciferin substrate, vargulin. We find luciferin sulfotransferases (LSTs) of ostracods are not orthologous to known LSTs of fireflies or sea pansies; animals with distinct and convergently evolved bioluminescence systems compared to ostracods. Therefore, distantly related sulfotransferases were independently recruited at least three times, leading to parallel evolution of luciferin metabolism in three highly diverged organisms. Reuse of homologous genes is surprising in these bioluminescence systems because the other components, including luciferins and luciferases, are completely distinct. Whether convergently evolved traits incorporate ancient genes with similar functions or instead use distinct, often newer, genes may be constrained by how many genetic solutions exist for a particular function. When fewer solutions exist, as in genetic sulfation of small molecules, evolution may be more constrained to use the same genes time and again.
Automated optimization of the solubility of a hyper-stable α-amylase
Authors: Ali Montader , Greenig Matthew , Oeller Marc , Atkinson Misha , Xu Xing , Sormanni Pietro
Published: May 2024

Most successes in computational protein engineering to date have focused on enhancing one biophysical trait, while multi-trait optimization remains a challenge. Different biophysical properties are often conflicting, as mutations that improve one tend to worsen the others. In this study, we explored the potential of an automated computational design strategy, called CamSol Combination, to optimize solubility and stability of enzymes without affecting their activity. Specifically, we focus on
Bacillus licheniformis
α-amylase (BLA), a hyper-stable enzyme that finds diverse application in industry and biotechnology. We validate the computational predictions by producing 10 BLA variants, including the wild-type (WT) and three designed models harbouring between 6 and 8 mutations each. Our results show that all three models have substantially improved relative solubility over the WT, unaffected catalytic rate and retained hyper-stability, supporting the algorithm’s capacity to optimize enzymes. High stability and solubility embody enzymes with superior resilience to chemical and physical stresses, enhance manufacturability and allow for high-concentration formulations characterized by extended shelf lives. This ability to readily optimize solubility and stability of enzymes will enable the rapid and reliable generation of highly robust and versatile reagents, poised to contribute to advancements in diverse scientific and industrial domains.
Children are sensitive to the number of sources when relying on gossip
Authors: Shinohara Asami , Kanakogi Yasuhiro , Okumura Yuko , Kobayashi Tessei
Published: May 2024

Gossip allows children to effectively identify cooperative or trustworthy partners. However, the risk of being deceived must be faced because gossip may be false. One clue for determining gossip's veracity is the number of its sources since multiple informants spreading identical reputational information about others might imply that another's moral traits are viewed unanimously among members of a social group. We investigated whether 7-year-olds (
N
= 108) would trust gossip from multiple independent sources. In our study, they received multiple pieces of positive/negative reputational information about one agent and neutral information about another agent by gossip from either single or multiple informants. Then they allocated rewards to and chose rewards from the gossip targets. The 7-year-olds acted upon positive gossip from multiple informants and did not rely on positive gossip from a single informant. By contrast, they relied on negative gossip regardless of the number of informants. In either valence, however, they were more likely to allocate rewards based on gossip from multiple informants than a single informant. This result indicates they are sensitive to an objective index, specifically the number of sources, for judging the veracity of gossip.
Big bang, low bar—risk assessment in the public arena
Authors: Price Huw
Published: May 2024

One of the basic principles of risk management is that we should always keep an eye on ways that things could go badly wrong, even if they seem unlikely. The more disastrous a potential failure, the more improbable it needs to be, before we can safely ignore it. This principle may seem obvious, but it is easily overlooked in public discourse about risk, even by well-qualified commentators who should certainly know better. The present piece is prompted by neglect of the principle in recent discussions about the potential existential risks of artificial intelligence. The failing is not peculiar to this case, but recent debates in this area provide some particularly stark examples of how easily the principle can be overlooked.
Discrete-to-continuum models of pre-stressed cytoskeletal filament networks
Authors: Köry J. , Hill N. A. , Luo X. Y. , Stewart P. S.
Published: May 2024

We introduce a mathematical model for the mechanical behaviour of the eukaryotic cell cytoskeleton. This discrete model involves a regular array of pre-stressed protein filaments that exhibit resistance to enthalpic stretching, joined at cross-links to form a network. Assuming that the inter-cross-link distance is much shorter than the length scale of the cell, we upscale the discrete force balance to form a continuum system of governing equations and deduce the corresponding macroscopic stress tensor. We use these discrete and continuum models to analyse the imposed displacement of a bead placed in the domain, characterizing the cell rheology through the force–displacement curve. We further derive an analytical approximation to the stress and strain fields in the limit of small bead radius, predicting the net force required to generate a given deformation and elucidating the dependency on the microscale properties of the filaments. We apply these models to networks of the intermediate filament vimentin and demonstrate good agreement between predictions of the discrete, continuum and analytical approaches. In particular, our model predicts that the network stiffness increases sublinearly with the filament pre-stress and scales logarithmically with the bead size.
Methods to assess antibacterial, antifungal and antiviral surfaces in relation to touch and droplet transfer: a review, gap-analysis and suggested approaches.
Authors: Cunliffe Alexander J , Askew Peter , Iredale Gillian , Marchant Abby , Redfern James
Published: May 2024

To help assess whether a potentially antimicrobial material, surface, or coating provides antimicrobial efficacy, a number of standardised test methods have been developed internationally. Ideally, these methods should generate data that supports the materials efficacy when deployed in the intended end-use application. These methods can be categorised based on their methodological approach such as suspension tests, agar plate/zone diffusion tests, surface inoculation tests, surface growth tests or surface adhesion tests. To support those interested in antimicrobial coating efficacy, this review brings together an exhaustive list of methods (for porous and non-porous materials), exploring the methodological and environmental parameters used to quantify antibacterial, antifungal, or viral activity. This analysis demonstrates that antimicrobial efficacy methods that test either fungi or viruses are generally lacking, whilst methods that test bacteria, fungi and viruses are not designed to simulate end-use/lack realistic conditions. As such, a number of applications for antimicrobial activity across medical touch screens, medical textiles and gloves and transport seat textiles are explored as example applications, providing guidance on modifications to existing methods that may better simulate the intended end-use of antimicrobial materials.
Flagellimonas halotolerans sp. nov., a novel bacterium isolated from the South China Sea
Authors: Guo Dan-Yuan , Liu Wen-Li , Li Jia-Ling , Wang Pan-Deng , Chen Sen-Hua , Liu Lan , Nie Guo-Xing , Yang Zi-Wen , Li Wen-Jun
Published: May 2024

Two Gram-stain-negative strains, designed SYSU M86414T and SYSU M84420, were isolated from marine sediment samples of the South China Sea (Sansha City, Hainan Province, PR China). These strains were aerobic and could grow at pH 6.0–8.0 (optimum, pH 7.0), 4–37 °C (optimum, 28 °C), and in the presence of 0–10 % NaCl (w/v; optimum 3 %). The predominant respiratory menaquinone of strains SYSU M86414T and SYSU M84420 was MK-6. The primary cellular polar lipid was phosphatidylethanolamine. The major cellular fatty acids (>10 %) in both strains were iso-C15 : 0, iso-C15 : 1 G, and iso-C17 : 0 3-OH. The DNA G+C content of strains SYSU M86414T and SYSU M84420 were both 42.10 mol%. Phylogenetic analyses based on 16S rRNA gene sequences and core genes indicated that these novel strains belonged to the genus Flagellimonas and strain SYSU M86414T showed the highest 16S rRNA gene sequence similarity to Flagellimonas marinaquae JCM 11811T (98.83 %), followed by Flagellimonas aurea BC31-1-A7T (98.62 %), while strain SYSU M84420 had highest 16S rRNA gene sequence similarity to F. marinaquae JCM 11811T (98.76 %) and F. aurea BC31-1-A7T (98.55 %). Based on the results of polyphasic analyses, strains SYSU M86414T and SYSU M84420 should be considered to represent a novel species of the genus Flagellimonas, for which the name Flagellimonas halotolerans sp. nov. is proposed. The type strain of the proposed novel isolate is SYSU M86414T (=GDMCC 1.3806T=KCTC 102040T).
Sex-dependent adipose glucose partitioning by the mitochondrial pyruvate carrier
Authors: Shannon Christopher E , Bakewell Terry , Fourcaudot Marcel J , Ayala Iriscilla , Romero Giovanna , Asmis Mara , Freitas Lima Leandro C , Wallace Martina , Norton Luke
Published: May 2024

Objective

The mitochondrial pyruvate carrier (MPC) occupies a critical node in intermediary metabolism, prompting interest in its utility as a therapeutic target for the treatment of obesity and cardiometabolic disease. Dysregulated nutrient metabolism in adipose tissue is a prominent feature of obesity pathophysiology, yet the functional role of adipose MPC has not been explored. We investigated whether the MPC shapes the adaptation of adipose tissue to dietary stress in female and male mice.

Methods

The impact of pharmacological and genetic disruption of the MPC on mitochondrial pathways of triglyceride assembly (lipogenesis and glyceroneogenesis) was assessed in 3T3L1 adipocytes and murine adipose explants, combined with analyses of adipose MPC expression in metabolically compromised humans. Whole-body and adipose-specific glucose metabolism were subsequently investigated in male and female mice lacking adipocyte MPC1 (Mpc1AD-/-) and fed either standard chow, high-fat western style, or high-sucrose lipid restricted diets for 24 weeks, using a combination of radiolabeled tracers and GC/MS metabolomics.

Results

Treatment with UK5099 or siMPC1 impaired the synthesis of lipids and glycerol-3-phosphate from pyruvate and blunted triglyceride accumulation in 3T3L1 adipocytes, whilst MPC expression in human adipose tissue was negatively correlated with indices of whole-body and adipose tissue metabolic dysfunction. Mature adipose explants fromMpc1AD-/-mice were intrinsically incapable of incorporating pyruvate into triglycerides.In vivo, MPC deletion restricted the incorporation of circulating glucose into adipose triglycerides, but only in female mice fed a zero fat diet, and this associated with sex-specific reductions in tricarboxylic acid cycle pool sizes and compensatory transcriptional changes in lipogenic and glycerol metabolism pathways. However, whole-body adiposity and metabolic health were preserved inMpc1AD-/-mice regardless of sex, even under conditions of zero dietary fat.

Conclusion

These findings highlight the greater capacity for mitochondrially driven triglyceride assembly in adipose from female versus male mice and expose a reliance upon MPC-gated metabolism for glucose partitioning in female adipose under conditions of dietary lipid restriction.
Maximizing photon utilization in spectroscopic single-molecule localization microscopy using symmetrically dispersed dual-wedge prisms
Authors: Yeo Wei-Hong , Brenner Benjamin , Lee Youngseop , Kweon Junghun , Sun Cheng , Zhang Hao F.
Published: May 2024

Single-molecule localization microscopy (SMLM) enables super-resolution imaging on conventional fluorescent microscopes. Spectroscopic SMLM (sSMLM) further allows highly multiplexed super-resolution imaging. We report an easy-to-implement symmetrically dispersed dual-wedge prism (SDDWP)-sSMLM design that maximizes photon utilization. We first symmetrically dispersed photons to the −1stand +1storders in an optical assembly using two identical dual-wedge prisms (DWPs). Then we computationally extracted the fluorophores’ spatial position and spectral characteristics using photons in both the −1stand +1storders. Theoretical analysis and experimental validation showed lateral and spectral precisions of 10.1 nm and 0.3 nm, respectively, representing improvements of 28% and 48% over our previous DWP-based system, where emitted photons are divided separately for spatial and spectral analyses.
Cortical evoked activity is modulated by the sleep state in a ferret model of tinnitus. A case study
Authors: Milinski Linus , Nodal Fernando R. , Emmerson Matthew K.J. , King Andrew J. , Vyazovskiy Vladyslav V. , Bajo Victoria M.
Published: May 2024

Subjective tinnitus is a phantom auditory perception in the absence of an actual acoustic stimulus. It affects 15% of the global population and can be associated with disturbed sleep, poor mental health and quality of life. To date, there is no effective treatment for tinnitus. We used adult ferrets exposed to mild noise trauma as an animal model of tinnitus. We assessed the phantom percept using two operant paradigms sensitive to tinnitus, silent gap detection and silence detection, before and up to six months after the mild acoustic trauma. The integrity of the auditory brainstem was assessed over the same period using auditory brainstem response recordings.

Following noise overexposure, ferrets developed lasting, frequency–specific impairments in operant behaviour and evoked brainstem activity. To explore the interaction between sleep and tinnitus, in addition to tracking the behavioural markers of noise–induced tinnitus and hearing impairment after noise overexposure, we evaluated sleep–wake architecture and spontaneous and auditory–evoked EEG activity across vigilance states. Behavioural performance and auditory–evoked activity measurements after noise overexposure suggested distinct degrees of tinnitus and hearing impairment between individuals. Animals that developed signs of tinnitus consistently developed sleep impairments, suggesting a link between the emergence of noise–induced tinnitus and sleep disruption. However, neural markers of tinnitus were reduced during sleep, suggesting that sleep may transiently mitigate tinnitus.

These results reveal the importance of sleep–wake states in tinnitus and suggest that understanding the neurophysiological link between sleep and tinnitus may provide a new angle for research into the causes of phantom percepts and inform future treatments.
BODY SURFACE GASTRIC MAPPING DELINEATES SPECIFIC PATIENT PHENOTYPES IN ADOLESCENTS WITH FUNCTIONAL DYSPEPSIA AND GASTROPARESIS
Authors: Humphrey Gayl , Keane Celia , Schamberg Gabriel , Benitez Alain , Calder Stefan , Xu Binghong , Sadaka Christian , Andrews Christopher N. , O’Grady Greg , Gharibans Armen , Mousa Hayat
Published: May 2024

Importance

Persistent upper gastroduodenal symptoms, such as nausea, vomiting, bloating, and abdominal pain, are widespread among pediatric patients. Multiple overlapping symptoms complicate the diagnostic process, necessitating the development of novel gastric function tests with actionable biomarkers. Body Surface Gastric Mapping (BSGM) has emerged as a promising diagnostic tool for gastroduodenal disorders, and this is the first detailed evaluation in adolescents.

Objective

This study aimed to assess the utility of BSGM in delineating specific patient phenotypes among adolescents with functional dyspepsia (FD) and gastroparesis in order to guide clinical decision-making.

Design

A prospective cross-sectional study recruited adolescents aged 12 to 21 between 2022 and 2024.

Setting

Controls were recruited from New Zealand (controls) and Patients from the Children’s Hospital of Philadelphia, USA.

Participants

Prospectively recruited participants included controls without gastroduodenal symptoms or motility-related medication usage and patients diagnosed with either gastroparesis (delayed gastric emptying test (GET)) or FD according to ROME IV criteria and a normal GET.

Procedures

BSGM was performed using a standardized protocol, including simultaneous symptom reporting and the completion of validated symptom, psychometric and physical health questionnaires.

Main Outcome

The primary outcome was to evaluate if BSGM could delineate specific patient phenotypes and provide clinically meaningful distinctions between gastroparesis and FD diagnoses, utilizing BSGM spectral outcome data.

Results

Fifty-six subjects were recruited (31 controls, 25 patients); median age 16; 96% of patients were female. Control data showed that adult reference intervals provided an acceptable interpretation framework. Patients with FD (n=10) and gastroparesis (n=15) had common symptoms, mental health, quality of life and functional disability (all p>0.05). Three distinct BSGM phenotypes were identified:BSGM Normal(n=10),BSGM Delay(n=8), andLow Stability/Low Amplitude(n=7), having spectral differences in BMI-Adjusted Amplitude 34.6 vs 39.1 vs 19.9 (p=.01) and Gastric Alimetry Rhythm Index: 0.45 vs 0.45 vs 0.19 (p=.003).

BSGM phenotypes demonstrated differences in symptoms (nauseap=0.04), physical health (p=.04) and psychometrics (anxietyp=.03).

Conclusion and Relevance

Adolescent patients with FD and gastroparesis have overlapping clinical profiles, making individualized treatment challenging. Conversely, employing BSGM to categorize patients into distinct phenotypes revealed clinically relevant differences, offering potential avenues for individualized therapeutic pathways.
Empowering PET Imaging Reporting with Retrieval-Augmented Large Language Models and Reading Reports Database: A Pilot Single Center Study
Authors: Choi Hongyoon , Lee Dongjoo , Kang Yeon-koo
Published: May 2024

Introduction

The potential of Large Language Models (LLMs) in enhancing a variety of natural language tasks in clinical fields includes medical imaging reporting. This pilot study examines the efficacy of a retrieval-augmented LLM system considering zero-shot learning capability of LLMs, integrated with a comprehensive PET reading reports database, in improving referring previous reports and decision-making.

Methods

We developed a custom LLM framework enhanced with retrieval capabilities, leveraging a database encompassing nine years of PET imaging reports from a single center. The system employs vector space embedding of the reports database to facilitate retrieval based on similarity metrics. Queries prompt the system to retrieve embedded vectors, generating context-based answers and identifying similar cases or differential diagnoses from the historical reports database.

Results

The system efficiently organized embedded vectors from PET reading reports, showing that imaging reports were accurately clustered within the embedded vector space according to the diagnosis or PET study type. Based on this system, a proof-of-concept chatbot was developed and showed the framework’s potential in referencing reports of previous similar cases and identifying exemplary cases for various purposes. Additionally, it demonstrated the capability to offer differential diagnoses, leveraging the vast database to enhance the completeness and precision of generated reports.

Conclusions

The integration of a retrieval-augmented LLM with a large database of PET imaging reports represents an advancement in medical reporting within nuclear medicine. By providing tailored, data-driven insights, the system not only improves the relevance of PET report generation but also supports enhanced decision-making and educational opportunities. This study underscores the potential of advanced AI tools in transforming medical imaging reporting practices.
Cone bipolar cell synapses generate transient versus sustained signals in parallel ON pathways of the mouse retina
Authors: Kuo Sidney P. , Yu Wan-Qing , Srivastava Prerna , Okawa Haruhisa , Santina Luca Della , Berson David M. , Awatramani Gautam B. , Wong Rachel O.L. , Rieke Fred
Published: May 2024

Parallel processing is a fundamental organizing principle in the nervous system, and understanding how parallel neural circuits generate distinct outputs from common inputs is a key goal of neuroscience. In the mammalian retina, divergence of cone signals into multiple feed-forward bipolar cell pathways forms the initial basis for parallel retinal circuits dedicated to specific visual functions. Here, we used patch-clamp electrophysiology, electron microscopy and two photon imaging of a fluorescent glutamate sensor to examine how kinetically distinct responses arise in transient versus sustained ON alpha RGCs (ON-T and ON-S RGCs) of the mouse retina. We directly compared the visual response properties of these RGCs with their presynaptic bipolar cell partners, which we identified using 3D electron microscopy reconstruction. Different ON bipolar cell subtypes (type 5i, type 6 and type 7) had indistinguishable light-driven responses whereas extracellular glutamate signals around RGC dendrites and postsynaptic excitatory currents measured in ON-T and ON-S RGCs in response to the identical stimuli used to probe bipolar cells were kinetically distinct. Anatomical examination of the bipolar cell axon terminals presynaptic to ON-T and ON-S RGCs suggests bipolar subtype-specific differences in the size of synaptic ribbon-associated vesicle pools may contribute to transient versus sustained kinetics. Our findings indicate bipolar cell synapses are a primary point of divergence in kinetically distinct visual pathways.
Hemin-induced platelet activation is regulated via ACKR3 chemokine surface receptor - implications for passivation of vulnerable atherosclerotic plaque
Authors: Laspa Zoi , Dicenta-Baunach Valerie , Schaale David , Sigle Manuel , Hochuli Ravi , Castor Tatsiana , Bayrak Alp , Harm Tobias , Mueller Karin Anne Lydia , Pillaiyar Thanigaimalai , Laufer Stefan , Rohlfing Anne-Katrin , Gawaz Meinrad Paul
Published: May 2024

In vulnerable atherosclerotic plaques intraplaque hemorrhages (IPH) result in hemolysis of red blood cells and release of hemoglobin and free hemin. Hemin activates platelets and leads to thrombosis. Agonism of the inhibitory platelet receptor ACKR3 inhibits hemin-dependent platelet activation and thrombus formation.

To characterize the effect of hemin and ACKR3 agonism on isolated human platelets, multi-color flow cytometry and classical experimental setup such as light transmission aggregometry and a flow chamber assay have been used.

Hemin induces platelet aggregation andex vivoplatelet-dependent thrombus formation on immobilized collagen under low shear rate 500 s-1indicating that free hemin is a strong activator for platelet-dependent thrombosis. Recently, we described that ACKR3 is a prominent inhibitory receptor of platelet activation. Specific ACKR3 agonists but not conventional antiplatelet compounds such as COX-1 inhibitor (indomethacin), ADP-receptor blocker (cangrelor), or PAR1 inhibitor (ML161) inhibit both hemin-dependent aggregation and thrombus formation. To further characterize the effect of hemin on platelet subpopulations we established a multi-color flow cytometry assay. We found that hemin induces procoagulant (CD42bpos/ PAC-1neg/ AnnexinVpos), aggregatory (CD42bpos/ PAC-1pos/ AnnexinVneg) and inflammatory (CD42bpos/ CXCR4pos/ACKR3pos/ AnnexinVpos) platelet subpopulations. Treatment with ACKR3 agonists significantly decrease the formation of procoagulant and ACKR3posplatelets in response to hemin.

We conclude that hemin is a strong activator for the formation of procoagulant platelets and thrombus formation which is dependent on the function of ACKR3. Activation of ACKR3 through specific agonists may offer a therapeutic strategy to control vulnerability of atherosclerotic plaques in areas of IPH.

Graphical abstract

Intraplaque hemorrhages (IPH) results in hemolysis and liberation of iron containing heme and its oxidized metabolite hemin. Hemin activates platelets and has strong pro-thrombotic activity. Agonism of the atypical chemokine receptor 3 (ACKR3) inhibits hemin-induced platelet activation.
EEG denoising during transcutaneous auricular vagus nerve stimulation across simulated, phantom and human data
Authors: Woller Joshua P. , Menrath David , Gharabaghi Alireza
Published: May 2024

Objective

The acquisition of electroencephalogram (EEG) data during neurostimulation, particularly concurrent transcutaneous electrical stimulation of the auricular vagus nerve, introduces unique challenges for data preprocessing and analysis due to the presence of significant stimulation artifacts. This study evaluates various denoising techniques to address these challenges effectively.

Methods

A variety of denoising techniques were investigated, including interpolation methods, spectral filtering, and spatial filtering techniques. The techniques evaluated included low-pass and notch filtering, spectrum interpolation, average artifact subtraction, the Zapline algorithm, and advanced methods such as independent component analysis (ICA), signal-space projection (SSP), and generalized eigendecomposition with stimulation artifact source separation (GED/SASS). The efficacy of these algorithms was evaluated across three distinct datasets: simulated data, data from a gelatin phantom model, and real human subject data.

Results

Our findings indicate that GED (SASS) and SSP significantly outperformed other methods in reducing artifacts while preserving the integrity of the EEG signal. ICA and Zapline were effective too, but came with important limitations. These methods demonstrated robustness across different data types and conditions, providing effective artifact mitigation with minimal disruption to other essential signal components.

Conclusion

This comprehensive analysis demonstrates the efficacy of advanced spatial filtering techniques in the preprocessing of EEG data during auricular vagus nerve stimulation. These methods offer promising avenues for enhancing the quality and reliability of neurostimulation-associated EEG data, facilitating a deeper understanding and wider applications in clinical and research settings.
The development of aperiodic and periodic resting-state power between early childhood and adulthood: new insights from optically pumped magnetometers
Authors: Vandewouw Marlee M. , Sato Julie , Safar Kristina , Rhodes Natalie , Taylor Margot J.
Published: May 2024

Neurophysiological signals, comprised of both periodic (e.g., oscillatory) and aperiodic (e.g., non-oscillatory) activity, undergo complex developmental changes between childhood and adulthood. With much of the existing literature primarily focused on the periodic features of brain function, our understanding of aperiodic signals is still in its infancy. Here, we are the first to examine age-related changes in periodic (peak frequency and power) and aperiodic (slope and offset) activity using optically pumped magnetometers (OPMs), a new, wearable magnetoencephalography (MEG) technology that is particularly well-suited for studying development. We examined age-related changes in these spectral features in a sample (N=65) of toddlers (1-3 years), children (4-5 years), young adults (20-26 years), and adults (27-38 years). Consistent with the extant literature, we found significant age-related decreases in the aperiodic slope and offset, and changes in peak frequency and power that were frequency-specific; we are the first to show that the effect sizes of these changes also varied across brain regions. This work not only adds to the growing body of work highlighting the advantages of using OPMs, especially for studying development, but also contributes novel information regarding the variation of neurophysiological changes with age across the brain.
Race/ethnicity and socioeconomic status affect the assessment of lipoprotein(a) levels in clinical practice
Authors: Pavlyha Marianna , Li Yihao , Crook Sarah , Anderson Brett R. , Reyes-Soffer Gissette
Published: May 2024

Background and Objective

High Lp(a) levels are a risk factor for ASCVD, however Lp(a) ordering in clinical practice is low. This study examines how race/ethnicity and socioeconomic status influence Lp(a) ordering.

Methods

This is a single center, retrospective study (2/1/2020-6/30/2023) using electronic medical records of adults with at least one ICD-10 diagnosis of ASCVD or resistant hyperlipidemia (LDL-C >160 mg/dL on statin therapy). We evaluated Lp(a) level differences among racial/ethnic groups and sexes. We also assessed associations between diagnosis type, diagnosis number, age at diagnosis, race, socioeconomic score (based on zip codes), public health coverage and presence of Lp(a) orders.

Results

4% of our cohort (N=56,833) had an Lp(a) order (17.3% Hispanic, 8.7% non-Hispanic Black, 47.5% non-Hispanic White and, 27% Asian/others). Non-Hispanic Black and Hispanic patients had lower rates of Lp(a) orders (0.17%, 0.28%, respectively) when compared to non-Hispanic White patients (2.35%), p<0.001, however, their median Lp(a) levels were higher. Individuals belonging to deprived socioeconomic groups or on Medicaid, were less likely to have an Lp(a) order (RR=0.39, p<0.001 and RR=0.40, p<0.001 respectively). Certain diagnoses (carotid stenosis, family history of ASCVD and FH) and multiple diagnoses (>2) resulted in more Lp(a) orders compared to those with only one diagnosis (p<0.001).

Conclusions

Lp(a) ordering is low in patients with ASCVD. Non-Hispanic Black and Hispanic patients at risk are less likely to have an Lp(a) order. Individuals residing in socioeconomically deprived neighborhoods and on Medicaid are also less like have Lp(a) order. Lp(a) orders depend on the type and number of patients’ diagnoses.
Effect of developmental and adult diet composition on reproductive aging inDrosophila melanogaster
Authors: Ruchitha B G , Kumar Devashish , Chandrakanth Mohankumar , Farooq Itibaw , Kumar Nishant , Sura Chand , Chetan S. , Tung Sudipta
Published: May 2024

Diet significantly affects reproductive outcomes across species, yet the precise effects of macronutrient compositions beyond caloric intake on reproductive aging are understudied. Existing literature presents conflicting views on the fertility impacts of nutrient-rich versus nutrient-poor developmental diets, underscoring a notable research gap. This study addresses these gaps by examining effects of isocaloric diets with varied protein-to-carbohydrate ratios during both developmental and adult stages on reproductive aging of a large, outbred Drosophila melanogaster population (n = ∼2100). Our results clearly demonstrate an age-dependent dietary impact on reproductive output, initially dominated by the developmental diet, then by a combination of developmental and adult diets in early to mid-life, and ultimately by the adult diet in later life. Importantly, we found that the effects of developmental and adult diets on reproductive output are independent, with no significant interaction. Further investigations into the mechanisms revealed that the effect of developmental diet on fecundity is regulated via ovarioles formation and vitellogenesis; while, the effect of adult diet on fecundity is mostly regulated only via vitellogenesis. These insights resolve disputes in the literature about dietary impacts on fertility and offer valuable perspectives for optimizing fertility strategies in improving public health and conservation efforts in this changing world.

Highlights

Effect of developmental and adult diet composition on reproduction is age-dependent

Developmental diet affects early-life; adult diet late-life; and both affect mid-life

But the effect of developmental and adult diets do not interact with each other

Developmental diet regulates reproduction via ovarioles formation and vitellogenesis

Whereas, adult diet regulates reproduction via differential vitellogenesis across age
BlueRecording: A pipeline for the efficient calculation of extracellular recordings in large-scale neural circuit models
Authors: Tharayil Joseph , Blanco Alonso Jorge , Farcito Silvia , Lloyd Bryn , Romani Armando , Boci Elvis , Cassara Antonino , Schürmann Felix , Neufeld Esra , Kuster Niels , Reimann Michael
Published: May 2024

As the size and complexity of network simulations accessible to computational neuroscience grows, new avenues open for research into extracellularly recorded electric signals. Biophysically detailed simulations permit the identification of the biological origins of the different components of recorded signals, the evaluation of signal sensitivity to different anatomical, physiological, and geometric factors, and selection of recording parameters to maximize the signal information content. Simultaneously, virtual extracellular signals produced by these networks may become important metrics for neuro-simulation validation. To enable efficient calculation of extracellular signals from large neural network simulations, we have developedBlueRecording, a pipeline consisting of standalone Python code, along with extensions to the Neurodamus simulation control application, the CoreNEURON computation engine, and the SONATA data format, to permit online calculation of such signals. In particular, we implement a general form of the reciprocity theorem, which is capable of handling non-dipolar current sources, such as may be found in long axons and recordings close to the current source, as well as complex tissue anatomy, dielectric heterogeneity, and electrode geometries. To our knowledge, this is the first application of this generalized (i.e., non-dipolar) reciprocity-based approach to simulate EEG recordings. We use these tools to calculate extracellular signals from anin silicomodel of the rat somatosensory cortex and hippocampus and to study signal contribution differences between regions and cell types.
Targeted Degradation of CDK9 Potently Disrupts the MYC Transcriptional Network
Authors: Toure Mohammed A. , Motoyama Keisuke , Xiang Yichen , Urgiles Julie , Kabinger Florian , Koglin Ann-Sophie , Iyer Ramya S. , Gagnon Kaitlyn , Kumar Amruth , Ojeda Samuel , Harrison Drew A. , Rees Matthew G. , Roth Jennifer A. , Ott Christopher J. , Schiavoni Richard , Whittaker Charles A. , Levine Stuart S. , White Forest M. , Calo Eliezer , Richters Andre , Koehler Angela N.
Published: May 2024

Cyclin-dependent kinase 9 (CDK9) coordinates signaling events that regulate RNA polymerase II (Pol II) pause-release states. It is an important co-factor for transcription factors, such as MYC, that drive aberrant cell proliferation when their expression is deregulated. CDK9 modulation offers an approach for attenuating dysregulation in such transcriptional programs. As a result, numerous drug development campaigns to inhibit CDK9 kinase activity have been pursued. More recently, targeted degradation has emerged as an attractive approach. However, comprehensive evaluation of degradation versus inhibition is still critically needed to assess the biological contexts in which degradation might offer superior therapeutic benefits. We validated that CDK9 inhibition triggers a compensatory mechanism that dampens its effect on MYC expression and found that this feedback mechanism was absent when the kinase is degraded. Importantly, CDK9 degradation is more effective than its inhibition for disrupting MYC transcriptional regulatory circuitry likely through the abrogation of both enzymatic and scaffolding functions of CDK9.

Highlights

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KI-CDK9d-32 is a highly potent and selective CDK9 degrader.

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KI-CDK9d-32 leads to rapid downregulation of MYC protein and mRNA transcripts levels.

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KI-CDK9d-32 represses canonical MYC pathways and leads to a destabilization of nucleolar homeostasis.

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Multidrug resistance ABCB1 gene emerged as the strongest resistance marker for the CDK9 PROTAC degrader.
PIEZO acts in an intestinal valve to regulate swallowing inC. elegans
Authors: Park Yeon-Ji , Yeon Jihye , Cho Jihye , Kim Do-Young , Bai Xiaofei , Oh Yuna , Kim Jimin , Nam HoJin , Hwang Hyeonjeong , Heo Woojung , Kim Jinmahn , Jun Seoyoung , Lee Kyungeun , Kang KyeongJin , Kim Kyuhyung
Published: May 2024

Sensations of the internal state of the body play crucial roles in regulating the physiological processes and maintaining homeostasis of an organism. However, our understanding of how internal signals are sensed, processed, and integrated to generate appropriate biological responses remains limited. Here, we show that theC. elegansPIEZO channel, encoded bypezo-1, regulates food movement in the intestine by detecting food accumulation in the anterior part of the intestinal lumen, thereby triggering rhythmical movement of the pharynx, referred to as the pharyngeal plunge.pezo-1deletion mutants exhibit defects in the pharyngeal plunge, which is rescued by PEZO-1 or mouse PIEZO1 expression, but not by PIEZO2, in a single isolated non-neuronal tissue of the digestive tract, the pharyngeal-intestinal valve. Genetic ablation or optogenetic activation of this valve inhibits or induces the pharyngeal plunge, respectively. Moreover, pressure built in the anterior lumen of the intestine results in apezo-1-dependent pharyngeal plunge, which is driven by head muscle contraction. These findings illustrate how interoceptive processes in a digestive organ regulate swallowing through the PIEZO channel, providing insights into how interoception coordinates ingestive processes in higher animals, including humans.
Proteins associated withCryptococcusspp. extracellular polysaccharides are implicated in virulence, capsule integrity, and biofilm formation
Authors: Stempinski Piotr R. , Jacobs Ella , Lopes Livia Liporagi , Rodrigues Dos Santos Junior Samuel , Rojas Kevin , Wear Maggie P. , Casadevall Arturo
Published: May 2024

Cryptococcus neoformansandCryptococcus gattiiare pathogenic fungi comprising species complexes that are the etiological agents of cryptococcosis. Both fungal species complexes possess a variety of virulence factors that include a polysaccharide capsule, melanin production, enzymes, and the release of polysaccharides. In this study, we characterized the proteins associated with cryptococcal polysaccharides and analyzed their function by studying mutants deficient in their expression. Mass spectrometry analysis of exopolysaccharide fractions revealed 62 proteins, many of which were previously uncharacterized. Analysis of capsule size, structure, and integrity in protein-deficient mutants allowed us to identify four proteins, which we namedExtracellular PolysaccharideRelated proteins (Exa1-4), and whose absence affected proper capsule assembly and EPS release. In summary, cryptococcal exopolysaccharide is associated with proteins that are implicated in virulence, capsular integrity, and biofilm formation. Our results associated new phenotypes for four previously unknown genes and show that the filtered polysaccharide preparations are a rich source of proteins that can inform capsular assembly, virulence, and immunological studies.
Neural correlates of embodied and vibratory mechanisms associated with vocal emotion production
Authors: Selosse Garance , Grandjean Didier , Ceravolo Leonardo
Published: May 2024

Despite a large body of literature on the psychological and brain mechanisms of vocal emotion perception, less is known on expression and production mechanisms, especially the vibrations originating in the vocal cords and their role in emotional voice production. In the present study, we aimed to fill this gap. Participants had to produce angry, happy and neutral emotional vocalizations in different production conditions (‘normal’, ‘whisper’, ‘articulate’). An accelerometer recorded the vibrations on the throat, close to the vocal folds. Results showed effects of the Emotion factor with activations in the bilateral temporal voice areas, the inferior frontal gyri as well as motor and supplementary motor areas. The Production factor and its interaction with Emotion revealed significant effects in motor, somatosensory cortices, insula and inferior frontal cortex. Exploratory analysis of the brain correlates of emotional vocal tract vibrations specific to ‘normal’ voice production showed significant correlations with brain regions involved in interoceptive processing (insula, inferior frontal cortex, cerebellum). Our results highlight the crucial role of vibro-tactile body resonances in vocal emotion production that might play an important role for the interoceptive phenomena involved in the representation of our own emotions such as in emergent feelings related to emotional vocal production.