bluuebunny/crossref_metadata_2025_split huggingface dataset:
Soft skeletons transmit force with variable gearing
Authors: Ellers Olaf , Ellers Kai-Isaak , Johnson Amy S. , Po Theodora , Heydari Sina , Kanso Eva , McHenry Matthew J. 
Published: March 2024

ABSTRACTA hydrostatic skeleton allows a soft body to transmit muscular force via internal pressure. A human’s tongue, an octopus’ arm, and a nematode’s body illustrate the pervasive presence of hydrostatic skeletons among animals, which has inspired the design of soft engineered actuators. However, there is a need for a theoretical basis for understanding how hydrostatic skeletons apply mechanical work. We therefore model the shape change and mechanics of natural and engineered hydrostatic skeletons to determine their mechanical advantage (MA) and displacement advantage (DA). These models apply to a variety of biological structures, but we explicitly consider the tube feet of a sea star and the body segments of an earthworm, and contrast them with a hydraulic press and a McKibben actuator. A helical winding of stiff, elastic fibers around these soft actuators plays a critical role in their mechanics by maintaining a cylindrical shape, distributing forces throughout the structure, and storing elastic energy. In contrast to a single-joint lever system, soft hydrostats exhibit variable gearing with changes in MA generated by deformation in the skeleton. We found that this gearing is affected by the transmission efficiency of mechanical work (MA × DA) or, equivalently, the ratio of output to input work), which changes with the capacity to store elastic energy within helically wrapped fibers or associated musculature. This modeling offers a conceptual basis for understanding the relationship between the morphology of hydrostatic skeletons and their mechanical performance.
A Synergistic Desmin-SPARC Axis Influences Cardiac Stem Cell Differentiation and Promotes Cardiomyogenesis through Autocrine Regulation
Authors: Leitner Lucia , Schultheis Martina , Hofstetter Franziska , Rudolf Claudia , Kizner Valeria , Fiedler Kerstin , Konrad Marie-Therese , Höbaus Julia , Genini Marco , Kober Julia , Ableitner Elisabeth , Gmaschitz Teresa , Walder Diana , Weitzer Georg 
Published: March 2024

AbstractBACKGROUNDThe mammalian heart contains cardiac stem cells throughout life, but it has not been possible to harness or stimulate these cells to repair damaged myocardium in vivo. Assuming physiological relevance of these cells, which have evolved and have been maintained throughout evolution, we are investigating their function using mouse cardiac stem cell lines as an in vitro model system.METHODSHere we use genetically modified embryonic stem cells and cardiac stem cells from the mouse as model systems to study the influence of desmin and Secreted Protein Acidic and Rich in Cysteine (SPARC) on cardiomyogenesis in embryoid bodies and cardiac bodies. We analyze their expression in self-renewing and differentiating stem cells by fluorescence microscopy, RT-qPCR, quantitative Western blotting and fluorescence activated cell sorting, and assess their influence on the expression of myocardial transcription factors.RESULTSIn embryoid bodies, desmin induces expression and secretion of SPARC, which promotes cardiomyogenesis. Cardiac stem cells secrete substantial amounts of SPARC, which also promotes cardiomyogenesis in a concentration-dependent, autocrine manner and promotes expression of myocardial transcription factors anddesmin. Desmin and SPARC interact genetically and form a positive feedback loop and secreted SPARC negatively influences sparc mRNA expression. Finally, SPARC rescues cardiomyogenic desmin-haploinsufficiency in cardiac stem cells in a glycosylation-dependent manner, increases the phosphorylation of Smad2 and induces the expression ofgata4, nkx2.5andmef2C.CONCLUSIONSDemonstration that desmin-induced autocrine secretion of SPARC in cardiac stem cells promotes cardiomyogenesis raises the possibility that a physiological function of cardiac stem cells in the adult and aging heart may be the gland-like secretion of factors such as SPARC that modulate age-related and adverse environmental influences and thereby contribute to cardiac homeostasis throughout life.
Lost Opportunity in Tobacco Cessation Care: Impact of Underbilling in a Large Health System
Authors: Baughman Derek J , Rauhut Marcus , Anselm Edward 
Published: March 2024

AbstractIntroductionTobacco cessation remains a critical challenge in healthcare, with evidence-based interventions often under-utilized due to misaligned economic incentives and inadequate training. This study aims to quantify the economic impact of missed billing opportunities for tobacco cessation in a healthcare system, thereby assessing potential revenue loss and evaluating the effectiveness of systems-based approaches in enhancing tobacco cessation efforts.MethodsA retrospective cohort study utilized aggregated de-identified patient health data from an 8-hospital regional health system across Pennsylvania and Maryland, from 1/1/21 to 12/31/23. The analysis focused on primary care encounters eligible for tobacco cessation counseling (CPT codes 99406 or 99407), with potential revenue calculated based on the Medicare reimbursement rate.ResultsOver three years, and 507,656 office visits, only 1,557 (0.3%) of encounters with persons using tobacco were billed for cessation services. The estimated total potential revenue gained if each person who was identified as using tobacco was billed consistently for tobacco cessation counseling was $5,947,018.13, and $1,982,339.38 annually.ConclusionsThe study reveals a significant gap between the potential and actual billing for tobacco cessation services, highlighting not only the financial implications of missed opportunities but the validation of health system’s public health impact. Underbilling contributes to considerable annual revenue loss and undermines primary prevention efforts against tobacco-related diseases. Our findings illuminate the need for enhanced billing practices and systemic changes, including policy improvements that influence proper billing to promote public health benefits through improved tobacco cessation interventions.
Perinatal Impacts of Cannabis and Nicotine: An Analysis of the Cannabis Use During Development and Early Life Study
Authors: Trammel Cassandra J. , Agrawal Arpana , Bogdan Ryan , Lawlor Megan , Raghuraman Nandini , Kelly Jeannie C. , Smyser Christopher D. , Rogers Cynthia , Carter Ebony B. 
Published: March 2024

ABSTRACTOBJECTIVEEvaluate associations between prenatal cannabis use (PCU) and perinatal outcomes.METHODSWe performed an interval analysis of a prospective cohort study of pregnant individuals with pre-pregnancy cannabis use and negative self-report of nicotine use, comparing those who continued cannabis through pregnancy with those who stopped. Patients underwent interviews and urine drug screening for cannabis and cotinine, a nicotine metabolite, in each trimester. The primary outcome was small for gestational age (SGA) at delivery. Secondary outcomes included antenatal and postpartum complications, mode of delivery, and neonatal outcomes. Secondary analyses included stratification by intensity of cannabis use and urinary cotinine positivity.RESULTSBirthing persons with PCU differed in age (25.5 vs 27.8 years, p=0.001), body mass index (BMI; 27.4 vs 30.9, p=0.001), area deprivation index percentiles (92% PCU vs 88%, p=0.013), cotinine positivity (42.8% vs 10.8%, p<0.001), Hispanic ethnicity (2% vs 7.2%, p=0.009), and education attainment beyond high school (29.4% vs 50%, p<0.001) compared to controls. Birthing person outcomes did not differ. Risks of SGA and other neonatal outcomes did not differ when adjusted for confounders on initial analysis, or with stratification by intensity of cannabis use. Despite negative self-report for nicotine, 42.8% of PCU patients tested positive for cotinine (PCU+c). PCU+c was associated with increased risk of SGA and birthweight less than the 5thpercentile, compared to PCU cases without nicotine exposure (17.4% vs 8.3%, aRR 2.7 [1.21-5.38], 35.8% vs 18.6%, aRR 2.4 [1.51-3.48]), and controls (35.8% vs 12.9%, aRR 2.75 [1.64-4.13]). Cotinine-negative PCU patients and controls did not differ.CONCLUSIONPCU was not independently associated with adverse birthing person outcomes. Many patients demonstrated nicotine exposure, either via inadvertent exposure or undisclosed use. While neonates exposed to cannabis alone did not differ from unexposed neonates, those exposed to both cannabis and nicotine were at increased risk of SGA.
Utility of quantitative measurement ofT2using Restriction Spectrum Imaging for detection of clinically significant prostate cancer
Authors: Domingo Mariluz Rojo , Conlin Christopher C , Karunamuni Roshan A , Ollison Courtney , Baxter Madison T , Kallis Karoline , Do Deondre D , Song Yuze , Kuperman Joshua M , Shabaik Ahmed S , Hahn Michael E , Murphy Paul M , Rakow-Penner Rebecca , Dale Anders M , Seibert Tyler M 
Published: March 2024

AbstractBackgroundThe Restriction Spectrum Imaging restriction score (RSIrs) has demonstrated higher diagnostic accuracy for clinically significant prostate cancer (csPCa) than conventional DWI. Both diffusion andT2properties of prostate tissue inform the RSI signal, and studies have shown that each may be valuable for csPCa discrimination.PurposeTo determine whether prostateT2varies across RSI compartments and in the presence of csPCa, and to evaluate whether consideration of compartmentalT2(cT2) improves csPCa detection over RSIrs alone.Study TypeRetrospective.PopulationTwo cohorts (46 and 195 patients) scanned for csPCa.Field Strength/Sequence3T multi-b-value DWI acquired at multiple TEs.AssessmentcT2values were computed from multi-TE RSI data and compared between RSI model compartments. csPCa detection was compared between RSIrs and a logistic regression model (LRM) for predicting the probability of csPCa using cT2in combination with RSI measurements.Statistical TestsTwo-sample t-tests (α=0.05) were used to compare cT2values between compartments and between patients with and without csPCa. Area under the receiver operating characteristic curve (AUC) was used to evaluate csPCa detection performance.ResultsIn both cohorts,T2differed (p<0.05) across all RSI compartments (C1,C2,C3,C4). Voxel-level data from cohort 1 showed thatT2differed between normal and cancerous tissue inC1,C2,C3(p<0.001). Whole-prostateT2differed between patients with and without csPCa inC3(p=0.02). In cohort 2, whole-prostateT2differed inC1(p=0.01),C3(p=0.01), andC4(p<0.01). Consideration of cT2improved csPCa discrimination compared to diffusion alone, but not compared to RSIrs [cohort 1: 0.80 vs 0.70 (diffusion) and 0.80 (RSIrs), cohort 2: 0.72 vs 0.65 (diffusion) and 0.72 (RSIrs)].Data ConclusionSignificant differences in cT2were observed between normal and cancerous prostatic tissue. With our data, however, consideration of cT2did not significantly improve cancer detection performance over RSIrs alone.
Phenyllactic Acid is Physiologically Released from Skeletal Muscle and Contributes to the Beneficial Effects of Physical Exercise in Humans
Authors: Hoene Miriam , Zhao Xinjie , Hu Chunxiu , Birkenfeld Andreas L. , Peter Andreas , Nieß Andreas M. , Moller Anja , Li Qi , Lehmann Rainer , Plomgaard Peter , Xu Guowang , Weigert Cora 
Published: March 2024

AbstractAims/hypothesisWhile physical activity is clearly beneficial in combating type 2 diabetes, the underlying molecular mechanisms are incompletely understood. Moreover, there is a considerable degree of variability in the individual response to exercise-based lifestyle interventions that remains to be explained. We aimed to identify novel exercise-induced metabolites that could mediate the improvement in glycemic control and reduction of obesity and contribute to individual differences in the response to exercise interventions.MethodsWe studied acute exercise- and training-induced changes in plasma metabolites in sedentary subjects with overweight (8 male, 14 female) participating in an eight-week supervised training program flanked by two acute endurance exercise sessions. Plasma metabolites were quantified using LC- and CE-MS. In a separate study (n=9 lean males), we assessed metabolite fluxes over the leg using arterial and venous catheters. Functional analyses were performed in primary blood mononuclear cells (PBMCs) stimulated with lipopolysaccharide (LPS) or the saturated fatty acid palmitate.ResultsThe amino acid breakdown products 3-phenyllactic acid (PLA), 4-hydroxyphenyllactic acid and indolelactic acid were increased after both acute exercise and training. All three aromatic lactic acids, which so far mainly received attention as bacterial metabolites, exhibited an efflux from the leg. PLA showed the largest increase after both acute exercise and training, of 57% and 20% respectively. The magnitude of the acute exercise-induced increase in PLA correlated with a decrease in subcutaneous adipose tissue volume and an improvement in insulin sensitivity over the course of the intervention. Furthermore, both isomers, D- and L-PLA, counteracted inflammatory cytokine production in PBMCs.Conclusions/interpretationOur findings indicate that PLA is physiologically released from skeletal muscle and can contribute to the anti-inflammatory effects of exercise as well as to individual difference in the response to lifestyle interventions in humans. PLA and potentially, aromatic lactic acids in general may be particularly relevant metabolic regulators because they can be produced both endogenously and by the microbiome.Trial registrationClinicalTrials.govNCT03151590
Brugada ECG detection with self-supervised VICReg pre-training: a novel deep learning approach for rare cardiac diseases
Authors: Ronan Robert , Tarabanis Constantine , Chinitz Larry , Jankelson Lior 
Published: March 2024

AbstractExisting deep learning algorithms for electrocardiogram (ECG) classification rely on supervised training approaches requiring large volumes of reliably labeled data. This limits their applicability to rare cardiac diseases like Brugada syndrome (BrS), often lacking accurately labeled ECG examples. To address labeled data constraints and the resulting limitations of supervised training approaches, we developed a novel deep learning model for BrS ECG classification using the Variance-Invariance-Covariance Regularization (VICReg) architecture for self-supervised pre-training. The VICReg model outperformed a state-of-the-art neural network in all calculated metrics, achieving an area under the receiver operating and precision-recall curves of 0.88 and 0.82, respectively. We used the VICReg model to identify missed BrS cases and hence refine the previously underestimated institutional BrS prevalence and patient outcomes. Our results provide a novel approach to rare cardiac disease identification and challenge existing BrS prevalence estimates offering a framework for other rare cardiac conditions.
WHOLE GENOME TARGETED ENRICHMENT AND SEQUENCING OF HUMAN-INFECTINGCRYPTOSPORIDIUMspp.
Authors: Bayona-Vásquez NJ , Sullivan AH , Beaudry MS , Khan A , Baptista RP , Petersen KN , Bhuiyan MIU , Brunelle B , Robinson G , Chalmers RM , Alves-Ferreira EVC , Grigg ME , AlvesFerreira Kissinger JC , Glenn TC 
Published: March 2024

AbstractCryptosporidiumspp. are protozoan parasites that cause severe illness in vulnerable human populations. Obtaining pureCryptosporidiumDNA from clinical and environmental samples is challenging because the oocysts shed in contaminated feces are limited in quantity, difficult to purify efficiently, may derive from multiple species, and yield limited DNA (<40 fg/oocyst). Here, we develop and validate a set of 100,000 RNA baits (CryptoCap_100k) based on six human-infectingCryptosporidiumspp. (C. cuniculus,C. hominis,C. meleagridis,C. parvum,C. tyzzeri, andC. viatorum) to enrichCryptosporidiumspp. DNA from a wide array of samples. We demonstrate that CryptoCap_100k increases the percentage of reads mapping to targetCryptosporidiumreferences in a wide variety of scenarios, increasing the depth and breadth of genome coverage, facilitating increased accuracy of detecting and analyzing species within a given sample, while simultaneously decreasing costs, thereby opening new opportunities to understand the complex biology of these important pathogens.
Growth patterns of caudal fin rays are informed by both external signals from the regenerating organ and remembered identity autonomous to the local tissue
Authors: Autumn Melody , Hu Yinan , Zeng Jenny , McMenamin Sarah K. 
Published: March 2024

ABSTRACTRegenerating tissues must remember or interpret their spatial position, using this information to restore original size and patterning. The external skeleton of the zebrafish caudal fin is composed of 18 rays; after any portion of the fin is amputated, position-dependent regenerative growth restores each ray to its original length. We tested for transcriptional differences during regeneration of proximal versus distal tissues and identified 489 genes that differed in proximodistal expression. Thyroid hormone directs multiple aspects of ray patterning along the proximodistal axis, and we identified 364 transcripts showing a proximodistal expression pattern that was dependent on thyroid hormone context. To test what aspects of ray positional identity are directed by extrinsic cues versus remembered identity autonomous to the tissue itself, we transplanted distal portions of rays to proximal environments and evaluated regeneration within the new location. While neighboring proximal tissue showed robust expression ofscpp7, a transcript with thyroid-regulated proximal enrichment, regenerating rays originating from transplanted distal tissue showed reduced (distal-like) expression during outgrowth. These distal-to-proximal transplants regenerated far beyond the length of the graft itself, indicating that cues from the proximal environment promoted additional growth. Nonetheless, these transplants initially regenerated at a much slower rate compared to controls, suggesting memory of distal identity was retained by the transplanted tissue. This early growth retardation caused rays that originated from transplants to become noticeably shorter than their native neighboring rays. While several aspects of fin ray morphology (bifurcation, segment length) were found to be determined by the environment, regeneration speed and ray length are remembered autonomously by tissues, persisting across multiple rounds of amputation and regeneration.GRAPHICAL ABSTRACT
Ribonuclease Inhibitor and Angiogenin collaboratively regulate cell-type-specific global translation
Authors: Stillinovic Martina , Sarangdhar Mayuresh Anant , Andina Nicola , Tardivel Aubry , Greub Frédéric , Bombaci Giuseppe , Ansermet Camille , Heller Manfred , Keogh Adrian , Keller Irene , Angelillo-Scherrer Anne , Allam Ramanjaneyulu 
Published: March 2024

AbstractTranslation of mRNAs is a fundamental process that occurs in all cell-types of multicellular organisms. Conventionally, it has been considered a default step in gene expression, lacking specific regulation. However, recent studies have documented that certain mRNAs exhibit cell-type-specific translation1–3. Despite this, it remains unclear whether global translation is controlled in a cell-type-specific manner. Here we report that a ribosome-associated protein ribonuclease inhibitor-1 (RNH1) and its binding partner Angiogenin (ANG) collaboratively regulates cell-type-specific global translation. By employing human cell-lines and mouse models, we found that deletion of RNH1 decreases global translation selectively in hematopoietic origin cells but not in the non-hematopoietic origin cells. RNH1 mediated such cell-type-specific translation is mechanistically linked to ANG. We found that ANG, which is known to regulate ribosomal biogenesis4, is predominantly expressed in non-hematopoietic origin cells and absent in hematopoietic origin cells. ANG safeguards the non-hematopoietic origin cells from RNH1-knockout-mediated translation defects by upregulating ribosomal biogenesis. Further, we discovered that RNH1 controls the translation of ribosomal protein (RP) transcripts and influences mRNA circularization. Collectively, this study unravels the existence of cell-type-specific global translation regulators and highlights the complex translation regulation in vertebrates.
A Genome-wide CRISPR screen unveils the endosomal maturation protein WDR91 as a promoter of productive ASO activity in melanoma
Authors: Menchon Grégory , Gaci Aris , Matvere Antti , Aubry Marc , Bore Aurélien , Gilot David , Goyenvalle Aurélie , Pedeux Rémy 
Published: March 2024

ABSTRACTAntisense oligonucleotides (ASOs) belong to promising therapeutics for the treatment of neurologic, muscular and metabolic disorders. Several ASOs have been approved so far and more than a hundred clinical trials are currently underway covering a dozen therapeutic areas. Yet, the mechanisms of internalization and cell trafficking of these molecules remain poorly understood. Moreover, with only a small fraction of ASOs reaching the correct cellular compartment following systemic delivery, the majority of targeted diseases requires recurrent injections of ASOs. A deeper understanding of these mechanisms would guide the improvement of their potency and thus, reduce the amount of delivered ASOs and their potential side-effects. Here, using a CRISPR screen, we investigated intracellular proteins involved in ASOs efficiency using a whole genome approach and identified several potential regulators which could significantly impact ASOs potency in melanoma cells. We validated WD Repeat Domain 91 (WDR91), a regulator of endosomal maturation, as a modulator whose depletion significantly inhibits ASO productive activity. This study provides the first list of ASO modulators using a biologically relevant assay to estimate the role of these proteins. In conclusion, these data could lead to a better understanding of the mechanisms favoring productive uptake or improved endosomal escape of ASOs.
GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice
Authors: Takahashi Keigo , Rensing Nicholas R. , Eultgen Elizabeth M. , Wang Sophie H. , Nelvagal Hemanth R. , Le Steven Q. , Roberts Marie S. , Doray Balraj , Han Edward B. , Dickson Patricia I. , Wong Michael , Sands Mark S. , Cooper Jonathan D. 
Published: March 2024

AbstractGABAergic interneuron deficits have been implicated in the epileptogenesis of multiple neurological diseases. While epileptic seizures are a key clinical hallmark of CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), the etiology of these seizures remains elusive. Given thatCln2R207X/R207Xmice display fatal spontaneous seizures and an early loss of several cortical interneuron populations, we hypothesized that those two events might be causally related. To address this hypothesis, we first generated an inducible transgenic mouse expressing lysosomal membrane-tethered TPP1 (TPP1LAMP1) on theCln2R207X/R207Xgenetic background to study the cell-autonomous effects of cell-type-specific TPP1 deficiency. We crossed the TPP1LAMP1 mice withVgat-Cremice to introduce interneuron-specific TPP1 deficiency.Vgat-Cre; TPP1LAMP1 mice displayed storage material accumulation in several interneuron populations both in cortex and striatum, and increased susceptibility to die after PTZ-induced seizures. Secondly, to test the role of GABAergic interneuron activity in seizure progression, we selectively activated these cells inCln2R207X/R207Xmice using Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) in inVgat-Cre:Cln2R207X/R207Xmice. EEG monitoring revealed that DREADD-mediated activation of interneurons via chronic deschloroclozapine administration accelerated the onset of spontaneous seizures and seizure-associated death inVgat-Cre:Cln2R207X/R207Xmice, suggesting that modulating interneuron activity can exert influence over epileptiform abnormalities in CLN2 disease. Taken together, these results provide new mechanistic insights into the underlying etiology of seizures and premature death that characterize CLN2 disease.