bluuebunny/crossref_metadata_2025_split huggingface dataset:
The 10-year health impact, economic impact, and return on investment of the South African molecular diagnostics programme for HIV, Tuberculosis and SARS-CoV-2
Authors: Nichols Brooke E. , de Nooy Alexandra , Cassim Naseem , Hans Lucia , da Silva Manuel Pedro , Chetty Kamy , Grantz Kyra H. , Han Alvin X. , Phillips Andrew N. , Jamieson Lise , Scott Lesley E. , Stevens Wendy S. 
Published: March 2024

ABSTRACTTo ensure there is adequate investment into diagnostics, an understanding of the magnitude of impact and return on investment is necessary. We therefore sought to understand the health and economic impacts of the molecular diagnostic programme in South Africa, to deepen the understanding on the broad value of diagnostics and guide future healthcare investments. We calculated the 10-year (where data were available) total cost and DALYs averted associated with molecular diagnosis of molecular TB testing (2013-2022), HIV viral load monitoring (2013-2022), early infant diagnosis of HIV infection (2013-2022), and SARS-CoV-2 testing (2020-2022). We then calculated the economic value associated with those health gains and subsequent return on investment. Since the inception of the molecular diagnostics programme in South Africa, 3,035,782 DALYs have been averted as a direct consequence of this programme. This has generated an estimated $20.5 billion in economic value due to these health gains. The return on investment varied by specific diagnostic test (19.0 for tuberculosis, 1.4 for HIV viral load testing, 64.8 for early infant diagnosis of HIV, and 2.5 for SARS-CoV-2), for an average of 9.9 for the entire molecular diagnostics programme between 2013 and 2022- or $9.9 of value for each $1 invested. The molecular diagnostics programme in South Africa generated a significant amount of health gains and economic value associated with these health gains, and the return-on-investment rivals other high-impact public health interventions such as childhood vaccination. Consequently, the molecular diagnostics programme in South Africa is highly impactful, and will continue to be an excellent investment of South African public health expenditure.
Centhaquine Increases Stroke Volume and Cardiac Output in Patients with Hypovolemic Shock
Authors: Khanna Aman , Vaidya Krish , Shah Dharmesh , Ranjan Amaresh K. , Gulati Anil 
Published: March 2024

AbstractBackgroundCenthaquine is a resuscitative agent that acts on α2B adrenergic receptors to enhance venous return in hypovolemic shock. The effect of centhaquine on cardiac output in patients with hypovolemic shock has not been reported.MethodsTrans-thoracic echocardiography was utilized to measure stroke volume (SV), cardiac output (CO), left ventricular outflow tract-velocity time integral (LVOT-VTI), left ventricular outflow tract diameter (LVOTd), heart rate (HR), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (FS) and inferior vena cava (IVC) diameter before (0 min) and after centhaquine (0.01 mg/kg, iv infusion over 60 min) treatment (60 min, 120 min, and 300 min) in 12 randomly selected patients with hypovolemic shock enrolled in a prospective, multicenter, open-label phase IV clinical study (NCT05956418) of centhaquine in patients with hypovolemic shock.ResultsA significant increase in SV (mL) was observed after 60, 120, and 300 minutes of centhaquine treatment. CO (mL/min) increased significantly at 120 and 300 min despite a decrease in HR at these times. A significant increase in IVC diameter and LVOT-VTI (mL) at these time points was observed, which indicated increased venous return. The LVEF and FS did not change, while the mean arterial pressure (MAP, mmHg) increased in patients after 120 and 300 minutes of centhaquine treatment. Positive correlations between IVC diameter and SV (R2= 0.9556) and between IVC diameter and MAP (R2= 0.8928) were observed, which indicated the effect of centhaquine mediated increase in venous return on SV, CO, and MAP.ConclusionsCenthaquine mediated increase in venous return appears to play a critical role in enhancing SV, CO, and MAP in patients with hypovolemic shock; these changes could be pivotal for reducing shock-mediated circulatory failure, promoting tissue perfusion, and improving patient outcomes.Trial registrationThe phase IV trial reported in this study has Clinical Trials Registry, India; ctri.icmr.org.in, CTRI/2021/01/030263;clinicaltrials.gov,NCT05956418.
The Role of Cytokines in Acute and Chronic Postsurgical Pain in Pediatric Patients after Major Musculoskeletal Surgeries
Authors: Chidambaran Vidya , Duan Qing , Pilipenko Valentina , Glynn Susan M. , Sproles Alyssa , Martin Lisa J. , Lacagnina Michael J. , King Christopher D. , Ding Lili 
Published: March 2024

AbstractStudy ObjectiveTo determine if baseline cytokines and their changes over postoperative days 0-2 (POD0-2) predict acute and chronic postsurgical pain (CPSP) after major surgery.DesignProspective, observational, longitudinal nested study.SettingUniversity-affiliated quaternary children’s hospital.PatientsSubjects (≥8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure.MeasurementsDemographics, surgical, psychosocial measures, pain scores, and opioid use over POD0-2 were collected. Cytokine concentrations were analyzed in serial blood samples collected before and after (up to two weeks) surgery, using Luminex bead arrays. After data preparation, relationships between pre- and post-surgical cytokine concentrations with acute (% time in moderate-severe pain over POD0-2) and chronic (pain score>3/10 beyond 3 months post-surgery) pain were analyzed. After adjusting for covariates, univariate/multivariate regression analyses were conducted to associate baseline cytokine concentrations with postoperative pain, and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes.Main ResultsAnalyses included 3,164 measures of 16 cytokines from 112 subjects (median age 15.3, IQR 13.5-17.0, 54.5% female, 59.8% pectus). Acute postsurgical pain was associated with higher baseline concentrations of GM-CSF (β=0.95, SE 0.31;p=.003), IL-1β (β=0.84, SE 0.36;p=.02), IL-2 (β=0.78, SE 0.34;p=.03), and IL-12 p70 (β=0.88, SE 0.40;p=.03) and longitudinal postoperative elevations in GM-CSF (β=1.38, SE 0.57;p=.03), IFNγ (β=1.36, SE 0.6;p=.03), IL-1β (β=1.25, SE 0.59;p=.03), IL-7 (β=1.65, SE 0.7,p=.02), and IL-12 p70 (β=1.17, SE 0.58;p=.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 (β= -0.39, SE 0.17;p=.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 (β= -0.57, SE 0.26;p=.03), IL-8 (β= - 0.68, SE 0.24;p=.006), and IL-13 (β= -0.48, SE 0.22;p=.03). Furthermore, higher odds for CPSP were found for females (vs.males) for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNFα, and for pectus (vs.spine) surgery for IL-8 and IL-10.ConclusionWe identified pro-inflammatory cytokines associated with increased acute postoperative pain and anti-inflammatory cytokines associated with lower CPSP risk, with potential to serve as predictive and prognostic biomarkers.
Statistical Relationship Between Bitcoin and Synthetic Opioid Mortalities: Are DEA Enforcement Actions Aligning with Trends in Drug Related Deaths?
Authors: Kang Daihun 
Published: March 2024

AbstractBackgroundThe intersection of cryptocurrency, especially Bitcoin, with public health issues, particularly synthetic opioid-related deaths, presents an emerging field of study. This research explores the statistical relationship between Bitcoin market fluctuations and synthetic opioid mortalities, against the backdrop of Drug Enforcement Administration (DEA) enforcement actions.MethodsUtilizing data from 2009 to 2022, this study employs Pearson correlation and linear regression models to investigate the relationship between annual Bitcoin price fluctuations and synthetic opioid-related death rates, alongside DEA domestic arrest trends.ResultsA pronounced positive correlation (r = 0.92) was found between Bitcoin price changes and synthetic opioid mortality rates, with the Bitcoin price accounting for approximately 84.78% of the variance in opioid-related deaths (R² = 0.8478). The analysis also notes a disparity between increasing synthetic opioid fatalities and decreasing DEA domestic arrests.ConclusionsThe findings reveal significant correlations between Bitcoin price fluctuations and synthetic opioid-related fatalities, highlighting potential gaps in current drug enforcement strategies. This study underscores the need for an interdisciplinary approach to address the complexities introduced by cryptocurrency in the opioid crisis and suggests the necessity of integrating financial and public health strategies to combat emerging drug abuse trends.
SMYD1-mediated Mono-Methylation of Lysine K35 of the sarcomeric Myosin Heavy Chain (MHC) is fundamental for thick filament assembly in zebrafish and human iPSC-derived cardiomyocytes
Authors: Diofano Federica , Amadi Chidinma , Gahr Bernd , Weinmann Karolina , Rottbauer Wolfgang , Just Steffen 
Published: March 2024

AbstractThe SMYD family is a unique class of lysine methyltransferases (KMTases) known to methylate histones but also non-histone proteins. Among the five SMYD family members (1-5), SMYD1 was identified as a heart- and skeletal muscle-specific KMTase, which, together with Unc45b and Hsp90a, interacts with Myosin thereby regulating thick filament assembly. However, the process by which SMYD1 orchestrates Myosin assembly is largely unknown. Here, we found that SMYD1 physically interacts with Myosin heavy chain (Myh) at its N-terminus and that the Myh N-terminus specifically gets mono-methylated by SMYD1 at lysine 35 (K35). Accordingly, methylated Myh is properly integrated into functional sarcomeres, whereas unmethylated Myh molecules in Smyd1-deficient zebrafish are efficiently degraded by the Ubiquitin Proteasome System (UPS) leading to defective thick filament assembly. Although the inhibition of the UPS by MG132 is able to reconstitute Myosin levels in Smyd1-deficient zebrafish embryos, thick filament assembly is still blocked due to the lack of K35 Myh mono-methylation. Similar to the situation in zebrafish striated muscle cells, SMYD1-mediated MYH methylation is also critical for thick filament assembly in human cardiomyocytes, indicating cross-species conservation of this fundamental mechanism of Myosin methylation, which has been first described about 40 years ago. Further investigations will now be essential to explore the therapeutic potential of targeting this pathway in cardiomyopathies and skeletal muscle disorders.
Resource allocation in biochemically structured metabolic networks
Authors: Seeger Leon , Pinheiro Fernanda , Lässig Michael 
Published: March 2024

AbstractMicrobes tune their metabolism to environmental challenges by changing protein expression levels, metabolite concentrations, and reaction rates simultaneously. Here, we establish an analytical model for microbial resource allocation that integrates enzyme biochemistry and the global architecture of metabolic networks. We describe the production of protein biomass from external nutrients in pathways of Michaelis-Menten enzymes and compute the resource allocation that maximizes growth under constraints of mass conservation and metabolite dilution by cell growth. This model predicts generic patterns of growth-dependent microbial resource allocation to proteome and metabolome. In a nutrient-rich medium, optimal protein expression depends primarily on the biochemistry of individual synthesis steps, while metabolite concentrations and fluxes decrease along successive reactions in a metabolic pathway. Under nutrient limitation, individual protein expression levels change linearly with growth rate, the direction of change depending again on the enzyme’s biochemistry. Metabolite levels and fluxes show a stronger, nonlinear decline with growth rate. We identify a simple, metabolite-based regulatory logic by which cells can be tuned to near-optimal growth. Finally, our model predicts evolutionary stable states of metabolic networks, including local biochemical parameters and the global metabolite mass fraction, in tune with empirical data.
Sequential-GAM constructs the single-cell geometric 3D genome structure
Authors: Li Yongge , Wang Kaili , Shi Minglei , Zhang Michael Q. , Gao Juntao 
Published: March 2024

AbstractThree-dimensional structure of the chromatin is crucial for cell identity and gene regulation. However, how genome-wide hierarchical geometric structure is organized in single cells remains elusive. Here we developed Sequential-GAM (Sequential Genome Architecture Mapping) to construct the hierarchical geometric structure and estimated the radial position of chromosomes, compartments, subcompartments, and genes in single cells by capturing contiguous thin sections of the nucleus. We found that several epigenomic features distributed gradually from the nuclear center to the periphery, including histone modifications and subcompartments. Besides, we estimated the variance of hierarchical structure and revealed the dynamic radial position of subcompartments B1 and B2. Furthermore, we defined the quasi-stable TADs set (q-stable TADs), in which TADs maintain a relatively stable distance to each other. Interestingly, q-stable TADs revealed the correlation between the stability of chromatin structure and chromatin activity. Finally, we discovered that the radial distance and the stability of radial positions for genes in single cells were negatively correlated with their expressions. Taken together, Sequential-GAM is able to estimate 3D genome’s geometric structure in single cell, and to reveal the structural stability and inter-cell heterogeneity.
Loss of the Familial Dysautonomia geneElp1in cerebellar granule cell progenitors leads to ataxia in mice
Authors: Manz Frederik , da Silva Patricia Benites Goncalves , Schouw Mackenna E. , Lukasch Chiara , Bianchini Luca , Sieber Laura , Garcia-Lopez Jesus , Ahmad Shiekh Tanveer , Li Yiran , Lin Hong , Joshi Piyush , Spänig Lisa , Radoš Magdalena , Roiuk Mykola , Sepp Mari , Zuckermann Marc , Northcott Paul A. , Patrizi Annarita , Kutscher Lena M. 
Published: March 2024

AbstractFamilial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have been described. ELP1 is highly expressed in the normal developing and adult cerebellum, but its role in cerebellum development is unknown. To investigate the cerebellar function of Elp1, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent 7 days after birth, when Elp1cKOanimals also exhibited fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 within the developing cerebellum, and suggests that Elp1 loss in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.
Dynamic binding of the bacterial chaperone Trigger factor to translating ribosomes
Authors: Hävermark Tora , Metelev Mikhail , Lundin Erik , Volkov Ivan L. , Johansson Magnus 
Published: March 2024

AbstractThe bacterial chaperone Trigger factor (TF) binds to ribosome-nascent chain complexes (RNCs) and co-translationally aids the folding of proteins in bacteria. Decades of studies have given a broad, but often conflicting, description of the substrate specificity of TF, its RNC-binding dynamics, and competition with other RNC-binding factors, such as the Signal Recognition Particle (SRP). Previous RNC-binding kinetics experiments were conducted on stalled RNCs in reconstituted systems, and consequently, may not represent the interaction of TF with ribosomes translating mRNA in the cytoplasm of the cell. Here, we used single-particle tracking (SPT) to measure TF binding to actively translating ribosomes inside livingEscherichia coli. In cells, TF displays two distinct binding modes — long (ca 1 s) target-specific RNC binding, and shorter (ca 50 ms) sampling of non-target RNCs. RNC binding events are interrupted only by transient excursions to a freely diffusing state (ca 40 ms). We also show that TF competes with SRP for RNC bindingin vivo, and in doing so, tunes the binding selectivity of SRP.
A 3D in vitro assay to study combined immune cell infiltration and cytotoxicity
Authors: Crawford Ashleigh J. , Johnston Adrian , Du Wenxuan , Hanna Eban A. , Schell David , Wan Zeqi , Chen Ting-Hsi , Wu Fan , Ren Kehan , Lim Yeongseo , Nair Praful , Wirtz Denis 
Published: March 2024

AbstractImmune cell-mediated killing of cancer cells in a solid tumor is prefaced by a multi-step infiltration cascade of invasion, directed migration, and cytotoxic activities. In particular, immune cells must invade and migrate through a series of different extracellular matrix (ECM) boundaries and domains before reaching and killing their target tumor cells. These infiltration events are a central challenge to the clinical success of CAR T cells against solid tumors. The current standard in vitro cell killing assays measure cell cytotoxicity in an obstacle-free, two-dimensional (2D) microenvironment, which precludes the study of 3D immune cell-ECM interactions. Here, we present a 3D combined infiltration/cytotoxicity assay based on an oil-in-water microtechnology. This assay measures stromal invasion following extravasation, migration through the stromal matrix, and invasion of the solid tumor in addition to cell killing. We compare this 3D cytotoxicity assay to the benchmark 2D assay through tumor assembloid cocultures with immune cells and engineered immune cells. This assay is amenable to an array of imaging techniques, which allows direct observation and quantification of each stage of infiltration in different immune and oncological contexts. We establish the 3D infiltration/cytotoxicity assay as an important tool for the mechanistic study of immune cell interactions with the tumor microenvironment.Graphical AbstractThe 3D combined infiltration/cytotoxicity assay captures three important steps of immune cell infiltration into the solid tumor microenvironment: (1) circulating immune cells extravasate and invade the stromal matrix, (2) immune cells migrate through the stromal matrix to reach the tumor core, and (3) immune cells that successfully navigate the stroma must cross a basement membrane boundary secreted by the cancer cells to contact and kill the cancer cells within a solid tumor.
Identifying and targeting key driver genes for collagen production within the 11q13/14 breast cancer amplicon
Authors: Araiza-Olivera Daniela , Prudnikova Tatiana Y. , Uribe-Alvarez Cristina , Cai Kathy Q. , Franco-Barraza Janusz , Dones Jesús M. , Raines Ronald T. , Chernoff Jonathan 
Published: March 2024

AbstractGenetic studies indicate that breast cancer can be divided into several basic molecular groups. One of these groups, termed IntClust-2, is characterized by amplification of a small portion of chromosome 11 and has a median survival of only five years. Several cancer-relevant genes occupy this portion of chromosome 11, and it is thought that overexpression of a combination of driver genes in this region is responsible for the poor outcome of women in this group. In this study we used a gene editing method to knock out, one by one, each of 198 genes that are located within the amplified region of chromosome 11 and determined how much each of these genes contributed to the survival of breast cancer cells. In addition to well-known drivers such asCCND1andPAK1, we identified two different genes (SERPINH1andP4HA3), that encode proteins involved in collagen synthesis and organization. Using bothin vitroandin vivofunctional analyses, we determined thatP4HA3and/orSERPINH1provide a critical driver function on IntClust-2 basic processes, such as viability, proliferation, and migration. Inhibiting these enzymes via genetic or pharmacologic means reduced collagen synthesis and impeded oncogenic signaling transduction in cell culture models, and a small-molecule inhibitor of P4HA3 was effective in treating 11q13 tumor growth in an animal model. As collagen has a well-known association with tissue stiffness and aggressive forms of breast cancer, we believe that the two genes we identified provide an opportunity for a new therapeutic strategy in IntClust-2 breast cancers.
The Hill function is the universal Hopfield barrier for sharpness of input-output responses
Authors: Martinez-Corral Rosa , Nam Kee-Myoung , DePace Angela H. , Gunawardena Jeremy 
Published: March 2024

AbstractThe Hill functions, ℋh(x) =xh/(1 +xh), have been widely used in biology for over a century but, with the exception of ℋ1, they have had no justification other than as a convenient fit to empirical data. Here, we show that they are the universal limit for the sharpness of any input-output response arising from a Markov process model at thermodynamic equilibrium. Models may represent arbitrary molecular complexity, with multiple ligands, internal states, conformations, co-regulators, etc, under core assumptions that are detailed in the paper. The model output may be any linear combination of steady-state probabilities, with components other than the chosen input ligand held constant. This formulation generalises most of the responses in the literature. We use a coarse-graining method in the graph-theoretic linear framework to show that two sharpness measures for input-output responses fall within an effectively bounded region of the positive quadrant, Ωm⊂ (ℝ+)2, for any equilibrium model withminput binding sites. Ωmexhibits a cusp which approaches, but never exceeds, the sharpness of ℋmbut the region and the cusp can be exceeded when models are taken away from thermodynamic equilibrium. Such fundamental thermodynamic limits are called Hopfield barriers and our results provide a biophysical justification for the Hill functions as the universal Hopfield barriers for sharpness. Our results also introduce an object, Ωm, whose structure may be of mathematical interest, and suggest the importance of characterising Hopfield barriers for other forms of cellular information processing.