Browse Articles

Blood-based biomarkers suggest prolonged axonal Injury following pediatric mild traumatic brain injury

Abstract Pediatric mild traumatic brain injury (pmTBI) affects millions of youth annually but underlying pathophysiology and time for physiological recovery remains unknown. Non-fasting plasma samples were obtained in 59 pmTBI (28 females; age 14.9 ± 2.7) at approximately 7 days and 4 months post-injury and in 41 matched healthy controls (HC: 20 females; age 14.3 ± 2.8). Samples were analyzed for GFAP, NFL, Tau, pTau181 and UCH-L1 protein concentrations in conjunction with a clinical battery. Significant effects of diagnosis (pmTBI > HC) existed at ~ 7 days (p < 0.001; Cohen’s d = 0.72) and ~ 4 months (p = 0.015; Cohen’s d = 0.41) post-injury for NFL. NFL was also elevated in pmTBI with significant alterations to mental status (e.g., post-traumatic amnesia) relative to patients without (p = 0.014; Cohen’s d = 0.77). UCH-L1, GFAP and pTau181 did not differ between groups, but demonstrated negative associations with days post-injury (small to medium effect sizes) suggestive of a more rapid release/clearance. Post-concussive symptoms had the best diagnostic classification accuracy at ~ 7 days, but NFL ranked higher at 4 months post-injury. Preliminary findings highlight dynamic fluctuations in blood-based biomarkers in the first week of pmTBI, with ongoing evidence of protein release (NFL) at 4 months. NFL demonstrated additional promise for delineating injury severity within the spectrum of pmTBI.

Maria Iandolo New (1928–2024): Pioneering pediatric endocrinologist

Correction for Cao et al., Circadian clock cryptochrome proteins regulate autoimmunity

Untargeted metabolomic and proteomic analysis implicates SIRT2 as a novel therapeutic target for diabetic nephropathy

Embryology cannot establish the “Protura-sister”

Synthesis of novel magnesium ferrite Schiff base chitosan nanocomposite for efficient removal of pb(II) ions from aqueous media

Cyanobacteria and Chloroflexota cooperate to structure light-responsive biofilms

Microbial mats are stratified communities often dominated by unicellular and filamentous phototrophs within an exopolymer matrix. It is challenging to quantify the dynamic responses of community members in situ as they experience steep gradients and rapid fluctuations of light. To address this, we developed a binary consortium using two representative isolates from hot spring mats: the unicellular oxygenic phototrophic cyanobacterium Synechococcus OS-B′ (Syn OS-B′) and the filamentous anoxygenic phototroph Chloroflexus MS-CIW-1 (Chfl MS-1). We quantified the motility of individual cells and entire colonies and demonstrated that Chfl MS-1 formed bundles of filaments that moved in all directions with no directional bias to light. Syn OS-B′ was slightly less motile but exhibited positive phototaxis. This binary consortium displayed cooperative behavior by moving further than either species alone and formed ordered arrays where both species aligned with the light source. No cooperative motility was observed when a nonmotile pilB mutant of Syn OS-B′ was used instead of Syn OS-B′. The binary consortium also produced more adherent biofilm than individual species, consistent with the close interspecies association revealed by electron microscopy. We propose that cyanobacteria and Chloroflexota cooperate in forming natural microbial mats by colonizing new niches and building robust biofilms.

New method for cytological evaluation using direct nipple discharge without aspiration

Reply to Machida et al.: Although embryology cannot establish the “Protura-sister”, phylogenomics can

Core features of positive mental health in adolescents and their protective role against psychopathology

Serine phosphorylation facilitates protein degradation by the human mitochondrial ClpXP protease

ClpXP is a two-component mitochondrial matrix protease. The caseinolytic mitochondrial matrix peptidase chaperone subunit X (ClpX) recognizes and translocates protein substrates into the degradation chamber of the caseinolytic protease P (ClpP) for proteolysis. ClpXP degrades damaged respiratory chain proteins and is necessary for cancer cell survival. Despite the critical role of ClpXP in mitochondrial protein quality control, the specific degrons, or modifications that tag substrate proteins for degradation by human ClpXP, are still unknown. We demonstrated that phosphorylated serine (pSer) targets substrates to ClpX and facilitates their degradation by ClpXP in biochemical assays. In contrast, ClpP hyperactivated by the small-molecule drug ONC201 lost the preference for phosphorylated substrates. Hydrogen deuterium exchange mass spectrometry combined with biochemical assays showed that pSer binds the RKL loop of ClpX. ClpX variants with substitutions in the RKL loop failed to recognize phosphorylated substrates. In intact cells, ClpXP also preferentially degraded substrates with pSer. Moreover, ClpX substrates with the pSer were selectively found in aggregated mitochondrial proteins. Our work uncovers a mechanism for substrate recognition by ClpXP, with implications for targeting acute myeloid leukemia and other disorders involving ClpXP dysfunction.

Decision-making model for production and operation of underground gold mines considering low-carbon condition

Abstract Within the framework of a low-carbon transition and integrated mineral resource exploitation, this study presents an innovative system dynamics (SD) model designed to optimize decision-making and enhance profitability in underground gold mining operations. The novel approach seamlessly integrates critical subsystems, including reserves, mining, ore dressing, smelting, financial, and carbon reduction, offering a comprehensive framework for the analysis of efficiency and sustainability. Utilizing causal loop and system flow diagrams, the model elucidates the synergistic impacts of index variations on mine operational efficiency. The model is applied to a case study involving three mining areas within a specific gold mine in China, where sensitivity analysis identifies key indicators affecting profitability. Furthermore, it examines dynamic trends under varying carbon tax scenarios. The findings reveal that mining strategic adjustments can significantly enhance profitability, extend the operational lifespan of mines, and reduce emissions.

Subunit-specific conductance of single homomeric and heteromeric HCN pacemaker channels at femtosiemens resolution

In mammals, the four subunit isoforms HCN1–4 assemble to form functional homotetrameric and heterotetrameric hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channels. Despite the outstanding relevance of HCN channels for organisms, including generating electrical rhythmicity in cardiac pacemaker cells and diverse types of brain neurons, key channel properties are still elusive. In particular, the unitary conductance, γ, of HCN channels is highly controversial. We analyzed the unitary conductance at femtosiemens resolution of all four homotetrameric channels of the mouse, mHCN1–4. All conductance values are in the range of 1 pS which is exceptionally small compared to most other ion channels. Surprisingly, the conductance among the isoforms differs up to threefold (γ mHCN2 = 1.54 pS > γ mHCN1 = 0.84 pS > γ mHCN3 = 0.54 pS ≈ γ mHCN4 = 0.51 pS) though the residues in the two narrow parts of the pore, the selectivity filter and the inner gate, are conserved. Mutagenesis and all-atom molecular dynamics simulations demonstrate that the differences in the conductance are generated by different amounts of negative charges in the outer channel vestibule, which control ion accumulation. In line with these results, heterotetrameric channels exhibit intermediate unitary conductance values with respect to the homotetrameric channels. Our approach demonstrates how HCN channels can be functionally differentiated at the single-channel level, paving the way to target specific channels with selective drugs.

Chromosome-level reference genome assembly of the gyrfalcon (Falco rusticolus) and population genomics offer insights into the falcon population in Mongolia

Enzymes in a human cytoplasm model organize into submetabolon complexes

Enzyme–enzyme interactions are fundamental to the function of cells. Their atomistic mechanisms remain elusive mainly due to limitations of in-cell measurements. We address this challenge by atomistically modeling, for a total of ≈80 μs, a slice of the human cell cytoplasm that includes three successive enzymes along the glycolytic pathway: glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK), and phosphoglycerate mutase (PGM). We tested the model for nonspecific protein stickiness, an artifact of current atomistic force fields in crowded environments. The simulations reveal that the human enzymes co-organize in-cell into transient submetabolon complexes, consistent with previous experimental results. Our data both reiterate known specificity between GAPDH and PGK and reveal extensive direct interactions between GAPDH and PGM. Our simulations further reveal, through force field benchmarking, the critical role of protein solvation in facilitating these enzyme–enzyme interactions. Transient interenzyme interactions with μs lifetime occur repeatedly in our simulations via specific sticky protein surface patches, with interactions often mediated by charged patch residues. Some of the residues that interact frequently with one another lie in or near the active site of the enzymes. We show that some of these patches correspond to a general mode to interact with several partners for promiscuous enzymes like GAPDH. We further show that the non-native yeast PGK is stickier than human PGK in our human cytoplasm model, supporting the idea of evolutionary pressure to reduce sticking. Our cytoplasm modeling paves the way toward capturing the atomistic dynamics of an entire enzymatic pathway in-cell.

Socio-demographic disparities in global trends of lip and oral cavity neoplasms from 1990 to 2021

Abstract Oral cancer, the 13th most common globally, is primarily squamous cell carcinoma linked to tobacco, alcohol, and HPV. Despite advances in care, it remains a major health concern due to high mortality and its impact on quality of life. This study analyzed socio-demographic disparities in oral cancer burden using data from 1990 to 2021. We analyzed annual incidence, mortality, and DALYs across 204 countries, using age-standardized rates and the Socio-demographic Index (SDI) to assess development-related impacts. Statistical methods included Kruskal–Wallis tests, linear regression, joinpoint regression for trends, and Exponential Smoothing for forecasts (2022–2030), with analyses conducted in STATA and Python, and p < 0.05 as significant. Incidence was highest in high SDI countries, while mortality and DALYs were highest in low and middle SDI countries (p < 0.001). From 1990 to 2021, incidence increased (AAPC: 0.5–1.0%), while mortality (APC: − 0.5%) and DALYs (APC: − 0.6%) declined in low SDI regions. Significant disparities across SDI categories (p < 0.001) showed incidence rising with socio-demographic development (R2 = 0.102, p < 0.001), with high-middle SDI regions bearing the highest mortality and DALYs. These findings highlight the need for awareness, prevention, early detection, and accessible care, especially in lower SDI regions.

Neomorphic leukemia-derived mutations in the TET2 enzyme induce genome instability via a substrate shift from 5-methylcytosine to thymine

Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (mC) in DNA, contributing to the regulation of gene transcription. Diverse mutations of TET2 are frequently found in various blood cancers, yet the full scope of their functional consequences has been unexplored. Here, we report that a subset of TET2 mutations identified in leukemia patients alter the substrate specificity of TET2 from acting on mC to thymine. This neomorphic activity results from substitutions at key residues involved in the interactions with the mC base, including Asn1387 and His1904. Recombinant human TET2 proteins harboring the mutation of these residues can catalyze the oxidation of thymine to 5-hydroxymethyluracil (hmU) and 5-formyluracil (fU). Exogenous expression of the mutant TET2 Asn1387Thr (N1387T) in HEK293T cells leads to hmU accumulation, with levels further increased in cells lacking the glycosylase SMUG1. Endogenous knock-in of N1300T, the murine equivalent of N1387T, in mouse embryonic stem cells induces hmU production, causing DNA lesions and transcriptional activation of DNA damage response genes. N1300T cells accumulate more additional mutations with extended culture and exhibit heightened sensitivity to ATR inhibition compared to Tet2 knockout cells. Our study reveals that certain patient-derived TET2 mutations can acquire unexpected gain-of-function activities beyond impairing mC oxidation, offering a fresh perspective on the diverse molecular etiology of mutant TET2-related leukemogenesis.

Measurements of stable ruthenium fission products in nuclear reactor fuel samples

Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain

Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson’s disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and Ub phosphorylation. In addition, we observe that a pool of the Rab-specific, protein phosphatase family member 1H phosphatase, is transcriptionally up-regulated and recruited to damaged mitochondria, independent of PINK1 or LRRK2 activity. Parallel signaling of LRRK2 and PINK1 pathways is supported by assessment of motor behavioral studies that show no evidence of genetic interaction in crossed mouse lines. Previously we showed loss of cilia in LRRK2 R1441C mice and herein we show that PINK1 KO mice exhibit a ciliogenesis defect in striatal cholinergic interneurons and astrocytes that interferes with Hedgehog induction of glial derived-neurotrophic factor transcription. This is not exacerbated in double-mutant LRRK2 and PINK1 mice. Overall, our analysis indicates that LRRK2 activation and/or loss of PINK1 function along parallel pathways to impair ciliogenesis, suggesting a convergent mechanism toward PD. Our data suggest that reversal of defects downstream of ciliogenesis offers a common therapeutic strategy for LRRK2 or PINK1 PD patients, whereas LRRK2 inhibitors that are currently in clinical trials are unlikely to benefit PINK1 PD patients.

Performance prediction and optimization of a high-efficiency tessellated diamond fractal MIMO antenna for terahertz 6G communication using machine learning approaches