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Point of no returns: researchers are crossing a threshold in the fight for funding
A probabilistic histological atlas of the human brain for MRI segmentation
Pre- and postsynaptic upregulation of FasII synergistically underlies neuropathological and behavioral phenotypes in a Drosophila model of myotonic dystrophy
Abstract Myotonic dystrophy type 1 is a multisystemic disorder that has been extensively studied for decades, yet our understanding of its neuropathological aspect remains rudimentary. Building on an established Drosophila model, we study the neuropathological features of the disease by expressing untranslated expanded CUG repeats at the Drosophila larval neuromuscular junction. In this model, we show that both pre- and postsynaptic expressions of CUG repeats participate in inducing phenotypes in synaptic boutons, arbors, transmission and larval locomotor activity. Furthermore, expression of CUG repeats in either motorneurons or body wall muscles induces upregulation of the cell adhesion molecule FasII (NCAM1 in mammals), and the knockdown of fasII is sufficient to rescue the phenotypes. Overexpression of FasII-C, a FasII isoform with no cytoplasmic domain, mimics the phenotypes of expanded CUG expression at the neuromuscular junction. In contrary, overexpression of FasII-A-PEST+ rescues the synaptic and behavioral defects. Our study provides insights into the fundamental mechanisms underlying synapse dysregulation in myotonic dystrophy type 1.
Genome-wide association study identifies novel variants in olfactory, vitamin A, vitamin B, and cadherin pathways associated with learning and memory
Abstract Learning and memory, as fundamental components of human cognition, are heritable traits that are highly variable between individuals and within populations. Investigation into the genetic basis of cognition is a prominent area of research, with genetic associations being previously reported for a wide range of cognitive phenotypes. Here we utilise a genome-wide association study (GWAS) approach to evaluate the contribution of genetic variation to learning and memory phenotypes in a comprehensively phenotyped, well-characterised, healthy, and unrelated cohort of individuals (n = 613). Cognitive phenotypes were assessed using nine comprehensive test batteries consisting of twenty-one cognitive performance assessments including IQ, five measures for visual and verbal learning, and fifteen measures for semantic, working, episodic and prospective memory. Principal component analysis was utilised to amalgamate correlated test scores into additional new cognitive phenotypes. Our study identified genome wide significant associations for 13 loci across all phenotypes. A novel association was identified between the rs817826 SNP at 9q31.2 and verbal learning discrimination (p = 2.71 × 10 − 9 ). GWAS of cognitive PCs identified three variants in the vicinity of thiamine (Vitamin B 1 ) transporter gene SLC19A3 (most significant SNP rs12105620, p = 2.17 × 10 − 9 ), a 3’ UTR variant in PPARD (rs9658167, p = 1.47 × 10 − 8 ), and an intronic variant in RBFOX1 (rs17138790, p = 4.24 × 10 − 8 ) associated with the cognitive PC related to visual and verbal learning. The cognitive PC relating to prospective and retrospective memory revealed a locus containing a synonymous variant in NXPE3 (rs2305990, p = 6.56 × 10 − 9 ) and intronic variants in RD3 (rs17189035, p = 2.71 × 10 − 8 ) and WLS/GNG12-AS1 (rs17130484, p = 4.13 × 10 − 8 ). Pathway analysis identified olfactory, vitamin A, and cadherin pathways as being significantly overrepresented across multiple cognitive domains. The novel associations identified provide candidates for further investigation and necessitate replication in similarly characterised independent cohorts.
Missing molybdenum and the composition of the continental crust inferred from molybdenum isotopes
Abstract Accurately constraining the molybdenum (Mo) isotope composition (δ 98/95 Mo) of Earth’s major reservoirs is essential for understanding its evolution. However, δ 98/95 Mo of the continental crust (CC), particularly the middle and lower crust, remains poorly constrained. Here we show the Mo isotope data for the Gangdese arc section in combination with published data from ultramafic-mafic, intermediate and felsic intrusions, representing the lower, middle and upper CC, respectively, constrain variability within the CC. Mass balance calculations using several crustal depth models generate an average δ 98/95 Mo of the bulk CC of −0.116 ± 0.011‰ (2 s.d.), resolvably heavier than the bulk silicate Earth. Global scale mass balance modeling demonstrates that the Mo isotope compositions of the CC and the depleted mantle are presently near balanced. Lower crustal delamination is an additional mechanism capable of contributing to the subchondritic Mo isotope composition of the depleted mantle. Over the course of Earth’s history, new crustal growth and destruction have reached dynamic equilibrium.
Preoperative red cell width distribution to albumin ratio predicts early radial artery occlusion following coronary intervention via conventional transradial access
Real-time capture of domain movements during copper amine oxidase catalysis by mix-and-inject serial crystallography
Combined effects of ocean acidification, warming, and salinity on the fertilization success in an Arctic population of sea urchins
Abstract Anthropogenic stressors, including ocean acidification (OA), ocean warming (OW), and salinity changes, are rapidly altering marine ecosystems, with Arctic regions being particularly vulnerable. This study investigates the combined effects of these stressors on the fertilization success of the green sea urchin ( Strongylocentrotus droebachiensis ) from Kongsfjorden, Svalbard. We exposed gametes to various levels of pH, temperature, and salinity to assess their individual and combined impacts on fertilization performance. Our results show that temperature and pH significantly influenced fertilization success, with temperature having the strongest effect, while salinity had no significant impact. A significant statistical interaction between temperature and pH indicated that warming enhanced fertilization more effectively at higher pH levels, while low pH suppressed this increase. To compare the relative influence of each stressor, we used a conceptual model based on standardized slopes, which supported temperature as the dominant driver, followed by pH. These findings highlight the importance of considering the effects of combined stressors when assessing marine organism responses to climate change, especially in polar ecosystems. Our study underscores the need for further research into the mechanisms driving these combined effects, given that Arctic ecosystems face accelerated environmental changes.
Structural insights into C3 convertase activity of the classical pathway of complement
Abstract Immune protection by the complement system depends on C3 cleavage by C3 convertases that is critical to all three activation pathways. Structural data on convertase formation in the classical pathway and on C3-substrate binding to convertases is lacking. We present the cryo-EM structures of the proconvertase (C4b2), convertase (C4b2b), and convertase-substrate complex (C4b2b-C3) of the classical pathway. The data show that C2 and C4b form proconvertases and convertases like factor B and C3b of the alternative pathway. Substrate C3 binds C4b of the convertase through two interfaces: one also found in the SCIN-inhibited C3bBb dimer, and another facilitated by conformational changes in C3. Bending of C3 and swinging of the C2 protease bring the C3-scissile loop into the active site. The second, charged, C4b-interaction site favors C3- substrate binding, but upon cleavage repels product C3b. Thus, a charge switch-over mechanism effects the catalytic turnover of the convertases producing opsonin C3b.
Single cell RNAseq signatures refined with combiroc enhance identification of NK cells in blood and solid tissues
Abstract Cytotoxic CD8 T lymphocytes (CTLs) and natural killer (NK) cells share the common objective of controlling infections and detecting and removing tumor cells, albeit through distinct target recognition mechanisms. Although CTLs belong to the adaptive immune system and NK cells are innate lymphoid cells, they frequently exhibit considerable overlap in their molecular phenotypes. This overlap, as with many others in cell biology, poses challenges for distinguishing cells in the context of single cell transcriptomics. Building on a previous ROC-driven combinatorial approach, we developed a new computational framework for single-cell RNA-seq with the combiroc R package, and in this study we showed that it can identify non-canonical marker combinations for NK cells in Peripheral Blood Mononuclear Cell datasets. These combinatorial markers were in line with the Human Protein Atlas and we validated them through cytometry staining and functional assays. Markers selected with combiroc exhibit exceptional discriminatory power for identifying NK cells, both in blood and solid tumoral tissues. Besides this finding, we showed that our approach vastly optimizes standard differential expression signatures: it reduces dimensionality while improving interpretability and transferability to diagnostic applications, offering a practical solution for refining immune cell identities in complex transcriptomic datasets.
Fully integrated hybrid multimode-multiwavelength photonic processor with picosecond latency
Performance analysis and dead layer profiling of a carbon-fiber encapsulated p-type HPGe detector
Molecular mechanisms of receptor recognition and antibody neutralization of coxsackievirus A6
Abstract Coxsackievirus A6 (CVA6), a major cause of hand, foot, and mouth disease, lacks approved vaccines or drugs. KRM1 is its only known receptor, but its precise role remains unclear. This study investigates CVA6’s entry mechanism and antibody neutralization. Cryo-EM shows CVA6 clinical strain HeB primarily exists as mature virions. KRM1 binding within the canyon triggers conversion to uncoating intermediate, defining KRM1 as an uncoating receptor for CVA6. However, KRM1 knockout reduces CVA6 infectivity without affecting attachment. Conversely, disrupting heparan sulfate proteoglycan (HSPG) impairs both viral attachment and infectivity, and CVA6 virions bind heparin directly. These results support a two-receptor entry model for CVA6: HSPG mediates viral attachment, while KRM1 induces uncoating. Additionally, we develop two CVA6-specific protective antibodies (1F4 and 3H7), targeting a new antigenic site near the three-fold axis of the viral capsid. These antibodies sterically block KRM1 binding and function post-attachment, consistent with KRM1’s role. The findings elucidate CVA6 entry and offer a basis for antibody interventions.
The influence of fiber reinforcement on the physico-mechanical properties and microstructure of artificial stones with marble and quartzite waste aggregates
Abstract This study fabricated artificial stone samples using marble (carbonate-based) and quartzite (siliceous-based) waste aggregates, their corresponding fine powders, and Unsaturated Polyester Resin (UPR) via the Vacuum, Vibration, and Compression (VVC) method. After evaluating three resin percentages for each aggregate, the optimal formulations- Artificial Marble with 10 wt% resin (AM-10R) and Artificial Quartzite with 12 wt% resin (AQ-12R) were reinforced with Polypropylene (PP) and Glass fibers (GF). Different results were observed despite identical processing conditions. Fiber reinforcement in artificial quartzite maintained compressive strength (up to + 5% relative to the control) and showed a trend toward improved flexural strength (up to + 12.6% in the optimal formulation). In contrast, artificial marble exhibited significant reductions in compressive strength (16.5–22.8%) and flexural strength (4–21%), primarily attributed to increased porosity from 2.75% to 5.83%. Laser particle size analysis attributed this divergence to the different powder characteristics. The marble powder was significantly finer due to marble’s lower hardness, resulting in a stiffer resin-powder mixture with reduced workability. This impeded efficient air removal during the VVC process. The addition of fibers further worsened this issue in the marble-based composite, leading to higher porosity and diminished reinforcement efficiency. Therefore, Effective fiber reinforcement for strength improvement depends on precise porosity control through optimized manufacturing parameters, which is highly dependent on the aggregate-powder system’s properties. These findings provide practical guidance for producing stronger, eco-friendly artificial stones from industrial waste using optimized fiber–resin systems.