Miracle-dz/UniFAR-FTUs huggingface dataset:
Background to the European seismic design provisions for retrofitting RC elements using FRP materials

This paper is a comprehensive background document on the state of the art in European seismic design provisions which was assembled by fib committee 5.1 to support the development of design guidelines regarding the use of externally applied fibre reinforced polymer (FRP) materials in the seismic retrofitting of reinforced concrete structures. In the context of developing design guidelines, the underlying mechanistic models that support the derivation of provisions were assembled following critical evaluation of the existing proposals and with careful reference to the experimental evidence available, the comparative assessment of past models in the literature and requirements established from first principles.
Between heuristics and optimality: Flexible integration of cost and evidence during information sampling

Effective decision making in an uncertain world requires balancing the benefits of acquiring relevant information with the costs of delaying choice. Optimal strategies for information sampling can be accurate but computationally expensive, whereas heuristic strategies are often computationally simple but rigid. To characterize the computations that underlie information sampling, we examined choice processes in human participants who sampled sequences of images (e.g. indoor and outdoor scenes) and attempted to infer the majority category (e.g. indoor or outdoor) under two reward conditions. We examined how behavior maps onto potential information sampling strategies. We found that choices were best described by a flexible function that lay between optimality and heuristics; integrating the magnitude of evidence favoring each category and the number of samples collected thus far. Integration of these criteria resulted in a trade-off between evidence and samples collected, in which the strength of evidence needed to stop sampling decreased linearly as the number of samples accumulated over the course of a trial. This non-optimal trade-off best accounted for choice behavior even under high reward contexts. Our results demonstrate that unlike the optimal strategy, humans are performing simple accumulations instead of computing expected values, and that unlike a simple heuristic strategy, humans are dynamically integrating multiple sources of information in lieu of using only one source. This evidence-by-costs tradeoff illustrates a computationally efficient strategy that balances competing motivations for accuracy and cost minimization.
The Spike-Stabilizing D614G Mutation Interacts with S1/S2 Cleavage Site Mutations To Promote the Infectious Potential of SARS-CoV-2 Variants

The first SARS-CoV-2 variant that spread worldwide in early 2020 carried a D614G mutation in the viral spike, making this protein more stable in its cleaved form at the surface of virions. The Alpha and Delta variants, which spread in late 2020 and early 2021, respectively, proved increasingly transmissible and pathogenic compared to the original strain. ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remained genetically stable during the first 3 months of the pandemic, before acquiring a D614G spike mutation that rapidly spread worldwide and then generating successive waves of viral variants with increasingly high transmissibility. We set out to evaluate possible epistatic interactions between the early-occurring D614G mutation and the more recently emerged cleavage site mutations present in spike of the Alpha, Delta, and Omicron variants of concern. The P681H/R mutations at the S1/S2 cleavage site increased spike processing and fusogenicity but limited its incorporation into pseudoviruses. In addition, the higher cleavage rate led to higher shedding of the spike S1 subunit, resulting in a lower infectivity of the P681H/R-carrying pseudoviruses compared to those expressing the Wuhan wild-type spike. The D614G mutation increased spike expression at the cell surface and limited S1 shedding from pseudovirions. As a consequence, the D614G mutation preferentially increased the infectivity of P681H/R-carrying pseudoviruses. This enhancement was more marked in cells where the endosomal route predominated, suggesting that more stable spikes could better withstand the endosomal environment. Taken together, these findings suggest that the D614G mutation stabilized S1/S2 association and enabled the selection of mutations that increased S1/S2 cleavage, leading to the emergence of SARS-CoV-2 variants expressing highly fusogenic spikes. IMPORTANCE The first SARS-CoV-2 variant that spread worldwide in early 2020 carried a D614G mutation in the viral spike, making this protein more stable in its cleaved form at the surface of virions. The Alpha and Delta variants, which spread in late 2020 and early 2021, respectively, proved increasingly transmissible and pathogenic compared to the original strain. Interestingly, Alpha and Delta both carried the mutations P681H/R in a cleavage site that made the spike more cleaved and more efficient at mediating viral fusion. We show here that variants with increased spike cleavage due to P681H/R were even more dependent on the stabilizing effect of the D614G mutation, which limited the shedding of cleaved S1 subunits from viral particles. These findings suggest that the worldwide spread of the D614G mutation was a prerequisite for the emergence of more pathogenic SARS-CoV-2 variants with highly fusogenic spikes.
Microglia Maintain Homeostatic Conditions in the Developing Rostral Migratory Stream

Visual Abstract Microglia invade the neuroblast migratory corridor of the rostral migratory stream (RMS) early in development. The early postnatal RMS does not yet have the dense astrocyte and vascular scaffold that helps propel forward migrating neuroblasts, which led us to consider whether microglia help regulate conditions permissive to neuroblast migration in the RMS. GFP-labeled microglia in CX3CR-1GFP/+ mice assemble primarily along the outer borders of the RMS during the first postnatal week, where they exhibit predominantly an ameboid morphology and associate with migrating neuroblasts. Microglia ablation for 3 d postnatally does not impact the density of pulse labeled BrdU+ neuroblasts nor the distance migrated by tdTomato electroporated neuroblasts in the RMS. However, microglia wrap DsRed-labeled neuroblasts in the RMS of P7 CX3CR-1GFP/+;DCXDsRed/+ mice and express the markers CD68, CLEC7A, MERTK, and IGF-1, suggesting active regulation in the developing RMS. Microglia depletion for 14 d postnatally further induced an accumulation of CC3+ DCX+ apoptotic neuroblasts in the RMS, a wider RMS and extended patency of the lateral ventricle extension in the olfactory bulb. These findings illustrate the importance of microglia in maintaining a healthy neuroblast population and an environment permissive to neuroblast migration in the early postnatal RMS.
Hindlimb muscle representations in mouse motor cortex defined by viral tracing

Descending pathways from the cortex to the spinal cord are involved in the control of natural movement. Although mice are widely used in the study of the neurobiology of movement and as models of neurodegenerative disease, an understanding of motor cortical organization is lacking, particularly for hindlimb muscles. In this study, we used the retrograde transneuronal transport of rabies virus to compare the organization of descending cortical projections to fast- and slow-twitch hindlimb muscles surrounding the ankle joint in mice. Although the initial stage of virus transport from the soleus muscle (predominantly slow-twitch) appeared to be more rapid than that associated with the tibialis anterior muscle (predominantly fast-twitch), the rate of further transport of the virus to cortical projection neurons in layer V was equivalent for the two injected muscles. After appropriate survival times, dense concentrations of layer V projection neurons were identified in three cortical areas: the primary motor cortex (M1), secondary motor cortex (M2), and primary somatosensory cortex (S1). The origin of the cortical projections to each of the two injected muscles overlapped almost entirely within these cortical areas. This organization suggests that cortical projection neurons maintain a high degree of specificity, even when they are involved in controlling muscles with different functional roles (fast-versus slow-twitch, extensor versus flexor). Our results represent an important addition to the understanding of the mouse motor system and lay the foundation for future studies investigating the mechanisms underlying motor system dysfunction and degeneration in diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy.
Metabolic, fibrotic and splicing pathways are all altered in Emery-Dreifuss muscular dystrophy spectrum patients to differing degrees

Emery-Dreifuss muscular dystrophy (EDMD) is a genetically and clinically variable disorder. Previous attempts to use gene expression changes find its pathomechanism were unavailing, so we here engaged a functional pathway analysis. RNA-Seq was performed on cells from 10 patients diagnosed with an EDMD spectrum disease with different mutations in 7 genes. Upon comparing to controls, the pathway analysis revealed that multiple genes involved in fibrosis, metabolism, myogenic signaling, and splicing were affected in all patients. Splice variant analysis revealed alterations of muscle-specific variants for several important muscle genes. Deeper analysis of metabolic pathways revealed a reduction in glycolytic and oxidative metabolism and reduced numbers of mitochondria across a larger set of 14 EDMD patients and 7 controls. Intriguingly, the gene expression signatures segregated the patients into three subgroups whose distinctions could potentially relate to differences in clinical presentation. Finally, differential expression analysis of miRNAs changing in the patients similarly highlighted fibrosis, metabolism, and myogenic signaling pathways. This pathway approach revealed a clear EDMD signature that can both be used as the basis for establishing a biomarker panel specific to EDMD and direct further investigation into its pathomechanism. Furthermore, the segregation of specific gene changes into three distinct categories that appear to correlate with clinical presentation may be developed into prognostic biomarkers, though this will first require their testing in a wider set of patients with more clinical information.
Bayesian Statistics Improves Biological Interpretability of Metabolomics Data from Human Cohorts

Background Univariate analyses of metabolomics data currently follow a frequentist approach, using p-values to reject a null-hypothesis. However, the usability of p-values is plagued by many misconceptions and inherent pitfalls. We here propose the use of Bayesian statistics to quantify evidence supporting different hypotheses and discriminate between the null hypothesis versus lack of statistical power. Methods We use metabolomics data from three independent human cohorts that studied plasma signatures of subjects with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). Data are publicly available, covering 84-197 subjects in each study with 562-888 identified metabolites of which 777 were common between two studies, and 93 compounds reported in all three studies. By comparing results from classic multiple regression against Bayesian multiple regression we show how Bayesian statistics incorporates results from one study as ‘prior information’ into the next study, thereby improving the overall assessment of the likelihood of finding specific differences between plasma metabolite levels and disease outcomes in ME/CFS. Results Whereas using classic statistics and Benjamini-Hochberg FDR-corrections, study 1 detected 18 metabolic differences, study 2 detected no differences. Using Bayesian statistics on the same data, we found a high likelihood that 97 compounds were altered in concentration in study 2, after using the results of study 1 as prior distributions. These findings included lower levels of peroxisome-produced ether-lipids, higher levels of long chain, unsaturated triacylglycerides, and the presence of exposome compounds that are explained by difference in diet and medication between healthy subjects and ME/CFS patients. Although study 3 reported only 92 reported compounds in common with the other two studies, these major differences were confirmed. We also found that prostaglandin F2alpha, a lipid mediator of physiological relevance, was significantly reduced in ME/CFS patients across all three studies. Conclusions The use of Bayesian statistics led to biological conclusions from metabolomic data that were not found through the frequentist analytical approaches more commonly employed. We propose that Bayesian statistics to be highly useful for studies with similar research designs if similar metabolomic assays are used.
KIAA1109 is required for survival and for normal development and function of the neuromuscular junction in mice

KIAA1109 (4932438A13Rik) is a novel gene linked to Alkuraya-Kucinska Syndrome, an autosomal recessive disorder with severe brain malformations and arthrogryposis in humans. The role of KIAA1109 in mammalian development and function remains poorly understood. Here, we characterize mutant mice deficient in Kiaa1109 (Kiaa1109−/−). We report that Kiaa1109−/− mice died during perinatal stages. These Kiaa1109−/− embryos exhibited impaired intramuscular nerve growth and reduced sizes of the neuromuscular junction (NMJ) compared with their littermate controls. Electrophysiological analysis further revealed defects in neuromuscular synaptic transmission in Kiaa1109−/− embryos. Notably, the frequency of spontaneous neurotransmitter release was markedly increased, whereas evoked neurotransmitter release and quantal content were reduced. Furthermore, neuromuscular synapses in Kiaa1109−/− embryos failed to respond to a repetitive, low frequency stimulation (10Hz). These results demonstrate that KIAA1109 is required for survival in mice and for proper development and function of the NMJ. Significance Statement This is the first report characterizing the phenotype of mutant mice deficient in KIAA1109 (4932438A13Rik), a novel gene in mammals. We show that KIAA1109 is required for survival in mice and that KIAA1109 plays important roles in normal development and function of the NMJ in mice.
Super-Resolved Imaging Deciphers Ligand Dependent Membrane Behaviour of the Onco-Immunogenic CCR5 Receptor

molecular stoichiometries indicative of dimeric sub-units independent of CCL5 perturbation. These biophysical methods can provide important insights into the structure and function of onco-immunogenic receptors and a plethora of other biomolecules. TIRF microscopy whilst retaining the high signal-to-noise ratio of molecules close to the coverslip surface. We then demonstrate how these methods can be used to investigate the surface expression and aggregation of CCR5 after exposure to the receptor’s CCL5 ligand.
Systematic evaluation of high-level visual deficits and lesions in posterior cerebral artery stroke

Knowledge about the consequences of stroke on high level vision comes primarily from single case studies of patients selected based on their behavioural profiles with deficits in the recognition of a specific visual category such as faces or words. There are, however, no systematic, detailed, large-scale evaluations of the more typical clinical behavioural and lesion profiles of impairments in high level vision that may follow posterior cerebral artery (PCA) stroke. These goals were met by the current study through the data collected in the Back of the Brain (BoB) project: to date, the largest (N=64) and most detailed examination of patients with cortical PCA strokes selected based on lesion location rather than behavioural symptoms. We present here two complementary analyses of the structural neuroimaging data and key indices of behavioural performance with the visual processing words, objects and faces: (1) a multivariate multiple regression analysis to establish the relationships between lesion volume, lesion laterality or the presence of a bilateral lesion with performance on words, objects and faces; and, (2) a voxel-based correlational method (VBCM) analysis to establish whether there are distinct or separate regions within the PCA territory that underpin the visual processing of these categories. In contrast to the characterization of specific stroke syndromes like pure alexia or prosopagnosia in the literature, most patients in our cohort showed more general deficits in high level vision (n=22) or no deficits at all (n=21). Category-selective deficits were rare (n=6), and were only found for words, which, interestingly could follow left or right hemisphere lesions. The lesion analyses mainly confirmed the pattern reported in more selective cases: word recognition impairments are associated with a left-sided pattern of damage and face recognition deficits with a bilateral albeit right-dominant lesion pattern. Importantly, however, both general and more selective impairment may follow from left or right unilateral as well as bilateral lesions. While the findings provide partial support for the relative laterality of posterior brain regions supporting reading in the left and, to a lesser extent, face processing in the right hemisphere, the results suggest that both hemispheres are involved in the visual processing of faces, words and objects. This has ramifications for researchers studying the healthy brain and for clinicians working with patients with PCA stroke. Clinicians are recommended to carry out formal assessment of face, word and object recognition as most patients are expected to present with a mixed picture of deficits.
Parieto-frontal Oscillations Show Hand Specific Interactions with Top-Down Movement Plans

To generate a hand-specific reach plan, the brain must integrate hand-specific signals with the desired movement strategy. Although various neurophysiology / imaging studies have investigated hand-target interactions in simple reach-to-target tasks, the whole-brain timing and distribution of this process remain unclear, especially for more complex, instruction-dependent motor strategies. Previously, we showed that a pro/anti-pointing instruction influences magnetoencephalographic (MEG) signals in frontal cortex that then propagate recurrently through parietal cortex (Blohm et al., 2019). Here, we contrasted left versus right hand pointing in the same task to investigate 1) which cortical regions of interest show hand specificity, and 2) which of those areas interact with the instructed motor plan. Eight bilateral areas – the parietooccipital junction (POJ), superior parietooccipital cortex (SPOC), supramarginal gyrus (SMG), middle / anterior interparietal sulcus (mIPS/aIPS), primary somatosensory / motor cortex (S1/M1), and dorsal premotor cortex (PMd) – showed hand-specific changes in beta band power, with four of these (M1, S1, SMG, aIPS) showing robust activation before movement onset. M1, SMG, SPOC, and aIPS showed significant interactions between contralateral hand specificity and the instructed motor plan, but not with bottom-up target signals. Separate hand / motor signals emerged relatively early and lasted through execution, whereas hand-motor interactions only occurred close to movement onset. Taken together with our previous results, these findings show that instruction-dependent motor plans emerge in frontal cortex and interact recurrently with hand-specific parietofrontal signals before movement onset to produce hand-specific motor behaviors. Impact Statement The brain must generate different motor signals, depending which hand is used. The distribution and timing of hand use / instructed motor plan integration is not understood at the whole-brain level. Using whole-brain MEG recordings we show that different sub-networks involved in action planning code for hand usage (alpha and beta frequencies) and integrating hand use information into a hand-specific motor plan (beta band). The timing of these signals indicates that frontal cortex first creates a general motor plan and then integrates hand-specific frontoparietal information to produce a hand-specific motor plan.
CAJAL : A general framework for the combined morphometric, transcriptomic, and physiological analysis of cells using metric geometry

Cell morphology reflects the progression of high-level cellular processes, such as neuronal diversification, cell migration, or immune cell activation, and is one of the most described cellular phenotypes in biology. Multimodal techniques like Patch-seq enable simultaneously profiling the morphological, transcriptomic, and physiological characteristics of individual cells. However, computational methods that can summarize the great diversity of complex cell shapes found in tissues and infer associations with other single-cell data remain scarce. Here we report a computational framework, named CAJAL , for the morphometric and multi-modal analysis of cells. CAJAL uses concepts from metric geometry to accurately build, visualize, and integrate cell morphology summary spaces and establish associations with molecular and physiological data of individual cells. We demonstrate the utility of CAJAL by applying it to published Patch-seq, patch-clamp, serial electron, and two-photon microscopy data, and show that it represents a substantial improvement in functionality, scope, and accuracy with respect to current methods for cell morphometry.
Recognition of BRAF by CDC37 and Re-Evaluation of the Activation Mechanism for the Class 2 BRAF-L597R Mutant

The kinome specific co-chaperone, CDC37, is responsible for delivering BRAF to the Hsp90 complex, where it is then translocated to the RAS complex at the plasma membrane for RAS mediated dimerization and subsequent activation. We identify a bipartite interaction between CDC37 and BRAF and delimitate the essential structural elements of CDC37 involved in BRAF recognition. We find an extended and conserved CDC37 motif, 20HPNID---SL--W31, responsible for recognising the C-lobe of BRAF kinase domain, while the C-terminal domain of CDC37 is responsible for the second of the bipartite interaction with BRAF. We show that dimerization of BRAF, independent of nucleotide binding, can act as a potent signal that prevents CDC37 recognition and discuss the implications of mutations in BRAF and the consequences on signalling, particularly for class 2 BRAF mutations.