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Mesoscale physics bridges the gap between the microscopic degrees of freedom of a system and its large-scale continuous behavior and highlights the role of a few key quantities in complex and multiscale phenomena, like dynamin-driven fission of lipid membranes. The dynamin protein wraps the neck formed during clathrin-mediated endocytosis, for instance, and constricts it until severing occurs. Although ubiquitous and fundamental for life, the cooperation between the GTP-consuming conformational changes within the protein and the full-scale response of the underlying lipid substrate is yet to be unraveled. In this work, we build an effective mesoscopic model from constriction to fission of lipid tubules based on continuum membrane elasticity and implicitly accounting for ratchet-like power strokes of dynamins. Localization of the fission event, the overall geometry, and the energy expenditure we predict comply with the major experimental findings. This bolsters the idea that a continuous picture emerges soon enough to relate dynamin polymerization length and membrane rigidity and tension with the optimal pathway to fission. We therefore suggest that dynamins found in in vivo processes may optimize their structure accordingly. Ultimately, we shed light on real-time conductance measurements available in literature and predict the fission time dependency on elastic parameters., (© 2024. The Author(s).)

Viral infections, fertilization, neurotransmission, and many other fundamental biological processes rely on membrane fusion. Straightforward calculations based on the celebrated Canham-Helfrich elastic model predict a large topological energy barrier that prevents the fusion process from being thermally activated. While such high energy is in accordance with the physical barrier function of lipid membranes, it is difficult to reconcile with the biological mechanisms involved in fusion processes. In this work, we use a Ginzburg-Landau type of free energy that recovers the Canham-Helfrich model in the limit of small width-to-vesicle-extension ratio, with the additional ability to handle topological transitions. We show that a local modification of the Gaussian modulus in the merging region both dramatically lowers the elastic energy barrier and substantially changes the minimal energy pathway for fusion, in accordance with experimental evidence. Therefore, we discuss biological examples in which such a modification might play a crucial role., (© 2024. The Author(s).)

This study revealed how Bacteria and Archaea communities and their metabolic functions differed between two groups of black deposits identified in gorge and cave environments. Scanning electron microscopy coupled with energy dispersive spectroscopy was used to analyse the presence of microbial biosignatures and the elemental composition of samples. Metabarcoding of the V3-V4 regions of 16S rRNA was used to investigate Bacteria and Archaea communities. Based on 16S rRNA sequencing results, PICRUSt software was used to predict metagenome functions. Micrographs showed that samples presented microbial biosignatures and microanalyses highlighted Mn concretions and layers on Al-Si surfaces. The 16S rRNA metabarcoding alpha-diversity metrics showed similar Simpson's and Shannon indices and different values of the Chao-1 index. The amplicon sequence variants (ASVs) analysis at the different taxonomic levels showed a diverse genera composition. However, the communities of all samples shared the presence of uncultured ASVs belonging to the Gemmatales family (Phylogenesis: Gemmataceae; Planctomycetes; Planctomycetota; Bacteria). The predicted metagenome functions analysis revealed diverse metabolic profiles of the Cave and Gorge groups. Genes coding for essential Mn metabolism were present in all samples. Overall, the findings on structure, microbiota, and predicted metagenome functions showed a similar microbial contribution to epigean and hypogean black deposits Mn metabolism., (© 2022. The Author(s).)

Preserving diversity of indigenous pig (Sus scrofa) breeds is a key factor to (i) sustain the pork chain (both at local and global scales) including the production of high-quality branded products, (ii) enrich the animal biobanking and (iii) progress conservation policies. Single nucleotide polymorphism (SNP) chips offer the opportunity for whole-genome comparisons among individuals and breeds. Animals from twenty European local pigs breeds, reared in nine countries (Croatia: Black Slavonian, Turopolje; France: Basque, Gascon; Germany: Schwabisch-Hällisches Schwein; Italy: Apulo Calabrese, Casertana, Cinta Senese, Mora Romagnola, Nero Siciliano, Sarda; Lithuania: Indigenous Wattle, White Old Type; Portugal: Alentejana, Bísara; Serbia: Moravka, Swallow-Bellied Mangalitsa; Slovenia: Krškopolje pig; Spain: Iberian, Majorcan Black), and three commercial breeds (Duroc, Landrace and Large White) were sampled and genotyped with the GeneSeek Genomic Profiler (GGP) 70 K HD porcine genotyping chip. A dataset of 51 Wild Boars from nine countries was also added, summing up to 1186 pigs (~ 49 pigs/breed). The aim was to: (i) investigate individual admixture ancestries and (ii) assess breed traceability via discriminant analysis on principal components (DAPC). Albeit the mosaic of shared ancestries found for Nero Siciliano, Sarda and Moravka, admixture analysis indicated independent evolvement for the rest of the breeds. High prediction accuracy of DAPC mark SNP data as a reliable solution for the traceability of breed-specific pig products., (© 2022. The Author(s).)

Phase Change Memory (PCM) is an emerging technology exploiting the rapid and reversible phase transition of certain chalcogenides to realize nanoscale memory elements. PCM devices are being explored as non-volatile storage-class memory and as computing elements for in-memory and neuromorphic computing. It is well-known that PCM exhibits several characteristics of a memristive device. In this work, based on the essential physical attributes of PCM devices, we exploit the concept of Dynamic Route Map (DRM) to capture the complex physics underlying these devices to describe them as memristive devices defined by a state-dependent Ohm's law. The efficacy of the DRM has been proven by comparing numerical results with experimental data obtained on PCM devices., (© 2022. The Author(s).)

Predicting cavitation has proved a formidable task, particularly for water. Despite the experimental difficulty of controlling the sample purity, there is nowadays substantial consensus on the remarkable tensile strength of water, on the order of -120 MPa at ambient conditions. Recent progress significantly advanced our predictive capability which, however, still considerably depends on elaborate fitting procedures based on the input of external data. Here a self-contained model is discussed which is shown able to accurately reproduce cavitation data for water over the most extended range of temperatures for which accurate experiments are available. The computations are based on a diffuse interface model which, as only inputs, requires a reliable equation of state for the bulk free energy and the interfacial tension. A rare event technique, namely the string method, is used to evaluate the free-energy barrier as the base for determining the nucleation rate and the cavitation pressure. The data allow discussing the role of the Tolman length in determining the nucleation barrier, confirming that, when the size of the cavitation nuclei exceed the thickness of the interfacial layer, the Tolman correction effectively improves the predictions of the plain Classical Nucleation Theory., (© 2021. The Author(s).)

Coronaviruses silently circulate in human and animal populations, causing mild to severe diseases. Therefore, livestock are important components of a "One Health" perspective aimed to control these viral infections. However, at present there is no example that considers pig genetic resources in this context. In this study, we investigated the variability of four genes (ACE2, ANPEP and DPP4 encoding for host receptors of the viral spike proteins and TMPRSS2 encoding for a host proteinase) in 23 European (19 autochthonous and three commercial breeds and one wild boar population) and two Asian Sus scrofa populations. A total of 2229 variants were identified in the four candidate genes: 26% of them were not previously described; 29 variants affected the protein sequence and might potentially interact with the infection mechanisms. The results coming from this work are a first step towards a "One Health" perspective that should consider conservation programs of pig genetic resources with twofold objectives: (i) genetic resources could be reservoirs of host gene variability useful to design selection programs to increase resistance to coronaviruses; (ii) the described variability in genes involved in coronavirus infections across many different pig populations might be part of a risk assessment including pig genetic resources.

Phase change memory (PCM) is being actively explored for in-memory computing and neuromorphic systems. The ability of a PCM device to store a continuum of resistance values can be exploited to realize arithmetic operations such as matrix-vector multiplications or to realize the synaptic efficacy in neural networks. However, the resistance variations arising from structural relaxation, 1/f noise, and changes in ambient temperature pose a key challenge. The recently proposed projected PCM concept helps to mitigate these resistance variations by decoupling the physical mechanism of resistance storage from the information-retrieval process. Even though the device concept has been proven successfully, a comprehensive understanding of the device behavior is still lacking. Here, we develop a device model that captures two key attributes, namely, resistance drift and the state dependence of resistance. The former refers to the temporal evolution of resistance, while the latter refers to the dependence of the device resistance on the phase configuration of the phase change material. The study provides significant insights into the role of interfacial resistance in these devices. The model is experimentally validated on projected PCM devices based on antimony and a metal nitride fabricated in a lateral device geometry and is also used to provide guidelines for material selection and device engineering.

Spiking neural networks (SNN) are computational models inspired by the brain's ability to naturally encode and process information in the time domain. The added temporal dimension is believed to render them more computationally efficient than the conventional artificial neural networks, though their full computational capabilities are yet to be explored. Recently, in-memory computing architectures based on non-volatile memory crossbar arrays have shown great promise to implement parallel computations in artificial and spiking neural networks. In this work, we evaluate the feasibility to realize high-performance event-driven in-situ supervised learning systems using nanoscale and stochastic analog memory synapses. For the first time, the potential of analog memory synapses to generate precisely timed spikes in SNNs is experimentally demonstrated. The experiment targets applications which directly integrates spike encoded signals generated from bio-mimetic sensors with in-memory computing based learning systems to generate precisely timed control signal spikes for neuromorphic actuators. More than 170,000 phase-change memory (PCM) based synapses from our prototype chip were trained based on an event-driven learning rule, to generate spike patterns with more than 85% of the spikes within a 25 ms tolerance interval in a 1250 ms long spike pattern. We observe that the accuracy is mainly limited by the imprecision related to device programming and temporal drift of conductance values. We show that an array level scaling scheme can significantly improve the retention of the trained SNN states in the presence of conductance drift in the PCM. Combining the computational potential of supervised SNNs with the parallel compute power of in-memory computing, this work paves the way for next-generation of efficient brain-inspired systems.

Cell therapy using T cell receptors (TCRs) and chimeric antigen receptors (CARs) represents a new wave of immunotherapies garnering considerable attention and investment. Further progress in this area of medicine depends in part on improving the functional capabilities of the engineered components, while maintaining the overall size of recombinant constructs to ensure their compatibility with existing gene delivery vehicles. We describe a single-variable-domain TCR (svd TCR) that utilizes only the variable domain of the β chain (Vβ). This Vβ module not only works in TCR and CAR formats, but also can be used to create single-chain bispecific CARs and TCRs. Comparison of individual ligand-binding Vβ domains in different formats suggests that the lone Vβ sequence controls the sensitivity and a major part of the specificity of the CAR or TCR construct, regardless of signaling format, in Jurkat and primary T cells.

Haematological and clinical-biochemical parameters are considered indicators of the physiological/health status of animals and might serve as intermediate phenotypes to link physiological aspects to production and disease resistance traits. The dissection of the genetic variability affecting these phenotypes might be useful to describe the resilience of the animals and to support the usefulness of the pig as animal model. Here, we analysed 15 haematological and 15 clinical-biochemical traits in 843 Italian Large White pigs, via three genome-wide association scan approaches (single-trait, multi-trait and Bayesian). We identified 52 quantitative trait loci (QTLs) associated with 29 out of 30 analysed blood parameters, with the most significant QTL identified on porcine chromosome 14 for basophil count. Some QTL regions harbour genes that may be the obvious candidates: QTLs for cholesterol parameters identified genes (ADCY8, APOB, ATG5, CDKAL1, PCSK5, PRL and SOX6) that are directly involved in cholesterol metabolism; other QTLs highlighted genes encoding the enzymes being measured [ALT (known also as GPT) and AST (known also as GOT)]. Moreover, the multivariate approach strengthened the association results for several candidate genes. The obtained results can contribute to define new measurable phenotypes that could be applied in breeding programs as proxies for more complex traits.

Since 2005, two cases of natural bovine spongiform encephalopathies (BSE) have been reported in goats. Furthermore, experimental transmissions of classical (C-BSE) and atypical (L-BSE) forms of BSE in goats were also reported. To minimize further spreading of prion diseases in small ruminants the development of a highly sensitive and specific test for ante-mortem detection of infected animals would be of great value. Recent studies reported high diagnostic value of a second generation of cerebrospinal fluid (CSF) Real-Time Quaking-Induced Conversion (RT-QuIC) assay across a wide spectrum of human prions. Here, we applied this improved QuIC (IQ-CSF) for highly efficient detection of TSEs prion protein in goat cerebrospinal fluid. IQ-CSF sensitivity and specificity were evaluated on CSF samples collected at disease endpoint from goats naturally and experimentally infected with scrapie or bovine isolates of C-BSE and L-BSE, respectively. Next, CSF samples collected from L-BSE infected goats during pre-symptomatic stage were also analysed. PrP L-BSE associated seeding activity was detected at early time points after experimental inoculation, with an average time of 439 days before clinical symptoms appeared. Taken together these data are indicative of the great potential of this in vitro prion amplification assay as ante-mortem TSE test for live and asymptomatic small ruminants.

Airway mucus responses to subclinical infections may explain variations in progression of chronic lung diseases and differences in clinical expression of respiratory infections across individuals. Pneumocystis associates to more severe Chronic Obstructive Pulmonary Disease (COPD), asthma, respiratory distress of premature newborns, and is a consistent subclinical infection between 2 and 5 months of age when hospitalizations for respiratory cause and infant mortality are higher. This atypical fungus associates to increased mucin 5AC (MUC5AC), a central effector of Th2-type allergic inflammation, in infant lungs. However, mucus progression, expression of MUC5B essential for airway defense, and potential for pharmacologic modulation of mucus during Pneumocystis infection remain unknown. We measured MUC5B and Pneumocystis in infant lungs, and progression of mucin levels and effect of inhibition of the STAT6/FoxA2 mucus pathway using Kaempferol, a JAK/STAT6 inhibitor, in immunocompetent rats during Pneumocystis primary infection. Pneumocystis associated to increased MUC5B in infant lungs. Muc5b increased earlier and more abundantly than Muc5ac during experimental primary infection suggesting an acute defensive response against Pneumocystis as described against bacteria, while increased Muc5ac levels supports an ongoing allergic, Th2 lymphocyte-type response during primary Pneumocystis infection. Kaempferol partly reversed Muc5b stimulation suggesting limited potential for pharmacological modulation via the STAT6-FoxA2 pathway.

H1069Q substitution represents the most frequent mutation of the copper transporter ATP7B causing Wilson disease in Caucasian population. ATP7B localizes to the Golgi complex in hepatocytes but moves in response to copper overload to the endo-lysosomal compartment to support copper excretion via bile canaliculi. In heterologous or hepatoma-derived cell lines, overexpressed ATP7B-H1069Q is strongly retained in the ER and fails to move to the post-Golgi sites, resulting in toxic copper accumulation. However, this pathogenic mechanism has never been tested in patients' hepatocytes, while animal models recapitulating this form of WD are still lacking. To reach this goal, we have reprogrammed skin fibroblasts of homozygous ATP7B-H1069Q patients into induced pluripotent stem cells and differentiated them into hepatocyte-like cells. Surprisingly, in HLCs we found one third of ATP7B-H1069Q localized in the Golgi complex and able to move to the endo-lysosomal compartment upon copper stimulation. However, despite normal mRNA levels, the expression of the mutant protein was only 20% compared to the control because of endoplasmic reticulum-associated degradation. These results pinpoint rapid degradation as the major cause for loss of ATP7B function in H1069Q patients, and thus as the primary target for designing therapeutic strategies to rescue ATP7B-H1069Q function.

Early identification of autism spectrum disorder (ASD) is crucial for the formulation of effective intervention programs. Language deficits may be a hallmark feature of ASD and language delay observed in ASD shows striking similarities to that observed in children with language impairment (LI). Auditory processing deficits are seen in both LI and ASD, however, they have not previously been compared directly using Event-Related Potentials (ERPs) in the two at-risk populations. This study aims to characterize infants at-risk for ASD (HR-ASD) at the electrophysiological level and to compare them with infants at-risk for LI (HR-LI) and controls, to find specific markers with predictive value. At 12-month-old, auditory processing in HR-ASD, HR-LI and controls was characterized via ERP oddball paradigm. All infants were then evaluated at 20 months, to investigate the associations between auditory processing and language/ASD-related outcomes. In both HR-ASD and HR-LI, mismatch response latency was delayed compared to controls, whereas only HR-ASD showed overall larger P3 amplitude compared to controls. Interestingly, these ERP measures correlated with later expressive vocabulary and M-CHAT critical items in the whole sample. These results may support the use of objective measurement of auditory processing to delineate pathophysiological mechanisms in ASD, as compared to LI.

The molecular mechanisms of symbiosis in cultivated peanut with a 'crack entry' infection process are largely understudied. In this study, we investigated the root transcriptional profiles of two pairs of non-nodulating (nod-) and nodulating (nod+) sister inbred peanut lines, E4/E5 and E7/E6, and their nod+ parents, F487A and PI262090 during rhizobial infection and nodule initiation by using RNA-seq technology. A total of 143, 101, 123, 215, 182, and 289 differentially expressed genes (DEGs) were identified in nod- E4, E7 and nod+ E5, E6, F487A, and PI262090 after inoculation with Bradyrhizobium sp. Different deficiencies at upstream of symbiotic signaling pathway were revealed in the two nod- genotypes. DEGs specific in nod+ genotypes included orthologs to some known symbiotic signaling pathway genes, such as NFR5, NSP2, NIN, ERN1, and many other novel and/or functionally unknown genes. Gene ontology (GO) enrichment analysis of nod+ specific DEGs revealed 54 significantly enriched GO terms, including oxidation-reduction process, metabolic process, and catalytic activity. Genes related with plant defense systems, hormone biosynthesis and response were particularly enriched. To our knowledge, this is the first report revealing symbiosis-related genes in a genome-wide manner in peanut representative of the 'crack entry' species.

SQLE encodes squalene epoxidase, a key enzyme in cholesterol synthesis. SQLE has sporadically been reported among copy-number driven transcripts in multi-omics cancer projects. Yet, its functional relevance has never been subjected to systematic analyses. Here, we assessed the correlation of SQLE copy number (CN) and gene expression (GE) across multiple cancer types, focusing on the clinico-pathological associations in breast cancer (BC). We then investigated whether any biological effect of SQLE inhibition could be observed in BC cell line models. Breast, ovarian, and colorectal cancers showed the highest CN driven GE among 8,783 cases from 22 cancer types, with BC presenting the strongest one. SQLE overexpression was more prevalent in aggressive BC, and was an independent prognostic factor of unfavorable outcome. Through SQLE pharmacological inhibition and silencing in a panel of BC cell lines portraying the diversity of SQLE CN and GE, we demonstrated that SQLE inhibition resulted in a copy-dosage correlated decrease in cell viability, and in a noticeable increase in replication time, only in lines with detectable SQLE transcript. Altogether, our results pinpoint SQLE as a bona fide metabolic oncogene by amplification, and as a therapeutic target in BC. These findings could have implications in other cancer types.