Search

Abstract Epistasis refers to changes in the effect on phenotype of a unit of genetic information, such as a single nucleotide polymorphism or a gene, dependent on the context of other genetic units. Such interactions are both biologically plausible and good candidates to explain observations which are not fully explained by an additive heritability model. However, the search for epistasis has so far largely failed to recover this missing heritability. We identify key challenges and propose that future works need to leverage idealized systems, known biology and even previously identified epistatic interactions, in order to guide the search for new interactions.

Abstract The CYGNO experiment aims to build a large ( $$\mathcal {O}(10)$$ O ( 10 ) m $$^3$$ 3 ) directional detector for rare event searches, such as nuclear recoils (NRs) induced by dark matter (DM), such as weakly interactive massive particles (WIMPs). The detector concept comprises a time projection chamber (TPC), filled with a He:CF $$_4$$ 4 60/40 scintillating gas mixture at room temperature and atmospheric pressure, equipped with an amplification stage made of a stack of three gas electron multipliers (GEMs) which are coupled to an optical readout. The latter consists in scientific CMOS (sCMOS) cameras and photomultipliers tubes (PMTs). The maximisation of the light yield of the amplification stage plays a major role in the determination of the energy threshold of the experiment. In this paper, we simulate the effect of the addition of a strong electric field below the last GEM plane on the GEM field structure and we experimentally test it by means of a 10 $$\times $$ × 10 cm $$^2$$ 2 readout area prototype. The experimental measurements analyse stacks of different GEMs and helium concentrations in the gas mixture combined with this extra electric field, studying their performances in terms of light yield, energy resolution and intrinsic diffusion. It is found that the use of this additional electric field permits large light yield increases without degrading intrinsic characteristics of the amplification stage with respect to the regular use of GEMs.

Abstract Objective Neurofilament heavy‐chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. Methods Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta‐analyses of published case–control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole‐genome sequencing data. Results Fixed‐effects meta‐analysis found that rare (MAF

Mutational profiles of myelodysplastic syndromes (MDS) have established that a relatively small number of genetic aberrations, including SF3B1 and SRSF2 spliceosome mutations, lead to specific phenotypes and prognostic subgrouping. We performed a multi-omics factor analysis (MOFA) on two published MDS cohorts of bone marrow mononuclear cells (BMMNCs) and CD34 + cells with three data modalities (clinical, genotype, and transcriptomics). Seven different views, including immune profile, inflammation/aging, retrotransposon (RTE) expression, and cell-type composition, were derived from these modalities to identify the latent factors with significant impact on MDS prognosis. SF3B1 was the only mutation among 13 mutations in the BMMNC cohort, indicating a significant association with high inflammation. This trend was also observed to a lesser extent in the CD34 + cohort. Interestingly, the MOFA factor representing the inflammation shows a good prognosis for MDS patients with high inflammation. In contrast, SRSF2 mutant cases show a granulocyte-monocyte progenitor (GMP) pattern and high levels of senescence, immunosenescence, and malignant myeloid cells, consistent with their poor prognosis. Furthermore, MOFA identified RTE expression as a risk factor for MDS. This work elucidates the efficacy of our integrative approach to assess the MDS risk that goes beyond all the scoring systems described thus far for MDS.

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates common genetic association results from the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction of ALS risk and clinical characteristics. Methods: Genes associated with ALS were identified using GWAS summary statistic methodology including SuSiE SNP-based fine-mapping, and transcriptome- and proteome-wide association study (TWAS/PWAS) analyses. Using several approaches, gene associations were integrated with the DrugTargetor drug-gene interaction database to identify drugs that could be repurposed for the treatment of ALS. Furthermore, ALS gene associations from TWAS were combined with observed blood expression in two external ALS case-control datasets to calculate polytranscriptomic scores and evaluate their utility for prediction of ALS risk and clinical characteristics, including site of onset, age at onset, and survival. Results: SNP-based fine-mapping, TWAS and PWAS identified 118 genes associated with ALS, with TWAS and PWAS providing novel mechanistic insights. Drug repurposing analyses identified six drugs significantly enriched for interactions with ALS associated genes, though directionality could not be determined. Additionally, drug class enrichment analysis showed gene signatures linked to calcium channel blockers may reduce ALS risk, whereas antiepileptic drugs may increase ALS risk. Across the two observed expression target samples, ALS polytranscriptomic scores significantly predicted ALS risk (R2 = 5.1 %; p-value = 3.2 × 10−27) and clinical characteristics. Conclusions: Functionally-informed analyses of ALS GWAS summary statistics identified novel mechanistic insights into ALS aetiology, highlighted several therapeutic research avenues, and enabled statistically significant prediction of ALS risk.

CYGNO is an international collaboration with the aim of operating a Image 3 optical time projection chamber (TPC) for directional Dark Matter (DM) searches and solar neutrino spectroscopy, to be deployed at the Laboratori Nazionali del Gran Sasso (LNGS). A Image 1/Image 2 (60/40) mixture is used, along with a triple Gas Electron Multiplier (GEM) cascade to amplify the ionisation signal. The scintillation produced in the electron avalanches is read out using a scientific complementary metal–oxide–semiconductor (sCMOS) camera. This solution has proven to provide very high sensitivity to interactions in the few Image 4 energy range. The inclusion of a hydrogen-based gas will offer an even lighter target, resulting in a more efficient energy transfer in a DM particle collision, and consequently, a lower detection threshold. Additionally, longer track lengths of light nuclear recoils are easier to detect with a clearer direction. However, the addition of such gas will contribute to quenching the scintillation, jeopardizing the TPC performance. In this work, we demonstrate the feasibility of adding 1% to 5% isobutane to the Image 1/Image 2 (60/40) mixture by measuring the respective absolute scintillation yield output. The overall scintillation produced in the charge avalanches is not drastically suppressed by quenching due to the isobutane addition. The presence of Penning transfer from excited He atoms to isobutane molecules increases the number of electrons in the avalanches, partially compensating for the loss of scintillation due to quenching. For the highest applied GEM voltage, the total number of photons produced in the avalanche per Image 4 deposited in the absorption region presents a decrease of only a factor of about three, from 2.30(20)×104 to 8.2(4)×103 Image 5, as the isobutane content increases from 0 to 5%. The quantification of the visible component of the scintillation shows that isobutane quenches both visible and ultraviolet (UV) photons emitted by Image 1/Image 2.

Objective: Low grade gliomas (LGGs) account for 15 % of primary brain tumors. The paper has the aim to identifying prognostic factors affecting overall survival (OS) and progression-free survival (PFS), and to evaluate the outcome of patients. Methods: A total of 40 patients undergoing surgery for cerebral LGG (WHO grades I and II) at Our Institute were enrolled in the retrospective study. Inclusion criteria were: histological diagnosis of LGG, availability of complete clinical-instrumental documentation and follow-up data. For each patient, the following were analyzed: the clinical parameters in the preoperative and postoperative phases, the histological variant of the tumor, the extent of surgical resection (EOR) and any use of intraoperative methods, the Mib-1/Ki-67 proliferation index, the administration of adjuvant chemotherapy and/or radiotherapy and the occurrence of any complications. Results: The cohort included 14 males and 26 females. The independent predictors of OS at multivariate analysis were: age, pre-operative KPS, Ki67/Mib-1, EOR and adjuvant chemotherapy. With regard to PFS, statistical significance on multivariate analysis was observed for pre-operative KPS, Ki67/Mib-1, EOR, post-operative tumor volume and radiotherapy. An EOR

Abstract Amyotrophic lateral sclerosis (ALS) displays considerable clinical and genetic heterogeneity. Machine learning approaches have previously been utilised for patient stratification in ALS as they can disentangle complex disease landscapes. However, lack of independent validation in different populations and tissue samples have greatly limited their use in clinical and research settings. We overcame these issues by performing hierarchical clustering on the 5000 most variably expressed autosomal genes from motor cortex expression data of people with sporadic ALS from the KCL BrainBank (N = 112). Three molecular phenotypes linked to ALS pathogenesis were identified: synaptic and neuropeptide signalling, oxidative stress and apoptosis, and neuroinflammation. Cluster validation was achieved by applying linear discriminant analysis models to cases from TargetALS US motor cortex (N = 93), as well as Italian (N = 15) and Dutch (N = 397) blood expression datasets, for which there was a high assignment probability (80–90%) for each molecular subtype. The ALS and motor cortex specificity of the expression signatures were tested by mapping KCL BrainBank controls (N = 59), and occipital cortex (N = 45) and cerebellum (N = 123) samples from TargetALS to each cluster, before constructing case-control and motor cortex-region logistic regression classifiers. We found that the signatures were not only able to distinguish people with ALS from controls (AUC 0.88 ± 0.10), but also reflect the motor cortex-based disease process, as there was perfect discrimination between motor cortex and the other brain regions. Cell types known to be involved in the biological processes of each molecular phenotype were found in higher proportions, reinforcing their biological interpretation. Phenotype analysis revealed distinct cluster-related outcomes in both motor cortex datasets, relating to disease onset and progression-related measures. Our results support the hypothesis that different mechanisms underpin ALS pathogenesis in subgroups of patients and demonstrate potential for the development of personalised treatment approaches. Our method is available for the scientific and clinical community at https://alsgeclustering.er.kcl.ac.uk .

Abstract HSP90 has emerged as an appealing anti-cancer target. However, HSP90 inhibitors (HSP90i) are characterized by limited clinical utility, primarily due to the resistance acquisition via heat shock response (HSR) induction. Understanding the roles of abundantly expressed cytosolic HSP90 isoforms (α and β) in sustaining malignant cells’ growth and the mechanisms of resistance to HSP90i is crucial for exploiting their clinical potential. Utilizing multi-omics approaches, we identified that ablation of the HSP90β isoform induces the overexpression of HSP90α and extracellular-secreted HSP90α (eHSP90α). Notably, we found that the absence of HSP90α causes downregulation of PTPRC (or CD45) expression and restricts in vivo growth of BCR-ABL1+ leukemia cells. Subsequently, chronic long-term exposure to the clinically advanced HSP90i PU-H71 (Zelavespib) led to copy number gain and mutation (p.S164F) of the HSP90AA1 gene, and HSP90α overexpression. In contrast, acquired resistance toward other tested HSP90i (Tanespimycin and Coumermycin A1) was attained by MDR1 efflux pump overexpression. Remarkably, combined CDK7 and HSP90 inhibition display synergistic activity against therapy-resistant BCR-ABL1+ patient leukemia cells via blocking pro-survival HSR and HSP90α overexpression, providing a novel strategy to avoid the emergence of resistance against treatment with HSP90i alone.

Abstract The nature of dark matter is still unknown and an experimental program to look for dark matter particles in our Galaxy should extend its sensitivity to light particles in the GeV mass range and exploit the directional information of the DM particle motion (Vahsen et al. in CYGNUS: feasibility of a nuclear recoil observatory with directional sensitivity to dark matter and neutrinos, arXiv:2008.12587 , 2020). The Cygno project is studying a gaseous time projection chamber operated at atmospheric pressure with a Gas Electron Multiplier (Sauli in Nucl Instrum Meth A 386:531, https://doi.org/10.1016/S0168-9002(96)01172-2 , 1997) amplification and with an optical readout as a promising technology for light dark matter and directional searches. In this paper we describe the operation of a 50 l prototype named LIME (Long Imaging ModulE) in an overground location at Laboratori Nazionali di Frascati (LNF) of INFN. This prototype employs the technology under study for the 1 cubic meter Cygno demonstrator to be installed at the Laboratori Nazionali del Gran Sasso (LNGS) (Amaro et al. in Instruments 2022, 6(1), https://www.mdpi.com/2410-390X/6/1/6 , 2022). We report the characterization of LIME with photon sources in the energy range from few keV to several tens of keV to understand the performance of the energy reconstruction of the emitted electron. We achieved a low energy threshold of few keV and an energy resolution over the whole energy range of 10–20%, while operating the detector for several weeks continuously with very high operational efficiency. The energy spectrum of the reconstructed electrons is then reported and will be the basis to identify radio-contaminants of the LIME materials to be removed for future Cygno detectors.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

SQM-ISS is a detector that will search from the International Space Station for massive particles possibly present among the cosmic rays. Among them, we mention strange quark matter, Q-Balls, lumps of fermionic exotic compact stars, Primordial Black Holes, mirror matter, Fermi balls, etc. These compact, dense objects would be much heavier than normal nuclei, have velocities of galaxy-bound systems, and would be deeply penetrating. The detector is based on a stack of scintillator and piezoelectric elements which can provide information on both the charge state and mass, with the additional timing information allowing to determine the speed of the particle, searching for particles with velocities of the order of galactic rotation speed (v ≲ 250 km/s). In this work, we describe the apparatus and its observational capabilities.

Thanks to advancements in silicon photomultiplier sensors (SiPMs) and system-on-chip (SoC) technology, our INFN Roma1 group developed ArduSiPM in 2012, the first all-in-one scintillator particle detector in the literature. It used a custom Arduino Due shield to process fast signals, utilizing the Microchip Sam3X8E SoC’s internal peripherals to control and acquire SiPM signals. The availability of radiation-tolerant SoCs, combined with the goal of reducing system space and weight, led to the development of an innovative second-generation board, a better-performing device called Cosmo ArduSiPM, suitable for space missions. The architecture of the new detector is based on the Microchip SAMV71 300 MHz, 32-bit ARM® Cortex®-M7 (Microchip Technology Inc., Chandler, AZ, USA). While the analog front-end is essentially identical to the ArduSiPM, it utilizes components with the smallest possible package. The board fits in a CubeSat module. Thanks to the compact design, the board has two independent channels, with a total weight of only 40 grams within a CubeSat form factor. The ArduSiPM architecture is based on a single microcontroller and fast discrete analog electronics. It benefits from the continued development of SoCs related to the IoT (Internet of Things) market. Compared with a system with a custom ASIC, this architecture based on software and SoC capabilities offers considerable advantages in terms of cost and development time. The ability to incorporate new commercial SoCs, continuously emerging from advancements in the aerospace and automotive industries, provides the system with a robust foundation for sustained growth over the years. A detailed characterization of the hardware and the system’s response to different photon fluxes is presented in this article. Additionally, coupling the device with a scintillator was tested at the end of this article as a preliminary trial for future measurements, showing potential for further enhancement of the detector’s capabilities.

Background: Meniere’s disease (MD) is a disabling disease, especially in patients who are refractory to medical therapy. Moreover, selective vestibular neurectomy (VN), in these selected cases, can be considered a surgical alternative which preserves hearing function and facial nerve. Methods: We retrospectively studied 23 patients with MD diagnosis and history of failed extradural endolymphatic sac surgery (ELSS) who underwent combined micro-endoscopic selective VN, between January 2019 and August 2023, via a presigmoid retrolabyrinthine approach. All patients were stratified according to clinical features, assessing preoperative and postoperative hearing levels and quality of life. Results: At the maximum present follow-up of 2 years, this procedure is characterized by a low rate of complications and about 90% vertigo control after surgery. No definitive facial palsy or hearing loss was described in this series. One patient required reintervention for a CSF fistula. Statistically significant (p = 0.001) difference was found between the preoperative and the postoperative performance in terms of physical, functional, and emotive scales assessed via the DHI questionnaire. Conclusions: Selective VN via a presigmoid retrolabyrinthine approach is a safe procedure for intractable vertigo associated with MD, when residual hearing function still exists. The use of the endoscope and intraoperative neuromonitoring guaranteed a precise result, saving the cochlear fibers and facial nerve. The approach for VN is a familiar procedure to the otolaryngologist, as is lateral skull base anatomy to the neurosurgeon; therefore, the best results are obtained with multidisciplinary teamwork.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving selective vulnerability of energy-intensive motor neurons (MNs). It has been unclear whether mitochondrial function is an upstream driver or a downstream modifier of neurotoxicity. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial DNA copy number (mtCN). Across three cohorts including 6,437 ALS patients, we discovered that a set of mitochondrial haplotypes, chosen because they are linked to measurements of mitochondrial function, are a determinant of ALS survival following disease onset, but do not modify ALS risk. One particular haplotype appeared to be neuroprotective and was significantly over-represented in two cohorts of long-surviving ALS patients. Causal inference for mitochondrial function was achievable using mitochondrial haplotypes, but not autosomal SNPs in traditional Mendelian randomization (MR). Furthermore, rare loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to ∼50 % shorter ALS survival; both proteins are implicated in mitochondrial function. Both mtCN and cellular vulnerability are linked to DNA2 function in ALS patient-derived neurons. Finally, MtCN responds dynamically to the onset of ALS independently of mitochondrial haplotype, and is correlated with disease severity. We conclude that, based on the genetic measures we have employed, mitochondrial function is a therapeutic target for amelioration of disease severity but not prevention of ALS.

Motivation: For a number of neurological diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, and many others, certain genes are known to be involved in the disease mechanism. A common question is whether a structural variant in any such gene may be related to drug response in clinical trials and how this relationship can contribute to the lifecycle of drug development.Results: To this end, we introduce VariantSurvival, a tool that identifies changes in survival relative to structural variants within target genes. VariantSurvival matches annotated structural variants with genes that are clinically relevant to neurological diseases. A Cox regression model determines the change in survival between the placebo and clinical trial groups with respect to the number of structural variants in the drug target genes. We demonstrate the functionality of our approach with the exemplary case of the SETX gene. VariantSurvival has a user-friendly and lightweight graphical user interface built on the shiny web application package.

Background: The COVID-19 pandemic and its impact on hospitals' activity and organization has imposed a vast change in standard neurosurgical oncology practice to accommodate for shifting resources. Aims: This investigation aims to analyse the nationwide capability in reorganizing the surgical neuro-oncological activity during the COVID-19 pandemic to evaluate whether COVID-19-pandemic influenced the surgical management in these patients. Method: A web-based dataset model organized by the Italian Neurosurgical Society (SINCh) was sent to all the Italian neurosurgical departments in May 2021, requesting to report the types and numbers of surgical procedures performed in the pre-pandemic period (from March 9th 2019 to March 9th 2020) compared to the pandemic period (from March 10th 2020 to March 10th 2021). Results: This multicentre investigation included the surgical activity of 35 Italian Neurosurgical Departments in a pre-pandemic year versus a pandemic year. During the COVID period, 699 fewer neuro-oncological patients were operated on than in the pre-COVID period. We noted a slight increase in urgency and a more severe decrease in elective and benign pathology. None of these differences was statistically significant. Surgically treated patients who tested positive for SARS-CoV-2 were 36, of which 11 died. Death was found to be COVID-related only in 2 cases. Conclusion: The reorganization of the Italian Neurosurgical Departments was able to guarantee a redistribution of the CNS tumors during the inter-pandemic periods, demonstrating that patients even in the pandemic era could be treated without compromising the efficacy and safety of the surgical procedure.

Mutations in the superoxide dismutase 1 (SOD1) gene are the second most common known cause of ALS. SOD1 variants express high phenotypic variability and over 200 have been reported in people with ALS. It was previously proposed that variants can be broadly classified in two groups, ‘wild-type like’ (WTL) and ‘metal binding region’ (MBR) variants, based on their structural location and biophysical properties. MBR variants, but not WTL variants, were associated with a reduction of SOD1 enzymatic activity. In this study we used molecular dynamics and large clinical datasets to characterise the differences in the structural and dynamic behaviour of WTL and MBR variants with respect to the wild-type SOD1, and how such differences influence the ALS clinical phenotype. Our study identified marked structural differences, some of which are observed in both variant groups, while others are group specific. Moreover, collecting clinical data of approximately 500 SOD1 ALS patients carrying variants, we showed that the survival time of patients carrying an MBR variant is generally longer (∼6 years median difference, p