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This paper provides an epistemological and methodological analysis of the practice of using neural language models to simulate brain language processing. Firstly, neural language models are introduced; a study case showing how neural language models are being applied in cognitive neuroscience for simulative purposes is then presented; after recalling the main epistemological features of the simulative method in artificial intelligence, it is finally examined how the simulative method is modified when using neural language models. In particular, it is argued that the epistemic opacity of neural language models requires that the brain itself be used to simulate the model and to test hypotheses about the model, in what is called here a co-simulation.

Abstract Unaccustomed eccentric exercise (EE) is protective against muscle damage following a subsequent bout of similar exercise. One hypothesis suggests the existence of an alteration in motor unit (MU) behaviour during the second bout, which might contribute to the adaptive response. Accordingly, the present study investigated MU changes during repeated bouts of EE. During two bouts of exercise where maximal lengthening dorsiflexion (10 repetitions × 10 sets) was performed 3 weeks apart, maximal voluntary isometric torque (MVIC) and MU behaviour (quantified using high‐density electromyography; HDsEMG) were measured at baseline, during (after set 5), and post‐EE. The HDsEMG signals were decomposed into individual MU discharge timings, and a subset were tracked across each time point. MVIC was reduced similarly in both bouts post‐EE (Δ27 vs. 23%, P = 0.144), with a comparable amount of total work performed (∼1,300 J; P = 0.905). In total, 1,754 MUs were identified and the decline in MVIC was accompanied by a stepwise increase in discharge rate (∼13%; P

Abstract Dynamical Cobordism provides a powerful method to probe infinite distance limits in moduli/field spaces parameterized by scalars constrained by generic potentials, employing configurations of codimension-1 end of the world (ETW) branes. These branes, characterized in terms of critical exponents, mark codimension-1 boundaries in the spacetime in correspondence of finite spacetime distance singularities at which the scalars diverge. Using these tools, we explore the network of infinite distance singularities in the complex structure moduli space of Calabi-Yau fourfolds compactifications in M-theory with a four-form flux turned on, which is described in terms of normal intersecting divisors classified by asymptotic Hodge theory. We provide spacetime realizations for these loci in terms of networks of intersecting codimension-1 ETW branes classified by specific critical exponents which encapsulate the relevant information of the asymptotic Hodge structure characterizing the corresponding divisors.

Abstract Background Usher syndrome (USH) encompasses a group of disorders characterized by congenital sensorineural hearing loss (SNHL) and retinitis pigmentosa (RP). We described the clinical findings, natural history, and molecular analyses of USH patients identified during a large-scale screening to identify quantitative traits related to ocular disorders in the SardiNIA project cohort. Methods We identified 3 USH-affected families out of a cohort of 6,148 healthy subjects. 9 subjects presented a pathological phenotype, with SNHL and RP. All patients and their family members underwent a complete ophthalmic examination including best-corrected visual acuity, slit-lamp biomicroscopy, fundoscopy, fundus autofluorescence, spectral-domain optical coherence tomography, and electrophysiological testing. Audiological evaluation was performed with a clinical audiometer. Genotyping was performed using several arrays integrated with whole genome sequence data providing approximately 22 million markers equally distributed for each subject analyzed. Molecular diagnostics focused on analysis of the following candidate genes: MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2, USH2A, GPR98, DFNB31, CLRN1, and PDZD7. Results A single missense causal variant in USH2A gene was identified in homozygous status in all patients and in heterozygous status in unaffected parents. The presence of multiple homozygous patients with the same phenotypic severity of the syndromic form suggests that the Sardinian USH phenotype is the result of a founder effect on a specific pathogenic variant related haplotype. The frequency of heterozygotes in general Sardinian population is 1.89. Additionally, to provide new insights into the structure of usherin and the pathological mechanisms caused by small pathogenic in-frame variants, like p.Pro3272Leu, molecular dynamics simulations of native and mutant protein–protein and protein–ligand complexes were performed that predicted a destabilization of the protein with a decrease in the free energy change. Conclusions Our results suggest that our approach is effective for the genetic diagnosis of USH. Based on the heterozygous frequency, targeted screening of this variant in the general population and in families at risk or with familial USH can be suggested. This can lead to more accurate molecular diagnosis, better genetic counseling, and improved molecular epidemiology data that are critical for future intervention plans. Trial registration We did not perform any health-related interventions for the participants.

Abstract We consider the topological defect lines commuting with the spectral flow and the N $$ \mathcal{N} $$ = (4, 4) superconformal symmetry in two dimensional non-linear sigma models on K3. By studying their fusion with boundary states, we derive a number of general results for the category of such defects. We argue that while for certain K3 models infinitely many simple defects, and even a continuum, can occur, at generic points in the moduli space the category is actually trivial, i.e. it is generated by the identity defect. Furthermore, we show that if a K3 model is at the attractor point for some BPS configuration of D-branes, then all topological defects have integral quantum dimension. We also conjecture that a continuum of topological defects arises if and only if the K3 model is a (possibly generalized) orbifold of a torus model. Finally, we test our general results in a couple of examples, where we provide a partial classification of the topological defects.

Abstract Dynamical cobordisms implement the swampland cobordism conjecture in the framework of effective field theory, realizing codimension-1 end of the world (ETW) branes as singularities at finite spacetime distance at which scalars diverge to infinite field space distance. ETW brane solutions provide a useful probe of infinity in moduli/field spaces and the associated swampland constraints, such as the distance conjecture. We construct explicit solutions describing intersecting ETW branes in theories with multiple scalars and general potentials, so that different infinite field space limits coexist in the same spacetime, and can be simultaneously probed by paths approaching the ETW brane intersection. Our class of solutions includes physically interesting examples, such as intersections of Witten’s bubbles of nothing in toroidal compactifications, generalizations in compactifications on products of spheres, and possible flux dressings thereof (hence including charged objects at the ETW branes). From the cobordism perspective, the intersections can be regarded as describing the end of the world for end of the world branes, or as boundary domain walls interpolating between different ETW brane boundary conditions for the same bulk theory.

Gene co-expression network analysis enables identification of biologically meaningful clusters of co-regulated genes (modules) in an unsupervised manner. We present here the largest study conducted thus far of co-expression networks in white blood cells (WBC) based on RNA-seq data from 624 individuals. We identify 41 modules, 13 of them related to specific immune-related functions and cell types (e.g. neutrophils, B and T cells, NK cells, and plasmacytoid dendritic cells); we highlight biologically relevant lncRNAs for each annotated module of co-expressed genes. We further characterize with unprecedented resolution the modules in T cell sub-types, through the availability of 95 immune phenotypes obtained by flow cytometry in the same individuals. This study provides novel insights into the transcriptional architecture of human leukocytes, showing how network analysis can advance our understanding of coding and non-coding gene interactions in immune system cells.

This paper provides an epistemological and methodological analysis of the recent practice of using neural language models to simulate brain language processing. It is argued that, on the one hand, this practice can be understood as an instance of the traditional simulative method in artificial intelligence, following a mechanistic understanding of the mind; on the other hand, that it modifies the simulative method significantly. Firstly, neural language models are introduced; a study case showing how neural language models are being applied in cognitive neuroscience for simulative purposes is then presented; after recalling the main epistemological features of the simulative method in artificial intelligence, it is finally highlighted how the epistemic opacity of neural language models is tackled by using the brain itself to simulate the neural language model and to test hypotheses about it, in what is called here a co-simulation.

Abstract HER2+ breast cancer (BC) is an aggressive subtype genetically and biologically heterogeneous. We evaluate the predictive and prognostic role of HER2 protein/gene expression levels combined with clinico-pathologic features in 154 HER2+ BCs patients who received trastuzumab-based neoadjuvant chemotherapy (NACT). The tumoral pathological complete response (pCR) rate was 40.9%. High tumoral pCR show a scarce mortality rate vs subjects with a lower response. 93.7% of ypT0 were HER2 IHC3+ BC, 6.3% were HER2 IHC 2+/SISH+ and 86.7% of ypN0 were HER2 IHC3+, the remaining were HER2 IHC2+/SISH+. Better pCR rate correlate with a high percentage of infiltrating immune cells and right-sided tumors, that reduce distant metastasis and improve survival, but no incidence difference. HER2 IHC score and laterality emerge as strong predictors of tumoral pCR after NACT from machine learning analysis. HER2 IHC3+ and G3 are poor prognostic factors for HER2+ BC patients, and could be considered in the application of neoadjuvant therapy. Increasing TILs concentrations, lower lymph node ratio and lower residual tumor cellularity are associated with a better outcome. The immune microenvironment and scarce lymph node involvement have crucial role in clinical outcomes. The combination of all predictors might offer new options for NACT effectiveness prediction and stratification of HER2+ BC during clinical decision-making.

Abstract Small black holes are a powerful tool to explore infinite distances in moduli spaces. However, we show that in 4d theories with a scalar potential growing fast enough at infinity, it is energetically too costly for scalars to diverge at the core, and the small black hole puffs up into a regular black hole, or follows a runaway behaviour. We derive a critical exponent characterizing the occurrence or not of such small black hole explosions, both from a 4d perspective, and in the 2d theory after an S 2 truncation. The latter setup allows a unified discussion of fluxes, domain walls and black holes, solving an apparent puzzle in the expression of their potentials in the 4d N $$ \mathcal{N} $$ = 2 gauged supergravity context. We discuss the realization of these ideas in 4d N $$ \mathcal{N} $$ = 2 gauged supergravities. Along the way we show that many regular black hole supergravity solutions in the literature in the latter context are incomplete, due to Freed-Witten anomalies (or duals thereof), and require the emission of strings by the black hole. From the 2d perspective, small black hole solutions correspond to dynamical cobordisms, with the core describing an end of the world brane. Small black hole explosions represent obstructions to completing the dynamical cobordism. We study the implications for the Cobordism Distance Conjecture, which states that in any theory there should exist dynamical cobordisms accessing all possible infinite distance limits in scalar field space. The realization of this principle using small black holes leads to non-trivial constraints on the 4d scalar potential of any consistent theory; in the 4d N $$ \mathcal{N} $$ = 2 context, they allow to recover from a purely bottom-up perspective, several non-trivial properties of vector moduli spaces near infinity familiar from CY3 compactifications.

Objectives Workers in the construction industry have been exposed to asbestos in various occupations. In Italy, a National Mesothelioma Registry has been implemented more than 20 years ago. Using cases selected from this registry and exploiting existing control data sets, we estimated relative risks for pleural mesothelioma (PM) among construction workers.Design Case–control study.Setting Cases from the National Mesothelioma Registry (2000–2018), controls from three previous case–control studies.Methods We selected male PM incident cases diagnosed in 2000–2018. Population controls were taken from three studies performed in six Italian regions within two periods (2002–2004 and 2012–2016). Age-adjusted and period-adjusted unconditional logistic regression models were fitted to estimate odds ratios (OR) for occupations in the construction industry. We followed two approaches, one (primary) excluding and the other (secondary) including subjects employed in other non-construction blue collar occupations for >5 years. For both approaches, we performed an overall analysis including all cases and, given the incomplete temporal and geographic overlap of cases and controls, three time or/and space restricted sensitivity analyses.Results The whole data set included 15 592 cases and 2210 controls. With the primary approach (4797 cases and 1085 controls), OR was 3.64 (2181 cases) for subjects ever employed in construction. We found elevated risks for blue-collar occupations (1993 cases, OR 4.52), including bricklayers (988 cases, OR 7.05), general construction workers (320 cases, OR 4.66), plumbers and pipe fitters (305 cases, OR 9.13), painters (104 cases, OR 2.17) and several others. Sensitivity analyses yielded very similar findings. Using the secondary approach, we observed similar patterns, but ORs were remarkably lower.Conclusions We found markedly increased PM risks for most occupations in the construction industry. These findings are relevant for compensation of subjects affected with mesothelioma in the construction industry.

Drug resistance represents one of the great plagues of our time worldwide. This largely limits the treatment of common infections and requires the development of new antibiotics or other alternative approaches. Noteworthy, the indiscriminate use of antibiotics is mostly responsible for the selection of mutations that confer drug resistance to microbes. In this regard, recently, ozone has been raising interest for its unique biological properties when dissolved in natural oils. Ozonated oils have been reported to act in a non-specific way on microorganisms hindering the acquisition of advantageous mutations that result in resistance. Here, we focused on the antimicrobial effect of two commercial olive (OOO) and sunflower seeds (OSO) oils. Nuclear magnetic resonance spectroscopy and thermal analysis showed the change in the chemical composition of the oils after ozonation treatment. Different ozonated oil concentrations were then used to evaluate their antimicrobial profile against Candida albicans, Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli by agar diffusion and broth dilution methods. Cytotoxicity was also evaluated in keratinocytes and epithelial cells. Overall, our results revealed that both OOO and OSO showed a potent microbicidal effect, especially against C. albicans (IC50 = OOO: 0.3 mg/mL and OSO: 0.2 mg/mL) and E. faecalis (IC50 = OOO: 0.4 mg/mL and OSO: 2.8 mg/mL) albeit exerting a certain effect also against S. aureus and E. coli. Moreover, both OOO and OSO do not yield any relevant cytotoxic effect at the active concentrations in both cell lines. This indicates that the ozonated oils studied are not toxic for mammalian cells despite exerting a potent antimicrobial effect on specific microorganisms. Therefore, OOO and OSO may be considered to integrate standard therapies in the treatment of common infections, likely overcoming drug resistance issues.

Abstract We describe timelike linear dilaton backgrounds of supercritical string theories as time-dependent Dynamical Cobordisms in string theory, with their spacelike singularity as a boundary defining the beginning of time. We propose and provide compelling evidence that its microscopic interpretation corresponds to a region of (a strong coupling version of) closed tachyon condensation. We argue that this beginning of time is closely related to (and shares the same scaling behaviour as) the bubbles of nothing obtained in a weakly coupled background with lightlike tachyon condensation. As an intermediate result, we also provide the description of the latter as lightlike Dynamical Cobordism.

Abnormal deposition of α-synuclein is a key feature and biomarker of Parkinson's disease. α-Synuclein aggregates can propagate themselves by a prion-like seeding-based mechanism within and between tissues and are hypothesized to move between the intestine and brain. α-Synuclein RT-QuIC seed amplification assays have detected Parkinson's-associated α-synuclein in multiple biospecimens including post-mortem colon samples. Here we show intra vitam detection of seeds in duodenum biopsies from 22/23 Parkinson's patients, but not in 6 healthy controls by RT-QuICR. In contrast, no tau seeding activity was detected in any of the biopsies. Our seed amplifications provide evidence that the upper intestine contains a form(s) of α-synuclein with self-propagating activity. The diagnostic sensitivity and specificity for PD in this biopsy panel were 95.7% and 100% respectively. End-point dilution analysis indicated up to 106 SD50 seeding units per mg of tissue with positivity in two contemporaneous biopsies from individual patients suggesting widespread distribution within the superior and descending parts of duodenum. Our detection of α-synuclein seeding activity in duodenum biopsies of Parkinson's disease patients suggests not only that such analyses may be useful in ante-mortem diagnosis, but also that the duodenum may be a source or a destination for pathological, self-propagating α-synuclein assemblies.

Abstract The Cobordism Conjecture states that any Quantum Gravity configuration admits, at topological level, a boundary ending spacetime. We study the dynamical realization of cobordism, as spacetime dependent solutions of Einstein gravity coupled to scalars containing such end-of-the-world ‘branes’. The latter appear in effective theory as a singularity at finite spacetime distance at which scalars go off to infinite field space distance. We provide a local description near the end-of-the-world branes, in which the solutions simplify dramatically and are characterized in terms of a critical exponent, which controls the asymptotic profiles of fields and the universal scaling relations among the spacetime distance to the singularity, the field space distance, and the spacetime curvature. The analysis does not rely on supersymmetry. We study many explicit examples of such Local Dynamical Cobordisms in string theory, including 10d massive IIA, the 10d non-supersymmetric USp(32) theory, Bubbles of Nothing, 4d 𝒩 = 1 cosmic string solutions, the Klebanov-Strassler throat, Dp-brane solutions, brane configurations related to the D1/D5 systems, and small black holes. Our framework encompasses diverse recent setups in which scalars diverge at the core of defects, by regarding them as suitable end-of-the-world branes. We explore the interplay of Local Dynamical Cobordisms with the Distance Conjecture and other swampland constraints.

Purpose: This study aimed to verify whether the slowing of muscle contraction quickness, typically observed in states of fatigue, may worsen force control by decreasing the rate with which force fluctuations are modulated. Therefore, we investigated the relationship between rate of force development (RFD), and force fluctuations' magnitude (Coefficient of variation, CoV) and complexity (Approximate Entropy, ApEn; Detrended fluctuation analysis, DFAα). Methods: Fourteen participants performed intermittent ballistic isometric contractions of the plantar dorsiflexors at 70% of maximal voluntary force until task failure (under 60% twice). Results: Indices of RFD (RFDpeak, RFD50, RFD100, and RFD150) decreased over time by approximately 46, 32, 44, and 39%, respectively (p all ≤ 0.007). DFAα increased by 10% (p < 0.001), and CoV increased by 15% (p < 0.001), indicating decreased force complexity along with increased force fluctuations, respectively. ApEn decreased by just over a quarter (28%, p < 0.001). The linear hierarchical models showed negative associations between RFDpeak and DFAα (β = − 3.6 10–4, p < 0.001), CoV (β = − 1.8 10–3, p < 0.001), while ApEn showed a positive association (β = 8.2 × 10–5, p < 0.001). Conclusion: The results suggest that exercise-induced reductions in contraction speed, lead to smoother force complexity and diminished force control due to slower adjustments around the target force. The fatigued state resulted in worsened force producing capacity and overall force control. [ABSTRACT FROM AUTHOR]