Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation : a tale of the unexpected

ObjectiveTo assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state.MethodsWe studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals.ResultsThe index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis.ConclusionWe report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms

Integrable Schr\"odinger operators with magnetic fields: factorisation method on curved surfaces

The factorisation method for Schr\"odinger operators with magnetic fields on a two-dimensional surface $M^2$ with non-trivial metric is investigated. This leads to the new integrable examples of such operators and brings a new look at some classical problems such as Dirac magnetic monopole and Landau problem. The global geometric aspects and related spectral properties of the operators from the factorisation chains are discussed in details. We also consider the Laplace transformations on a curved surface and extend the class of Schr\"odinger operators with two integrable levels introduced in the flat case by S.P.Novikov and one of the authors.Comment: 20 page

Conformal and Superconformal Mechanics

We investigate the conformal and superconformal properties of a non-relativistic spinning particle propagating in a curved background coupled to a magnetic field and with a scalar potential. We derive the conditions on the couplings for a large class of such systems which are necessary in order their actions admit conformal and superconformal symmetry. We find that some of these conditions can be encoded in the conformal and holomorphic geometry of the background. Several new examples of conformal and superconformal models are also given.Comment: 46 pages, Phyzzx.te

Effect of deformation on components of internal stress tensor in grains of FCC-polycristal

Study of contributions of internal stress tensor components in deformed of austenitic steel was carriedout. The tensor components of internal stresses were determined with using bending extinction contours observing on electron microscope images of the steel

De Sitter Cosmic Strings and Supersymmetry

We study massive spinor fields in the geometry of a straight cosmic string in a de Sitter background. We find a hidden N=2 supersymmetry in the fermionic solutions of the equations of motion. We connect the zero mode solutions to the heat-kernel regularized Witten index of the supersymmetric algebra.Comment: Version similar to the one accepted by General Relativity and Gravitatio

Functional outcome and muscle wasting in adults with tetanus.

BACKGROUND: In many countries, in-hospital survival from tetanus is increasing, but long-term outcome is unknown. In high-income settings, critical illness is associated with muscle wasting and poor functional outcome, but there are few data from resource-limited settings. In this study we aimed to assess muscle wasting and long-term functional outcome in adults with tetanus. METHODS: In a prospective observational study involving 80 adults with tetanus, sequential rectus femoris ultrasound measurements were made at admission, 7 days, 14 days and hospital discharge. Functional outcome was assessed at hospital discharge using the Timed Up and Go test, Clinical Frailty Score, Barthel Index and RAND 36-item Short Form Health Survey (SF-36) and 3 and 6 months after discharge using the SF-36 and Barthel Index. RESULTS: Significant muscle wasting occurred between hospital admission and discharge (p70 y of age, functional recovery at 6 months was reduced compared with younger patients. Hospital-acquired infection and age were risk factors for muscle wasting. CONCLUSIONS: Significant muscle wasting during hospitalization occurred in patients with tetanus, the extent of which correlates with functional outcome

Topological A-Type Models with Flux

We study deformations of the A-model in the presence of fluxes, by which we mean rank-three tensors with antisymmetrized upper/lower indices, using the AKSZ construction. Generically these are topological membrane models, and we show that the fluxes are related to deformations of the Courant bracket which generalize the twist by a closed 3-from $H$, in the sense that satisfying the AKSZ master equation implies the integrability conditions for an almost generalized complex structure with respect to the deformed Courant bracket. In addition, the master equation imposes conditions on the fluxes that generalize $dH=0$. The membrane model can be defined on a large class of $U(m)$- and $U(m) \times U(m)$-structure manifolds, including geometries inspired by $(1,1)$ supersymmetric $\sigma$-models with additional supersymmetries due to almost complex (but not necessarily complex) structures in the target space. Furthermore, we show that the model can be defined on three particular half-flat manifolds related to the Iwasawa manifold. When only $H$-flux is turned on it is possible to obtain a topological string model, which we do for the case of a Calabi-Yau with a closed 3-form turned on. The simplest deformation from the A-model is due to the $(2,0)+ (0,2)$ component of a non-trivial $b$-field. The model is generically no longer evaluated on holomorphic maps and defines new topological invariants. Deformations due to $H$-flux can be more radical, completely preventing auxiliary fields from being integrated out.Comment: 30 pages. v2: Improved Version. References added. v3: Minor changes, published in JHE

Nonlinear Supersymmetry as a Hidden Symmetry

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The combined treatment of Molnupiravir and Favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model

BACKGROUND: Favipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV-2. First efficacy data have been recently reported in COVID-19 patients. METHODS: We here report on the combined antiviral effect of both drugs in a SARS-CoV-2 Syrian hamster infection model. The infected hamsters were treated twice daily with the vehicle (the control group) or a suboptimal dose of each compound or a combination of both compounds. FINDINGS: When animals were treated with a combination of suboptimal doses of Molnupiravir and Favipiravir at the time of infection, a marked combined potency at endpoint is observed. Infectious virus titers in the lungs of animals treated with the combination are reduced by ∼5 log10 and infectious virus are no longer detected in the lungs of >60% of treated animals. When start of treatment was delayed with one day a reduction of titers in the lungs of 2.4 log10 was achieved. Moreover, treatment of infected animals nearly completely prevented transmission to co-housed untreated sentinels. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs of treated animals. In the combo-treated hamsters, an increased frequency of C-to-T mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination. INTERPRETATION: Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir/Favipiravir in the treatment of COVID-19. FUNDING: stated in the acknowledgment