Here we describe the structure, the high-pressure, low-temperature (HP-LT) metamorphism and tectonic evolution of the Briançonnais distal margin units from the south Western Alps. The studied area extends southwest of the Dora-Maira (U)HP basement units and east-southeast of the classical Briançonnais nappes. A new structural map accompanied by geological profiles shows the thrusting of the oceanic nappes (Monviso and Queyras units) onto the distal Briançonnais units (D1 and D2 late Eocene deformation phases) under blueschist-facies conditions. Subsequent deformation during the Early Oligocene (D3 deformation phase) took place under greenschist-facies conditions and was associated with back-folding and -thrusting in the units overlying the Dora-Maira massif and with exhumation related to normal reactivation of former thrusts within the latter massif. Two large cover units, detached from their former distal Briançonnais basement, are redefined as the Maira-Sampeyre and Val Grana Allochthons (shortly: Maira-Grana Allochthons = MGA) including, (i) the Val Maira-Sampeyre unit involving Lower and Middle Triassic formations, seemingly detached from the Dora-Maira units during the subduction process, and (ii) the Val Grana unit with Middle-Upper Triassic and Early-Middle Jurassic formations, which was probably detached from the Maira-Sampeyre unit and correlates with the “Prepiemonte units” known from the Ligurian Alps to the Swiss Prealps. Three major shear zones involving tectonic mélanges of oceanic and continental rocks at the base of the Val Grana, Maira-Sampeyre and Dronero units testify to an early phase of exhumation within the subduction channel in front of the Adria plate. We present a new metamorphic map based on published and new petrological data, including new thermometric data obtained by Raman spectroscopy of carbonaceous material (RSCM). The T RSCM values range from ~ 400 °C to > 500 °C, going from the most external Val Grana unit and overlying Queyras schists to the uppermost Dora-Maira unit. During the Late Triassic, the width of the Briançonnais s.l. domain can be restored at ~ 100 km, whereas it reached ~ 150 km after the Jurassic rifting. A significant, second rifting event affected the Briançonnais domain during the Late Cretaceous-Paleocene, forming the Longet-Alpet chaotic breccias, which deserve further investigations.
l -Methionine is an amino acid, which provides anti-oxidative properties. We report on radicals and radical cations being likely (short-lived) intermediates formed upon photo-oxidation reactions of methionine. In this context, we present photo-CIDNP experiments indicating that the character of the photooxidants is decisive for the observation of CIDNP effects based on methionine. Based on calculated hyperfine data and pK a values and on our experimental observations, we suggest that CIDNP polarizations are produced by an overlay of at least three geminal radical pairs, i.e., two α -thio carbon-centered radicals D · and G ·, aminyl radical N ·, and, possibly, 2c–3e radical cation SN . + as short-lived reaction intermediates.
Background Plasmodium vivax sporozoites reside in the salivary glands of a mosquito before infecting a human host and causing malaria. Previous transcriptome-wide studies in populations of these parasite forms were limited in their ability to elucidate cell-to-cell variation, thereby masking cellular states potentially important in understanding malaria transmission outcomes. Methodology/Principal findings In this study, we performed transcription profiling on 9,947 P . vivax sporozoites to assess the extent to which they differ at single-cell resolution. We show that sporozoites residing in the mosquito’s salivary glands exist in distinct developmental states, as defined by their transcriptomic signatures. Additionally, relative to P . falciparum , P . vivax displays overlapping and unique gene usage patterns, highlighting conserved and species-specific gene programs. Notably, distinguishing P . vivax from P . falciparum were a subset of P . vivax sporozoites expressing genes associated with translational regulation and repression. Finally, our comparison of single-cell transcriptomic data from P . vivax sporozoite and erythrocytic forms reveals gene usage patterns unique to sporozoites. Conclusions/Significance In defining the transcriptomic signatures of individual P . vivax sporozoites, our work provides new insights into the factors driving their developmental trajectory and lays the groundwork for a more comprehensive P . vivax cell atlas.
We consider uniform random permutations in classes having a finite combinatorial specification for the substitution decomposition. These classes include (but are not limited to) all permutation classes with a finite number of simple permutations. Our goal is to study their limiting behavior in the sense of permutons. The limit depends on the structure of the specification restricted to families with the largest growth rate. When it is strongly connected, two cases occur. If the associated system of equations is linear, the limiting permuton is a deterministic X-shape. Otherwise, the limiting permuton is the Brownian separable permuton, a random object that already appeared as the limit of most substitution-closed permutation classes, among which the separable permutations. Moreover these results can be combined to study some non strongly connected cases. To prove our result, we use a characterization of the convergence of random permutons by the convergence of random subpermutations. Key steps are the combinatorial study, via substitution trees, of families of permutations with marked elements inducing a given pattern, and the singularity analysis of the corresponding generating functions.
A general strategy for the synthesis of 2-substituted cyclobutanone sulphides via a tandem Brønsted acid catalysed nucleophile addition/ring-contraction/C3-C4 ring-expansion reaction sequence has been exploited. The procedure led to a wide panel of four membered cyclic ketones in good to excellent yields and with broad substrate scope. Mechanistic aspects and kinetic parameters were investigated by quantum chemical DFT calculations allowing us to rationalize the different reactivity of 2-aryl- and 2-alkyl- substituted 2-hydroxycyclobutanones towards thiol nucleophiles in reactions mediated by sulphonic acids. NMR and in situ Raman techniques, were employed to better understand the reaction kinetics and parameters that affect the desired outcome.
The SARS-CoV-2 Omicron variant has very high levels of transmission, is resistant to neutralization by authorized therapeutic human monoclonal antibodies (mAb) and is less sensitive to vaccine-mediated immunity. To provide additional therapies against Omicron, we isolated a mAb named P2G3 from a previously infected vaccinated donor and showed that it has picomolar-range neutralizing activity against Omicron BA.1, BA.1.1, BA.2 and all other variants tested. We solved the structure of P2G3 Fab in complex with the Omicron spike using cryo-electron microscopy at 3.04 Å resolution to identify the P2G3 epitope as a Class 3 mAb that is different from mAb-binding spike epitopes reported previously. Using a SARS-CoV-2 Omicron monkey challenge model, we show that P2G3 alone, or in combination with P5C3 (a broadly active Class 1 mAb previously identified), confers complete prophylactic or therapeutic protection. Although we could select for SARS-CoV-2 mutants escaping neutralization by P2G3 or by P5C3 in vitro, they had low infectivity and ‘escape’ mutations are extremely rare in public sequence databases. We conclude that this combination of mAbs has potential as an anti-Omicron drug. A potent mAb shows promise in monkeys either alone or in a combination therapy for either prophylaxis or treatment of infection with SARS-CoV-2 Omicron BA.1, BA.1.1 and BA.2.
Objectives To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in ALPK1 , is an autoinflammatory disease. Methods This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of ALPK1 mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of ALPK1 mutations on protein function and immune signalling. Results The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys. Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients). Patients’ primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation. Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow. Conclusion ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy.
Several strikingly different aerobic and anaerobic pathways of nicotinate breakdown are extant in bacteria. Here, through reverse genetics and analytical techniques we elucidated in Aspergillus nidulans, a complete eukaryotic nicotinate utilization pathway. The pathway extant in this fungus and other ascomycetes, is quite different from bacterial ones. All intermediate metabolites were identified. The cognate proteins, encoded by eleven genes (hxn) mapping in three clusters are co-regulated by a specific transcription factor. Several enzymatic steps have no prokaryotic equivalent and two metabolites, 3-hydroxypiperidine-2,6-dione and 5,6-dihydroxypiperidine-2-one, have not been identified previously in any organism, the latter being a novel chemical compound. Hydrolytic ring opening results in α-hydroxyglutaramate, a compound not detected in analogous prokaryotic pathways. Our earlier phylogenetic analysis of Hxn proteins together with this complete biochemical pathway illustrates convergent evolution of catabolic pathways between fungi and bacteria. A novel nicotinate degradation pathway is described in Aspergillus nidulans, with metabolic products identified that were not previously found in prokaryotic species. This is the first such pathway to be described in a eukaryote.
Late-term fetal demise including fetal death in utero, late miscarriage and late termination of pregnancy are relatively frequent occurrences. Post-traumatic stress disorder (PTSD) is a pathology that finds its roots in exposure to a life-threatening event or an event related to death. Exposure to fetal death during a late-term fetal demise is, therefore, a situation at risk of trauma. The objective of this study was to assess the prevalence of PTSD symptoms in the short term among patients faced with late fetal demise, and to identify potential risk factors. All women were assessed at 15 days, one month, and three months after late fetal demise using the Impact of Event Scale-Revised (IES-R) and the Peritraumatic Dissociative Experiences Questionnaire (PDEQ). At 15 days, 44.2% of patients presented a pathological score on the IES-R (≥ 33). At one month and three months, this figure was 34.1% and 9.1% respectively. Factor associated with PTSD symptoms were: peritraumatic dissociation (p = 0.014), seeing the fetus during hospitalization (p = 0.035), holding the fetus in one’s arms (p = 0.046), and the organization of a funeral service (p = 0.025). Patients experiencing late fetal demise are at significant risk of trauma. Care providers should remain vigilant to identify high-risk situations to offer appropriate care. Clinical trials registration number: NCT03433989.
This perspective outlines a panoramic description of the nature of the chemical bond according to valence bond theory. It describes single bonds, and charge-shift bonds (CSBs) in which the entire/most of the bond energy arises from the resonance between the covalent and ionic structures of the bond. Many CSBs are homonuclear bonds. Hypervalent molecules are CSBs. Then we describe multiply bonded molecules with emphasis on C 2 and ³ O 2 . The perspective outlines an effective methodology of peeling the electronic structure to the necessary minimum: a structure with a quadruple bond, and two minor structures with double bonds, which stabilize the quadruple bond by resonance. ³ O 2 is chosen because it is a persistent diradical. The persistence of ³ O 2 is due to the large CSB resonance interaction of the π-3-electron bonds. Subsequently, we describe the roles of π vs. σ in the geometric preferences in unsaturated molecules, and their Si-based analogs. Then, the perspective discusses bonding in clusters of univalent metal-atoms, which possess only parallel spins, and are nevertheless bonded due to multiple resonance interactions. The bond energy reaches ~40 kcal/mol for a pair of atoms (in ⁿ⁺¹ Cu n ; n~10-12). The final subsection discusses singlet excited states in ethene, ozone and SO 2 . It demonstrates the capability of the breathing-orbital VB method to yield an accurate description of a variety of excited states using 10 or less VB structures. Furthermore, the method underscores covalent structures which play a key role in the correct description and bonding of these excited states.
Introduction: In SERAPHIN, a long-term, event-driven, double-blind randomised controlled trial in pulmonary arterial hypertension (PAH), macitentan 10 mg significantly reduced the risk of morbidity/mortality compared with placebo. Its open-label extension study (SERAPHIN OL) further assessed long-term safety and tolerability of macitentan 10 mg in PAH patients. Methods: Patients in SERAPHIN who completed the double-blind treatment period or experienced a morbidity event during the study could enter SERAPHIN OL. Patients received macitentan 10 mg once daily, and safety and survival were assessed until end of treatment (+ 28 days). Two overlapping sets were analysed for safety: (1) all patients in SERAPHIN OL (OL safety set); (2) patients randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Survival was evaluated as an exploratory endpoint in the latter set. Results: Of 742 patients randomised in SERAPHIN, 550 (74.1%) entered SERAPHIN OL (OL safety set); 242 patients were randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Median (min, max) exposure to macitentan 10 mg was 40.1 (0.1, 130.5) months (2074.7 patient-years; OL safety set) and 54.7 (0.1, 141.3) months (1151.0 patient-years; long-term safety/survival set). Safety in both analysis sets was comparable to the known safety profile of macitentan. Kaplan-Meier survival estimates (95% CI) at 1, 5, 7 and 9 years were 95.0% (91.3, 97.1), 73.3% (66.6, 78.9), 62.6% (54.6, 69.6) and 52.7% (43.6, 61.0), respectively (long-term safety/survival set; median follow-up: 5.9 years). Conclusions: This analysis provides the longest follow-up for safety and survival published to date for any PAH therapy. The safety profile of macitentan 10 mg over this extensive treatment period was in line with that observed in SERAPHIN. As the majority of patients were receiving other PAH therapy at macitentan initiation, our study provides additional insight into the long-term safety of macitentan, including as part of combination therapy. Trial registration: ClinicalTrials.gov Identifiers: NCT00660179 and NCT00667823.
We propose a physical representation of the log-periodicity law which has been evidenced in the field of seismic physics, species evolution, astronomical systems, economy, history, and human organizations. Calling “fractal state” a truncated fractal obtained for a finite number of iterations, i.e., defined for a finite scale range, we define a fractal length, a fractal time of interaction, and finally a fractal mass for the fractal states of a fractal. The introduction of the mass of a fractal allows showing the existence of a quantum structure due to the fractal structure which leads to a Planck–Einstein-like law. Inspired by the work of Louis de Broglie on the “hidden thermodynamics of the particle,” we introduce a “kinetic chain temperature” which gives access to a thermodynamical description of log-periodicity. We found that log-periodic systems are characterized by a constant entropy production between two consecutive fractal states. The parameter g of log-periodicity finds here a clear and simple physical interpretation. It quantifies the increase of fractal length or fractal time with the number of iterations of the fractal state.
HIV infection induces tissue damage including lymph node (LN) fibrosis and intestinal epithelial barrier disruption leading to bacterial translocation and systemic inflammation. Natural hosts of SIV, such as African Green Monkeys (AGM), do not display tissue damage despite high viral load in blood and intestinal mucosa. AGM mount a NK cell-mediated control of SIVagm replication in peripheral LN. We analyzed if NK cells also control SIVagm in mesenteric (mes) LN and if this has an impact on gut humoral responses and the production of IgA known for their anti-inflammatory role in the gut. We show that CXCR5 + NK cell frequencies increase in mesLN upon SIVagm infection and that NK cells migrate into and control viral replication in B cell follicles (BCF) of mesLN. The proportion of IgA+ memory B cells were increased in mesLN during SIVagm infection in contrast to SIVmac infection. Total IgA levels in gut remained normal during SIVagm infection, while strongly decreased in intestine of chronically SIVmac-infected macaques. Our data suggest an indirect impact of NK cell-mediated viral control in mesLN during SIVagm infection on preserved BCF function and IgA production in intestinal tissues. Differences between pathogenic and non-pathogenic SIV infections are investigated, in terms of NK cell location, function and IgA responses in gut associated lymphoid tissues (mesenteric lymph nodes, jejunum, ileon, colon).
Background and Aims Sugar-sweetened soda consumption is associated with most of the cardiometabolic risk factors. The role of artificially-sweetened beverages in cardiovascular disease (CVD) is inconclusive, but their consumption correlates with health impairment. Little is known about the contribution of soda consumption in subclinical stages of atherosclerosis. Therefore, we evaluated the relation between sugar- and artificially-sweetened soda consumption and carotid intima-media thickness (IMT) among Mexican women. Methods and results We cross-sectionally evaluated 1,093 women enrolled in the Mexican Teachers’ Cohort who were free of CVD, diabetes or cancer. Sugar- and artificially-sweetened soda consumption was estimated from a validated 140-item food frequency questionnaire in 2008 and all women underwent a carotid ultrasound assessment three years later. Participants were categorized into tertiles of soda consumption in servings/week. Subclinical atherosclerosis was defined as a mean left and/or right IMT ≥ 0.8mm or the presence of plaque on either common carotid artery. In multivariable regression models, women in the highest tertile of sugar-sweetened soda consumption had 2.6% (95%CI: 0.8, 4.5) mean increased IMT, and had 2-fold the risk of carotid atherosclerosis (PR: 2.0, 95%CI: 1.3, 3.2) compared to those in the lowest tertile. In stratified analyses, older and postmenopausal women who consumed sugar-sweetened soda had an increased IMT and atherosclerosis risk. Artificially-sweetened soda consumption was not associated with IMT or carotid atherosclerosis. Conclusions Sugar-sweetened soda consumption was associated with subclinical atherosclerosis among disease-free Mexican women. Public health strategies to decrease CVD should consider the impact of sugar-sweetened soda consumption, particularly in older women.
A bstract Non-standard interactions of neutrinos arising in many theories beyond the Standard Model can significantly alter matter effects in atmospheric neutrino propagation through the Earth. In this paper, a search for deviations from the prediction of the standard 3-flavour atmospheric neutrino oscillations using the data taken by the ANTARES neutrino telescope is presented. Ten years of atmospheric neutrino data collected from 2007 to 2016, with reconstructed energies in the range from ∼16 GeV to 100 GeV, have been analysed. A log-likelihood ratio test of the dimensionless coefficients ε μτ and ε ττ − ε μμ does not provide clear evidence of deviations from standard interactions. For normal neutrino mass ordering, the combined fit of both coefficients yields a value 1.7 σ away from the null result. However, the 68% and 95% confidence level intervals for ε μτ and ε ττ − ε μμ , respectively, contain the null value. Best fit values, one standard deviation errors and bounds at the 90% confidence level for these coefficients are given for both normal and inverted mass orderings. The constraint on ε μτ is among the most stringent to date and it further restrains the strength of possible non-standard interactions in the μ − τ sector.
We present the results of an experimental study of multiple scattering of positively charged high-energy particles in bent samples of monocrystalline silicon. This work confirms the recently discovered effect of a strong reduction in the rms multiple scattering angle of particles channeled in the silicon (111) plane. The effect is observed in the plane orthogonal to the bending plane. We show in detail the influence of angular constraints on the magnitude of the effect. Comparison of the multiple scattering process at different energies indicates a violation of the law of inverse proportionality of the rms angle of channeled particles with energy. By increasing the statistics, we have improved the results of multiple scattering measurements for particles moving, but not channeled, in silicon crystals.
Kidney dysplasia is one of the most frequent causes of chronic kidney failure in children. While dysplasia is a histological diagnosis, the term ‘kidney dysplasia’ is frequently used in daily clinical life without histopathological confirmation. Clinical parameters of kidney dysplasia have not been clearly defined, leading to imprecise communication amongst healthcare professional and with patients. This lack of consensus hampers precise disease understanding and the development of specific therapies. Based on a structured literature search, we here suggest a common basis for clinical, imaging, genetic, pathological, and basic science aspects of non-obstructive kidney dysplasia associated with functional kidney impairment. We propose to accept hallmark sonographic findings as surrogate parameters defining a clinical diagnosis of dysplastic kidneys. We suggest differentiated clinical follow-up plans for children with kidney dysplasia and summarize established monogenic causes for non-obstructive kidney dysplasia. Finally, we point out and discuss research gaps in the field.
Bat sarbecovirus BANAL-236 is highly related to SARS-CoV-2 and infects human cells, albeit lacking the furin cleavage site in its spike protein. To inform on the origin of SARS-CoV-2, we evaluated the clinical, epidemiological and evolutionary consequences of a potential BANAL-236 spillover into humans using animal models. The virus replicates efficiently and pauci-symptomatically in humanized mice and in macaques, where its tropism is enteric, strongly differing from that of SARS-CoV-2. BANAL-236 infection leads to protection against superinfection by a more virulent strain like Wuhan SARS-CoV-2. Yet we found no evidence of antibodies recognizing bat sarbecoviruses in populations highly exposed to bats, indicating that such infections, if they occur, are rare. Six passages in mice or in human intestinal cells, mimicking putative early spillover events, selected adaptive mutations without appearance of a furin cleavage site and not change in virulence. We thus conclude that the hypothesis of the SARS-CoV-2 pandemic being preceded by silent circulation in humans of BANAL-236-like strains leading to the acquisition of a furin cleavage site is unlikely. Our studies suggest that a specific search for a furin cleavage site in sarbecoviruses in the wild should be pursued to understand the origin of the SARS-CoV-2 pandemics.
Dry eye disease (DED) is a chronic inflammatory disease of the ocular surface requiring long-term therapy. Severe forms of DED generally do not respond to tear substitutes alone or combined, and often require treatment with topical anti-inflammatory agents to break the vicious circle of inflammation. This review summarises data from randomised controlled trials and real-world evidence on the efficacy and safety of ciclosporin A 0.1% cationic emulsion (Ikervis®) for the management of DED. Improvements in clinical signs and symptoms were reported from as early as 4 weeks after treatment initiation, although it can take a few months to reach the full benefits. Treatment periods of up to 12 months provide sustained benefit to patients. In the most responsive patients, treatment discontinuation is possible with no further substantial relapse over 12 months in over 65% of patients. Transient local ocular effects are the most commonly reported adverse events.
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