Emicizumab binds to activated factor IX and factor X, reproducing the bridging function of the missing factor VIII. In a trial of emicizumab prophylaxis, emicizumab every 1 or 2 weeks led to a lower ...bleeding rate than no prophylaxis.
Background and purpose
Guidelines on monogenic cerebral small‐vessel disease (cSVD) diagnosis and management are lacking. Endorsed by the Stroke and Neurogenetics Panels of the European Academy of ...Neurology, a group of experts has provided recommendations on selected monogenic cSVDs, i.e. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), autosomal dominant High Temperature Requirement A Serine Peptidase 1 (HTRA1), cathepsin‐A‐related arteriopathy with strokes and leukoencephalopathy (CARASAL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), Fabry disease, mitochondrial encephalopathy, lactic acidosis and stroke‐like episodes (MELAS) and type IV collagen (COL4)A1/2.
Methods
We followed the Delphi methodology to provide recommendations on several unanswered questions related to monogenic cSVD, including genetic testing, clinical and neuroradiological diagnosis, and management.
Results
We have proposed ‘red‐flag’ features suggestive of a monogenic disease. General principles applying to the management of all cSVDs and specific recommendations for the individual forms of monogenic cSVD were agreed by consensus.
Conclusions
The results provide a framework for clinicians involved in the diagnosis and management of monogenic cSVD. Further multicentre observational and treatment studies are still needed to increase the level of evidence supporting our recommendations.
The basic unit of genome packaging is the nucleosome, and nucleosomes have long been proposed to restrict DNA accessibility both to damage and to transcription. Nucleosome number in cells was ...considered fixed, but recently aging yeast and mammalian cells were shown to contain fewer nucleosomes. We show here that mammalian cells lacking High Mobility Group Box 1 protein (HMGB1) contain a reduced amount of core, linker, and variant histones, and a correspondingly reduced number of nucleosomes, possibly because HMGB1 facilitates nucleosome assembly. Yeast nhp6 mutants lacking Nhp6a and -b proteins, which are related to HMGB1, also have a reduced amount of histones and fewer nucleosomes. Nucleosome limitation in both mammalian and yeast cells increases the sensitivity of DNA to damage, increases transcription globally, and affects the relative expression of about 10% of genes. In yeast nhp6 cells the loss of more than one nucleosome in four does not affect the location of nucleosomes and their spacing, but nucleosomal occupancy. The decrease in nucleosomal occupancy is non-uniform and can be modelled assuming that different nucleosomal sites compete for available histones. Sites with a high propensity to occupation are almost always packaged into nucleosomes both in wild type and nucleosome-depleted cells; nucleosomes on sites with low propensity to occupation are disproportionately lost in nucleosome-depleted cells. We suggest that variation in nucleosome number, by affecting nucleosomal occupancy both genomewide and gene-specifically, constitutes a novel layer of epigenetic regulation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We discuss a small-scale experiment, called
ν
-cleus, for the first detection of coherent neutrino–nucleus scattering by probing nuclear-recoil energies down to the 10 eV regime. The detector ...consists of low-threshold CaWO
4
and Al
2
O
3
calorimeter arrays with a total mass of about 10 g and several cryogenic veto detectors operated at millikelvin temperatures. Realizing a fiducial volume and a multi-element target, the detector enables active discrimination of
γ
, neutron and surface backgrounds. A first prototype Al
2
O
3
device, operated above ground in a setup without shielding, has achieved an energy threshold of
∼
20
eV and further improvements are in reach. A sensitivity study for the detection of coherent neutrino scattering at nuclear power plants shows a unique discovery potential (5
σ
) within a measuring time of
≲
2
weeks. Furthermore, a site at a thermal research reactor and the use of a radioactive neutrino source are investigated. With this technology, real-time monitoring of nuclear power plants is feasible.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Microplastics were found in coastal waters and in fish gastrointestinal tract from the Tyrrhenian Sea.•Microplastics appeared in fragments or in filamentous shapes, in water and in fish ...respectively.•Microplastics have been characterized by FT-IR and Raman spectroscopies.
In this work it is reported for the first time the characterization of microplastics from sea water samples and in two congener species of seabreams: Pagellus erythrinus and P. bogaraveo, Mediterranean fish species of great commercial importance. An experimental survey was conducted on May–June 2017 in the southernmost part of the Tyrrhenian Sea. Microplastics found in the sea water and in the grastrointestinal tract of two teleosts were characterized by Raman and IR spectroscopies. Microplastics found in sea water samples appeared in the form of fragments made of plastics of low and high density (PVC and LPDE). All the microplastics found in fish belonged to Nylon 66, typical fibers used in industry and in fisheries. Our findings highlighted the importance of further studies along the food web chain for a better understanding of the diffusion and possible consequences of this terrible threat.
Mitochondrial diseases are the most common inheritable metabolic diseases, due to defects in oxidative phosphorylation. They are caused by mutations of nuclear or mitochondrial DNA in genes involved ...in mitochondrial function. The peculiarity of “mitochondrial DNA genetics rules” in part explains the marked phenotypic variability, the complexity of genotype-phenotype correlations and the challenge of genetic counseling. The new massive genetic sequencing technologies have changed the diagnostic approach, enhancing mitochondrial DNA-related syndromes diagnosis and often avoiding the need of a tissue biopsy.
Here we present the most common phenotypes associated with a mitochondrial DNA mutation with the recent advances in diagnosis and in therapeutic perspectives.
A study was carried out to identify biogeochemical reactions along a transect of a coastal dolomitic aquifer. In this transect, the physicochemical parameters of the groundwater as well as the ...microbial composition of samples taken at different depths and salinities were measured. Many of the dissolved ions measured in the groundwater follow a pattern that reflects the distribution of the water masses (fresh, interface and salt) in the aquifer, while others such as Ca and Mg ions deviate from this trend by identifying the zones of maximum dissolution of the carbonate matrix. The concentrations of minor ions, such as Fe and Mn, also follow a singular pattern, with maximum concentrations in the reducing zones of the aquifer and lower values in the oxidizing zones. Precipitates of Mn oxides along with other metals, such as Fe, Ba, Zn and Ni, were observed in the saline zone displaying oxidizing conditions close to the coastline, where a continuous core was recovered. This zone, which is located below the freshwater-seawater mixing zone and features percentages of seawater higher than 80 %, is characterized by the presence of Marinobacter as the predominant genus. These bacteria are also related to the formation of Mn-rich polymetallic oxides in other contexts such as the ocean floor (Wang et al., 2012; Cao et al., 2021). All in all, a biogeochemical reaction model is proposed that describes the formation of these oxides in areas close to the discharge zone of coastal aquifers. To do this, it has been necessary to integrate the results obtained from geochemical, hydrogeological and microbiological information.
Display omitted
•The geochemistry and microbiota of a dolomitic coastal aquifer has been studied.•Groundwater samples have been taken from several boreholes along the path flow.•MnO2 precipitation happens in saline and oxidative areas next to the coastal line.•Marinobacter and other genera can be the responsible of the MnO2 precipitation.
The energy threshold of a cryogenic calorimeter can be lowered by reducing its size. This is of importance since the resulting increase in signal rate enables new approaches in rare-event searches, ...including the detection of MeV mass dark matter and coherent scattering of reactor or solar neutrinos. A scaling law for energy threshold vs detector size is given. We analyze the possibility of lowering the threshold of a gram-scale cryogenic calorimeter to the few eV regime. A prototype 0.5 g Al2O3 device achieved an energy threshold of Eth=(19.7±0.9) eV, the lowest value reported for a macroscopic calorimeter.
Background: Patients with severe hemophilia may show very varied bleeding tendencies, and the reasons for this heterogeneous clinical expression are unclear. The factor VIII/FIX genotype is the main ...determinant of the residual factor activity; however, different bleeding phenotypes have also been reported in patients sharing the same mutation. Such global coagulation tests as thrombin generation assays are tools with which to investigate different coagulation profiles among severe hemophiliacs. Objectives, patients and methods: This case–control study was aimed at comprehensively evaluating the role of genotype and endogenous thrombin potential (ETP) as predictors of the clinical phenotype in severe hemophiliacs with an extremely mild bleeding tendency (cases, n = 22), in comparison with those showing a typical bleeding tendency (controls, n = 50). Results: Cases were more frequently affected by hemophilia B than by hemophilia A, and showed a lower incidence of severe FVIII/FIX gene defects (referred to as null mutations), higher FVIII and FIX antigen levels and higher ETP values in platelet‐rich plasma than controls (P < 0.05). By multivariate logistic regression, only non‐null mutations were confirmed as an independent predictor of a mild clinical phenotype. Conclusions: These results indicate that non‐null mutations represent the main determinant of the bleeding tendency, and that ETP measurement in platelet‐rich plasma is able to identify severe hemophiliacs with a mild clinical phenotype.
COSINUS is a dark matter (DM) direct search experiment that uses sodium iodide (NaI) crystals as cryogenic calorimeters. Thanks to the low nuclear recoil energy threshold and event-by-event ...discrimination capability, COSINUS will address the long-standing DM claim made by the DAMA/LIBRA collaboration. The experiment is currently under construction at the Laboratori Nazionali del Gran Sasso, Italy, and employs a large cylindrical water tank as a passive shield to meet the required background rate. However, muon-induced neutrons can mimic a DM signal therefore requiring an active veto system, which is achieved by instrumenting the water tank with an array of photomultiplier tubes (PMTs). This study optimizes the number, arrangement, and trigger conditions of the PMTs as well as the size of an optically invisible region. The objective was to maximize the muon veto efficiency while minimizing the accidental trigger rate due to the ambient and instrumental background. The final configuration predicts a veto efficiency of 99.63 ± 0.16% and 44.4 ± 5.6% in the tagging of muon events and showers of secondary particles, respectively. The active veto will reduce the cosmogenic neutron background rate to 0.11 ± 0.02 cts
·
kg
-
1
·
year
-
1
,
corresponding to less than one background event in the region of interest for the whole COSINUS-1
π
exposure of 1000 kg
·
days.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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