Characterization of bright betatron radiation generated by direct laser acceleration of electrons in plasma of near critical density

Directed x-rays produced in the interaction of sub-picosecond laser pulses of moderate relativistic intensity with plasma of near-critical density are investigated. Synchrotron-like (betatron) radiation occurs in the process of direct laser acceleration (DLA) of electrons in a relativisticlaser channel when the electrons undergo transverse betatron oscillations in self-generated quasi-static electric and magnetic fields. In anexperiment at the PHELIX laser system, high-current directed beams of DLA electrons with a mean energy ten times higher than the ponderomotive potential and maximum energy up to 100 MeV were measured at 10^(19) W/cm^(2)laser intensity. The spectrum of directed x-raysin the range of 5–60 keV was evaluated using two sets of Ross filters placed at 0°and 10°to the laser pulse propagation axis. The differential x-ray absorption method allowed for absolute measurements of the angular-dependent photon fluence. We report 10^(13) photons/sr withenergies >5 keV measured at 0°to the laser axis and a brilliance of 10^(21) photons s^(−1) mm^(−2) mrad−2(0.1%BW)−1. The angular distributionof the emission has an FWHM of 14°–16°. Thanks to the ultra-high photon fluence, point-like radiation source, and ultra-short emissiontime, DLA-based keV backlighters are promising for various applications in high-energy-density research with kilojoule petawatt-class laserfacilities.

Next generation drug connectivity mapping for acquiring therapeutic agents to differentially regulate myelination

The need for new therapeutic approaches:Conventional drug discovery is a lengthy and expensive process,taking decades and billions of dollars to get a drug from bench to bedside.Much of the costs incurred are at the pre-clinical stages,between drug design and synthesis to delineating the cellular“Mechanisms of Action”(MoA).Notably,there is a very high risk of failure,and only a very small proportion of therapeutic agents reach later-phase clinical trials.Accordingly,drug repositioning has become a valuable strategy aimed at fast-tracking treatments into clinical use and improving the chances of therapeutic success.A novel addition to this approach is connectivity mapping,which defines cell-specific transcriptional responses to small molecules in disease-dependent contexts.This commentary outlines how some of the latest innovations in connectivity mapping can be exploited for drug repurposing.

Choroid plexus imaging to track neuroinflammation—a translational model for mouse and human studies

The choroid plexus(ChP)is a highly vascularized and secretory tissue in each of the brain ventricles that represents the key structure between the blood and the cerebrospinal fluid(CSF).Besides its essential role in CSF production and brain waste clearance pathways,the ChP also contributes to the regulation of central nervous system(CNS)immunosurveillance(Ghersi-Egea et al.,2018).Indeed,the ChP forming the blood-CSF barrier(BCSFB)regulates the entry of immune cells and solute molecules into the brain and vice versa.When antigen-specific,autoreactive immune activation occurs in the periphery,inflammatory cells migrate through the brain barriers towards the CNS(Strominger et al.,2018),initiating neuroinflammatory diseases such as multiple sclerosis(MS).

Star power: harnessing the reactive astrocyte response to promote remyelination in multiple sclerosis

Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.

Evaluation of acoustic radiation force impulse imaging for determination of liver stiffness using transient elastography as a reference

AIM: To evaluate cut-off values and performance of acoustic radiation force impulse imaging (ARFI) using transient elastography [FibroScan■ (FS)] as a reference. METHODS: Six hundred and six patients were enrolled in this study.All patients underwent liver stiffness measurement with FS (FS-LS) and ARFI (with shear wave velocity quantification; ARFI-SWV) and the performance of ARFI in comparison to FS was determined. Sixtyeight patients underwent liver biopsy. RESULTS: Significantly higher success rates for the determination of liver stiffness were found using ARFI as compared to FS [604/606 (99.7%) vs 482/606 (79.5%); P < 0.001]. ARFI-SWV correlated significantly with FS-LS (r = 0.920, P < 0.001). ARFI-SWV increased significantly with the stage of fibrosis (1.09 ± 0.13 m/s for patients with no significant fibrosis (FS-LS < 7.6 kPa); 1.46 ± 0.27 m/s for patients with significant liver fibrosis (7.6 < FS-LS ≤ 13.0 kPa); and 2.55 ± 0.77 m/s for patients with liver cirrhosis (FS-LS > 13.0 kPa)). ARFI-SWV cut-off values were identified for no significant fibrosis (1.29 m/s; sensitivity 91.4% and specificity 92.6%) and for liver cirrhosis (1.60 m/s; sensitivity 92.3% and specificity 96.5%). The optimal cut-off value for predicting liver fibrosis (F ≥ 2) was 1.32 m/s (sensitivity 87.0% and specificity 80.0%) and for liver cirrhosis (F4) 1.62 m/s (sensitivity 100% and specificity 85.7%), for patients who underwent liver biopsy. An excellent inter-and intraobserver reproducibility was observed for ARFI-SWV determinations. CONCLUSION: An ARFI-SWV cut-off value of 1.29 m/s seems to be optimal for patients with no significant liver fibrosis and 1.60 m/s for patients with liver cirrhosis.

Nociception at the diabetic foot,an uncharted territory

The diabetic foot is characterised by painless foot ulceration and/or arthropathy;it is a typical complication of painless diabetic neuropathy.Neuropathy depletes the foot skin of intraepidermal nerve fibre endings of the afferent A-delta and C-fibres,which are mostly nociceptors and excitable by noxious stimuli only.However,some of them are cold or warm receptors whose functions in diabetic neuropathy have frequently been reported.Hence,it is well established by quantitative sensory testing that thermal detection thresholds at the foot skin increase during the course of painless diabetic neuropathy.Pain perception(nociception),by contrast,has rarely been studied.Recent pilot studies of pinprick pain at plantar digital skinfolds showed that the perception threshold was always above the upper limit of measurement of 512 m N(equivalent to 51.2 g) at the diabetic foot.However,deep pressure pain perception threshold at musculus abductor hallucis was beyond 1400 k Pa(equivalent to 14 kg;limit of measurement) only in every fifth case.These discrepancies of pain perception between forefoot and hindfoot,and between skin and muscle,demand further study.Measuring nociception at the feet in diabetes opens promising clinical perspectives.A critical nociception threshold may be quantified(probably corresponding to a critical number of intraepidermal nerve fibre endings),beyond which the individual risk of a diabetic foot rises appreciably.Staging of diabetic neuropathy according to nociception thresholds at the feet is highly desirable as guidance to an individualised injury prevention strategy.

Small intestine bleeding due to multifocal angiosarcoma

We report a case of an 84-year-old male patient with primary small intestinal angiosarcoma.The patient initially presented with anemia and melena.Consecutive endoscopy revealed no signs of upper or lower active gastrointestinal bleeding.The patient had been diagnosed 3 years previously with an aortic dilation,which was treated with a stent.Computed tomography suggested an aorto-intestinal fistula as the cause of the intestinal bleeding,leading to operative stent explantation and aortic replacement.However,an aorto-intestinal fistula was not found,and the intestinal bleeding did not arrest postoperatively.The constant need for blood transfusions made an exploratory laparotomy imperative,which showed multiple bleeding sites,predominately in the jejunal wall.A distal loop jejunostomy was conducted to contain the small intestinal bleeding and a segmental resection for histological evaluation was performed.The histological analysis revealed a lessdifferentiated tumor with characteristic CD31,cytokeratin,and vimentin expression,which led to the diagnosis of small intestinal angiosarcoma.Consequently,the infiltrated part of the jejunum was successfully resected in a subsequent operation,and adjuvant chemotherapy with paclitaxel was planned.Angiosarcoma of the small intestine is an extremely rare malignant neoplasm that presents with bleeding and high mortality.Early diagnosis and treatment are essential to improve outcome.A small intestinal angiosarcoma is a challenging diagnosis to make because of its rarity,nonspecific symptoms of altered intestinal function,nonspecific abdominal pain,severe melena,and acute abdominal signs.Therefore,a quick clinical and histological diagnosis and decisive measures including surgery and adjuvant chemotherapy should be the aim.

Models and Neural Bases of the Believing Process

Departing from the long debates on the role of faith/belief, recent interdisciplinary research has turned to characterize the features of the psychophysical processes underlying believing. Here we review recent cognitive neuroscience models of the believing process and propose a conceptual framework that integrates current theoretical and empiric knowledge about the processes of believing. There are theories that elegantly explain believing as a self-organization process of cognitive and emotional elements. Adding to the component of self-organized belief representation, dual-component models assume a belief evaluation component, which is probably supported by the right dorsolateral prefrontal cortex (DLPFC) and explains the stability of the belief despite the changing environment. Borrowing an idea from the neural models for the mental representation of action or situation, inclusion of both perceptive and action informations as the construct of belief representation allows the intimate relationship between a specific belief and a specific range of behaviour. Furthermore, inclusion of the personal value or affective information in the representation explains the deep impact of one’s emotional and physical state on the believing process. For associating perception, action, and value in a representation, the medial frontal cortex (MFC) may play a key role. Recent neuro-cognitive models of self-cognition explain the developmental origin of such a representation and the hierarchically nested structure of three levels of complexity in the representations: basic physical level, interpersonal level, and higher social level. The integrated model provides a comprehensive perspective of the believing process which suggests the importance and future directions of this interdisciplinary approach.

Resolving the age-related decline in central nervous system myelin turnover and drug discovery for oligodendroglial rejuvenation

Myel i n genes are amongst the most dysregulated genes in the aged brain:Just over half of the weight of an entire adult human brain is attributed to myelin,which wraps around neuronal axons and is essential for superfast axonal conduction and neuronal integrity.In the central nervous system,it is the function of specialized cells called oligodendrocytes(OLs)to make myelin,which is made up of lipids and proteins.OLs are generated throughout life by a significant population of oligodendrocyte progenitor cells(OPCs)that are responsible for the lifelong generation of OLs and myelin,essential for learning,as well as repair following pathological insults(i.e.in demyelinating diseases that include multiple sclerosis)(Simons and Nave,2015;Philips and Rothstein,2017).Changes in myelin content in the human brain over the lifespan of individuals have been well documented,as well as evidence of myelin loss in rodent models using classical histological approaches(Bartzokis et al.,2012;Soreq et al.,2017).

Extrahepatic intraductal ectopic hepatocellular carcinoma:bile duct filling defect

BACKGROUND:Obstructive jaundice caused by an intraductal hepatocellular carcinoma is a rare initial symptom.We report a rare case of an extrahepatic icteric type hepatocellular carcinoma.METHODS:A 75-year-old patient was admitted to our hospital because of obstructive jaundice 3 months after resection of multilocular hepatocellular carcinoma.A postoperative bile leakage was treated by placement of a decompressing stent in the common bile duct.Endoscopic retrograde choledochoscopy showed extended blood clots filling the bile duct system and computed tomography revealed a local swelling in the common extrahepatic bile duct.The level of alpha-fetoprotein(AFP)was only slightly elevated but that of CA19-9 was dramatically increased.Cholangiography showed an intraductal filling defect typical of a cholangiocellular carcinoma.RESULTS:Bile duct brushing cytology showed no cholangiocellular carcinoma but hepatocellular carcinoma cells in the extrahepatic bile duct.An extrahepatic bile duct resection was performed.Histological examination confirmed the diagnosis of extrahepatic intraductal growth of hepatocellular carcinoma.CONCLUSION:Ectopic hepatocellular carcinoma is a rare but important differentially diagnosed of extrahepatic bile duct filling defect.

Functional in vivo assessment of stem cell-secreted pro-oligodendroglial factors

The role of adult neural stem cells(NSCs)in demyelinating diseases of the central nervous system(CNS):Multipotent NSCs hold great potential for cell replacement in diseases and upon injury of the CNS.Originating from radial glial cells during nervous system development,adult NSCs are localized in the subgranular zone of the hippocampus and the subventricular zone(SVZ)of the lateral brain ventricles,the main neurogenic zones of the adult brain.Hippocampal precursor cells(type 1 cells)exhibiting properties of radial glial cells give rise to granule neurons through distinct intermediate precursor cells,and integrate into the hippocampal circuitry[reviewed by Kempermann et al.(2015)].Likewise,under physiological conditions,neuron generation by mouse SVZ-derived NSCs(also known as type B cells)is the predominant cell fate,which thereby results in large numbers of transient amplifying precursor cells(also known as type C cells)which in turn differentiate into neuroblasts(type A cells).These cells migrate along the rostral migratory stream into the olfactory bulb where they undergo maturation into local interneurons.The structure of the rodent SVZ differs from that of the human SVZ since the proliferative capacity is reduced,and migration of neuroblasts is a rare event in adult humans[reviewed by Lim and Alvarez-Buylla(2016)].

Strategies to prevent and detect intraoperative spinal cord ischemia during complex aortic surgery:from drainages and biomarkers

Spinal cord ischemia(SCI),a frequent complication following open and endovascular thoracoabdominal aortic aneurysm(TAAA)repair,is a feared complication with relevant impact on a patient's quality of life.In the early days of open TAAA repair,more than one third of the patients suffered from SCI.Nowadays,due to improved preventive measures and the option of staged endovascular TAAA repair,10%of all patients are affected by spinal cord problems after TAAA repair(Rocha et al.,2020).

A Third-Order Accurate Wave Propagation Algorithm for Hyperbolic Partial Differential Equations

We extend LeVeque's wave propagation algorithm,a widely used finite volume method for hyperbolic partial differential equations,to a third-order accurate method.The resulting scheme shares main properties with the original method,i.e.,it is based on a wave decomposition at grid cell interfaces,it can be used to approximate hyperbolic problems in divergence form as well as in quasilinear form and limiting is introduced in the form of a wave limiter.

Intense Long-Lived Fluorescence of 1,6-Diphenyl-1,3,5-Hexatriene: Emission from the S₁-State Competes with Formation of O₂Contact Charge Transfer Complex

The fluorescence kinetics of 1,6-diphenyl-1,3,5-hexatriene (DPH) dissolved in cyclohexane was investigated as a function of temperature, concentration and 355 nm excitation pulse energy. At concentrations above 2.5 μM and excitation energies above 1 mJ a long-lived, very intense emission, which appears within less than 5 ns and lasts up to 70 ns, is observed. During the first 50 ns the decay does not follow an exponential but rather a linear behaviour. In oxygen saturated solutions the long-lived emission is suppressed and solely short-lived fluorescence with τ 1-state and competes with the formation of DPH-O2 contact charge-transfer complexes and intersystem crossing which both quench the fluorescence. Our investigations show that even the small amount of oxygen dissolved in nitrogen saturated solutions has a distinct influence on the fluorescence kinetics of DPH.

Believing processes during the COVID-19 pandemic in individuals with bipolar disorder:An exploratory study

BACKGROUND Believing or“credition”refers to psychological processes that integrate the cognitions and emotions that influence our behavior.In the credition model by Angel and Seitz,four parameters are postulated:proposition,certainty,emotion and mightiness.It is assumed that believing processes are influenced by both the individual as well as socio-cultural factors and external circumstances.External or environmental circumstances can include threatening situations such as the ongoing pandemic.It has been hypothesized that believing processes related to the pandemic differ between individuals with bipolar disorder(BD)and healthy controls(HC).AIM To investigate credition in individuals with BD during the coronavirus disease 2019(COVID-19)pandemic.METHODS Psychiatrically stable individuals with BD(n=52)and age-and sex matched HC(n=52)participated in an online survey during the first lockdown of the COVID-19 pandemic.The survey took place between April 9^(th) and June 4^(th),2020,in Austria.Participants completed the Brief Symptom Inventory-18,the Beck Depression Inventory-Ⅱ,the Altman Self-Rating Mania Scale,the Pittsburgh Sleep Quality Index and a dedicated Believing Questionnaire assessing four parameters of credition(proposition,certainty,emotion and mightiness).The MAXQDA software was used to analyze the qualitative data.Statistical analyses included analyses of variance,a multivariate analysis of variance and a multivariate analysis of co-variance.RESULTS Individuals with BD reported significantly more negative propositions[F(1,102)=8.89,P=0.004,η2 p=0.08]and negative emotions[Welch´s F(1,82.46)=18.23,P<0.001,η2 p=0.18],while HC showed significantly more positive propositions[F(1,102)=7.78,P=0.006,η2 p=0.07]and emotions[F(1,102)=14.31,P<0.001,η2 p=0.12].In addition,individuals with BD showed a higher incongruence between their propositions and their emotions[F(1,102)=9.42,P=0.003,η2 p=0.08]and showed strong correlations between the parameters of the Believing Questionnaire and their psychiatric symptoms(r=0.51-0.77,all P<0.001).Positive as well as negative emotions and propositions were associated with scores measuring symptoms of depression,anxiety and sleep quality.CONCLUSION Believing parameters were associated with psychiatric symptoms in BD during the pandemic.Findings broaden knowledge about the susceptibility of believing processes for ambient challenges in individuals with BD.

A variant in IL6ST with a selective IL-11 signaling defect in human and mouse

The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6 st p.R279 Q. We show that human GP130 p.R281 Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6 st p.R279 Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11 RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

Neurotherapeutic potential of erythropoietin after ischemic injury of the central nervous system

Erythropoietin (EPO) is one of the most successful biopharmaceuticals in history and is used for treating anemia of different origins. However, it became clear that EPO could also work in a neuroprotective, antiapoptotic, antioxidative, angiogenetic and neurotropic way. It causes stimulation of cells to delay cell apoptosis, especially in the central nervous system. In rodent models of focal cerebral ischemia, EPO showed an impressive reduction of infarct size by 30% and improvement of neurobehavioral outcome by nearly 40%. A large animal model dealing with ischemia and reperfusion of the spinal cord showed that EPO could reduce the risk of spinal cord injury significantly. In addition, some clinical studies tested whether EPO works in real live clinical settings. One of the most promising studies showed the innocuousness and improvements in follow-up, outcome scales and in infarct size, of EPO-use in humans suffering from ischemic stroke. Another study ended unfortunately in a negative outcome and an increased overall death rate in the EPO group. The most possible reason was the involvement of patients undergoing simultaneously systemic thrombolysis with recombinant tissue plasminogen activator. An experimental study on rats demonstrated that administration of EPO might exacerbate tissue plasminogen activator-induced brain hemorrhage without reducing the ischemic brain damage. This case shows clearly how useful animal models can be to check negative side effects of a treatment before going into clinical trials. Other groups looked in human trials at the effects of EPO on the outcome after ischemic stroke, relation to circulating endothelial progerdtor cells, aneurysmal subarachnoid hemorrhage, traumatic brain injury, hemoglobin transfusion thresholds and elective first-time coronary artery bypass surgery. Most of the results were pos-让ive, but are based mostly on small group sizes. However, some of the most neglected facts when focusing on experimental setups of ischemia of the central nervous system are issues like age and comorbidities. It might be extremely worthy to consider these points for future projects, because EPO might influence all these factors.

Role of GSK3 in peripheral nerve regeneration

In recent years,GSK3 has emerged as a key regulatory kinase in the nervous system,which is involved in diverse processes ranging from neural development to mood stabilization to neurodegeneration.In addition,it has been described as a regulator of several aspects of neural morphology such as polarization,axon growth and branching （Seira and Del Rio, 2014）.

Oxidative eustress:the physiological role of oxidants

The perception of a pivotal role of reactive oxygen species(ROS)(Sies et al.,2022),reactive nitrogen species(RNS)and electrophiles(Parvez et al.,2018)in cell biology and physiology has gained widespread acceptance.In recent years,evidence for an important role of reactive sulfur species(RSS)has accumulated as well(Cirino et al.,2023).