The development of ultra-intense and ultra-short light sources is currently a subject of intense research driven by the discovery of novel phenomena in the realm of relativistic optics, such as the ...production of ultrafast energetic particle and radiation beams for applications. It has been a long-standing challenge to unite two hitherto distinct classes of light sources: those achieving relativistic intensity and those with pulse durations approaching a single light cycle. While the former class traditionally involves large-scale amplification chains, the latter class places high demand on the spatiotemporal control of the electromagnetic laser field. Here, we present a light source producing waveform-controlled 1.5-cycle pulses with a 719 nm central wavelength that can be focused to relativistic intensity at a 1 kHz repetition rate based on nonlinear post-compression in a long hollow-core fiber. The unique capabilities of this source allow us to observe the first experimental indications of light waveform effects in laser wakefield acceleration of relativistic energy electrons.
During gestation, the mother is the main source of thyroid hormones for the foetus. Thus, hypothyroidism during pregnancy and/or preterm birth compromise thyroid hormone supply for the foetus. ...Maternal hypothyroidism increases risk of preterm birth and both conditions are associated with respiratory distress in infants. Since thyroid hormones are essential for normal brain development, it is plausible that maternal thyroid hormone deficiency plays a role in respiratory disorders related to neurological immaturity in the newborn; however, this hypothesis is yet to be tested. Here, we used methimazole treatment (MMI; 0.05% v/w) from the onset of pregnancy until two weeks postpartum to induce thyroid hormone deficiency in rat pups. At 14–15 days of age, we used plethysmography to measure breathing at rest and in response to hypoxia (12% O2, 20 min) in intact pups. We then used a urethane/chloralose anesthetised preparation to measure cardiorespiratory inhibition induced by laryngeal chemoreflex stimulation. In intact pups, basal breathing did not differ between groups but the breathing frequency response to hypoxia of MMI-treated pups was lower than controls. Following anesthesia, breathing frequency of MMI pups was 60% lower than controls; following laryngeal chemoreflex stimulation, the drop in O2 saturation that was 82% greater in MMI-treated pups than controls. Inactivation of GABAA receptors (bicuculline; 0.5 mg/kg) raised the frequency of anesthetised MMI pups but not control. We conclude that gestational thyroid hormone deficiency interferes with the respiratory and autonomic control systems of the offspring. Thyroid hormone supplementation could alleviate cardiorespiratory disorders in newborn, especially those born preterm.
•Thyroid hormones are crucial for normal brain development.•Maternal hypothyroidism during pregnancy reduces thyroid hormone access for the foetus•Respiratory disorders due to neurological immaturity are clinically significant.•We determined if thyroid hormone deficiency induces respiratory disorders in rat pups.•Thyroid hormone deficient pups show abnormal reflexes that predispose to respiratory disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Proper telomere length is essential for embryonic stem cell (ESC) self-renewal and pluripotency. Mouse ESCs (mESCs) sporadically convert to a transient totipotent state similar to that of two-cell ...(2C) embryos to recover shortened telomeres. Zscan4, which exhibits a burst of expression in 2C-like mESCs, is required for telomere extension in these cells. However, the mechanism by which Zscan4 extends telomeres remains elusive. Here, we show that Zscan4 facilitates telomere elongation by inducing global DNA demethylation through downregulation of Uhrf1 and Dnmt1, major components of the maintenance DNA methylation machinery. Mechanistically, Zscan4 recruits Uhrf1 and Dnmt1 and promotes their degradation, which depends on the E3 ubiquitin ligase activity of Uhrf1. Blocking DNA demethylation prevents telomere elongation associated with Zscan4 expression, suggesting that DNA demethylation mediates the effect of Zscan4. Our results define a molecular pathway that contributes to the maintenance of telomere length homeostasis in mESCs.
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•2C-like mESCs show global DNA hypomethylation•Zscan4 is responsible for DNA demethylation in 2C-like mESCs•Zscan4 induces Uhrf1-dependent ubiquitination and degradation of Uhrf1 and Dnmt1•Blocking DNA demethylation prevents Zscan4-mediated telomere elongation
Mouse embryonic stem cells sporadically convert to a transient totipotent (2C-like) state in which shortened telomeres are extended dependent on Zscan4. Dan et al. demonstrate that Zscan4 facilitates telomere elongation by inducing Uhrf1-dependent Uhrf1 and Dnmt1 degradation, leading to global DNA demethylation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Rhythmic breathing is generated by neural circuits located in the brainstem. At its core is the preBötzinger Complex (preBötC), a region of the medulla, necessary for the generation of rhythmic ...breathing in mammals. The preBötC is comprised of various neuronal populations expressing neurokinin-1 receptors, the cognate G-protein-coupled receptor of the neuropeptide substance P (encoded by the tachykinin precursor 1 or
). Neurokinin-1 receptors are highly expressed in the preBötC and destruction or deletion of neurokinin-1 receptor-expressing preBötC neurons severely impairs rhythmic breathing. Although application of substance P to the preBötC stimulates breathing in rodents, substance P is also involved in nociception and locomotion in various brain regions, suggesting that
neurons found in the preBötC may have diverse functional roles. Here, we characterized the role of
-expressing preBötC neurons in the generation of rhythmic breathing
, as well as motor behaviors. Using a cre‑lox recombination approach, we injected adeno-associated virus containing the excitatory channelrhodopsin-2 ChETA in the preBötC region of
-cre mice. Employing a combination of histological, optogenetics, respiratory, and behavioral assays, we showed that stimulation of glutamatergic or
preBötC neurons promoted rhythmic breathing in both anesthetized and freely moving animals, but also triggered locomotion and overcame respiratory depression by opioid drugs. Overall, our study identified a population of excitatory preBötC with major roles in rhythmic breathing and behaviors.
•Thyroid hormones are crucial for normal brain development.•Thyroid hormones are effectors on microglia during development.•Microglial functions in lower brain regions (brainstem) are unknown.•Effect ...of T3 on microglial functions differs between brain areas.•Neurons are necessary for T3-induced microglial motility in the brainstem.
Microglia are critical for the refinement of neural networks that takes place during the perinatal period. Their phenotype and actions are guided by the signals produced by neighbouring cells and hormones present in their surrounding milieu. Cell populations and the signals they produce differ between regions. The fact that thyroid hormones (THs) promote the growth and morphological differentiation of microglia within the cortex contributes to the TH’s powerful actions on the developing brain. The brainstem is especially active during early life owing to its role in generation of the rhythmic respiratory motor command. Despite evidences indicating that THs are necessary to proper development of the neural networks regulating this vital homeostatic function, their actions on microglia originating from the brainstem remain unknown. Using primary cultured microglia from newborn mice (C57BL/6J), we first report that regulation of microglial motility by THs is different between cortex and brainstem. Microglial motility (μm traveled over 3 h) was monitored with or without triiodothyronine (T3, 1μM). Exposure to T3 did not stimulate microglial motility from brainstem, but significantly stimulated (316 %) when they were co-cultured with neurons. Motility of cortex microglia was stimulated to the similar extent either with or without neurons. These data suggest that the microglial function in different regions of the brain is determined by the surrounding environment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recent studies suggest that individual subunits of chromatin-remodeling complexes produce biologically specific meaning in different cell types through combinatorial assembly. Here we show that ...granulocyte development requires SMARCD2, a subunit of ATP-dependent SWI/SNF (BAF) chromatin-remodeling complexes. Smarcd2-deficient mice fail to generate functionally mature neutrophils and eosinophils, a phenotype reminiscent of neutrophil-specific granule deficiency (SGD) in humans, for which loss-of-function mutations in CEBPE (encoding CEBPɛ) have been reported. SMARCD2-containing SWI/SNF complexes are necessary for CEBPɛ transcription factor recruitment to the promoter of neutrophilic secondary granule genes and for granulocyte differentiation. The homologous SMARCD1 protein (63% identical at the amino acid level) cannot replace the role of SMARCD2 in granulocyte development. We find that SMARCD2 functional specificity is conferred by its divergent coiled-coil 1 and SWIB domains. Strikingly, both CEBPE and SMARCD2 loss-of-function mutations identified in patients with SGD abolish the interaction with SWI/SNF and thereby secondary granule gene expression, thus providing a molecular basis for this disease.
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IJS, NUK, SBMB, UL, UM, UPUK
Alcohol-related and alcohol withdrawal (AW) hospitalizations are routinely underestimated in the geriatric population and can have a significant impact on healthcare resource utilization.
To examine ...various patient-characteristics, hospitalization-outcomes, and prevalence of AW related-hospitalizations
In this retrospective study, we examined the objectives mentioned above over a 10-year period (2005 to 2014) using the Nationwide Inpatient Sample (NIS) in adults aged 65 years or older. National estimates of trends for AW prevalence and matched-regression analyses were conducted.
Increased prevalence of hospitalizations for AW was observed (148-cases-per-100,000-discharges in 2005 to 283-cases-per-100,000-discharges in 2014). Of the overall nationwide hospital admissions in patients aged 65 and older (128,111,787), 0.21% (264,786) with documented AW were identified. Of these, those of age 65-74 years accounted for 72.7% of admissions with the highest prevalence amongst males (males accounted for 74%, women 26%) and individuals of Caucasian ethnicity (79.9%).
On comparing AW to Non-AW related-hospitalizations, patients admitted with AW had a higher median length of stay (five vs. four days), more significant functional decline with only 44.2% discharges being discharged home (vs. 47.2%) and 34.4% AW related discharges requiring discharge to skilled nursing facilities (vs. 28.5%). Higher hospitalization costs totaling $4,000 more on bivariate analysis were observed for the AW group.
The prevalence of admissions with AW has increased in the inpatient geriatric population, contributing to increased length of stay, higher hospitalization costs, and greater functional decline. Recognition of these findings and the development of programs supporting older adults with alcohol use disorder may improve patient outcomes.
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DOBA, FSPLJ, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We demonstrate that a beam of x-ray radiation can be generated by simply focusing a single high-intensity laser pulse into a gas jet. A millimeter-scale laser-produced plasma creates, accelerates, ...and wiggles an ultrashort and relativistic electron bunch. As they propagate in the ion channel produced in the wake of the laser pulse, the accelerated electrons undergo betatron oscillations, generating a femtosecond pulse of synchrotron radiation, which has keV energy and lies within a narrow (50 mrad) cone angle.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Mice with experimental nerve damage can display long‑lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length ...(TL) reduction and p53‑mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve injury increased the number of p53‑positive spinal cord neurons, astrocytes, and microglia, but only in microglia was the increase male‑specific, matching a robust sex specificity of TL reduction in this cell type, which has been previously implicated in male‑specific pain processing. Pain hypersensitivity was reversed by repeated intrathecal administration of a p53‑specific senolytic peptide, only in male mice and only many months after injury. Analysis of UK Biobank data revealed sex-specific relevance of this pathway in humans, featuring male‑specific genetic association of the human p53 locus (TP53) with chronic pain and a male-specific effect of chronic pain on mortality. Our findings demonstrate the existence of a biological mechanism maintaining pain behavior, at least in males, occurring much later than the time span of virtually all extant preclinical studies.
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