Phase transitions involving biomolecular liquids are a fundamental mechanism underlying intracellular organization. In the cell nucleus, liquid-liquid phase separation of intrinsically disordered ...proteins (IDPs) is implicated in assembly of the nucleolus, as well as transcriptional clusters, and other nuclear bodies. However, it remains unclear whether and how physical forces associated with nucleation, growth, and wetting of liquid condensates can directly restructure chromatin. Here, we use CasDrop, a novel CRISPR-Cas9-based optogenetic technology, to show that various IDPs phase separate into liquid condensates that mechanically exclude chromatin as they grow and preferentially form in low-density, largely euchromatic regions. A minimal physical model explains how this stiffness sensitivity arises from lower mechanical energy associated with deforming softer genomic regions. Targeted genomic loci can nonetheless be mechanically pulled together through surface tension-driven coalescence. Nuclear condensates may thus function as mechano-active chromatin filters, physically pulling in targeted genomic loci while pushing out non-targeted regions of the neighboring genome.
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•The CasDrop system enables controlled liquid condensation at specific genomic loci•The IDR-driven condensates grow preferentially in regions of low chromatin density•Condensate formation leads to mechanical exclusion of non-targeted chromatin•Condensates pull in targeted genomic loci, serving as mechanical chromatin filters
Nuclear condensates physically pull in targeted genomic loci while excluding non-targeted regions of the neighboring genome.
Defect engineering represents a significant approach for atomically thick 2D semiconductor material development to explore the unique material properties and functions. Doping‐induced conversion of ...conductive polarity is particularly beneficial for optimizing the integration of layered electronics. Here, controllable doping behavior in palladium diselenide (PdSe2) transistor is demonstrated by manipulating its adatom‐vacancy groups. The underlying mechanisms, which originate from reversible adsorption/desorption of oxygen clusters near selenide vacancy defects, are investigated systematically via their dynamic charge transfer characteristics and scanning tunneling microscope analysis. The modulated doping effect allows the PdSe2 transistor to emulate the essential characteristics of photo nociceptor on a device level, including firing signal threshold and sensitization. Interestingly, electrostatic gating, acting as a neuromodulator, can regulate the adaptive modes in nociceptor to improve its adaptability and perceptibility to handle different danger levels. An integrated artificial nociceptor array is also designed to execute unique image processing functions, which suggests a new perspective for extension of the promise of defect engineered 2D electronics in simplified sensory systems toward use in advanced humanoid robots and artificial visual sensors.
Modulable conductive polarity is demonstrated in the PdSe2 ambipolar transistor by Se vacancy‐dominated defect engineering via laser irradiation. It endows the PdSe2 transistor‐based synaptic device with convertible plasticity to emulate the tunable adaptive features in the photo nociceptor, providing a new vista for the defect‐engineered van der Waals electronics to exploit novel applications toward advanced artificial intelligent machines.
Complementary circuits based on 2D materials show great promise for next‐generation electronics. An ambipolar all‐2D ReSe2 field‐effect transistor (FET) with a hexagonal boron nitride gate dielectric ...is fabricated and its electronic characteristics are comprehensively studied by temperature dependence and noise measurements. Ambipolar transfer characteristics are achieved owing to the tunable Fermi level of the graphene contact and negligible and 30 meV Schottky barrier heights for the n‐ and p‐channel regimes, respectively. An inverter is also fabricated to demonstrate ambipolar ReSe2 FET operation in a logic circuit. Furthermore, a p/n switchable unipolar FET is designed and shows potential for building complimentary circuits from a signal device. This work demonstrates the potential of all‐2D ReSe2 FETs and makes available new approaches for designing next‐generation devices.
An all‐2D ReSe2 field‐effect transistor (FET) with graphene contact, which enables switching between n‐ and p‐type behaviors, is fabricated. The transport mechanism is comprehensively studied through both temperature dependence and noise measurements. A “single‐device” ambipolar ReSe2 FET is further applied to build an inverter function. This work demonstrates the promise of all‐2D materials‐based ambipolar FET for analog circuit applications.
To determine the association of prior traumatic brain injury (TBI) with subsequent diagnosis of neurodegeneration disease.
All studies from 1980 to 2016 reporting TBI as a risk factor for diagnoses ...of interest were identified by searching PubMed, Embase, study references, and review articles. The data and study design were assessed by 2 investigators independently. A meta-analysis was performed by RevMan 5.3.
There were 18 studies comprising 3,263,207 patients. Meta-analysis revealed a significant association of prior TBI with subsequent dementia. The pooled odds ratio (OR) for TBI on development of dementia, FTD and TDP-43 associated disease were 1.93 (95% CI 1.47-2.55, p < 0.001), 4.44 (95% CI 3.86-5.10, p < 0.001), and 2.97 (95% CI 1.35-6.53, p < 0.001). However, analyses of individual diagnoses found no evidence that the risk of Alzheimer's disease, and Parkinson's disease in individuals with previous TBI compared to those without TBI.
History of TBI is not associated with the development of subsequent neurodegeneration disease. Care must be taken in extrapolating from these results because no suitable criteria define post TBI neurodegenerative processes. Therefore, further research in this area is needed to confirm these questions and uncover the link between TBI and neurodegeneration disease.
The human brain is often likened to an incredibly complex and intricate computer, rather than electrical devices, consisting of billions of neuronal cells connected by synapses. Different brain ...circuits are responsible for coordinating and performing specific functions. The reward pathway of the synaptic plasticity in the brain is strongly related to the features of both drug addiction and relief. In the current study, a synaptic device based on layered hafnium disulfide (HfS2) is developed for the first time, to emulate the behavioral mechanisms of drug dosage modulation for neuroplasticity. A strong gate‐dependent persistent photocurrent is observed, arising from the modulation of substrate‐trapping events. By controlling the polarity of gate voltage, the basic functions of biological synapses are realized under a range of light spiking conditions. Furthermore, under the control of detrapping/trapping events at the HfS2/SiO2 interface, positive/negative correlations of the An/A1 index, which significantly reflected the weight change of synaptic plasticity, are realized under the same stimulation conditions for the emulation of the drug‐related addition/relief behaviors in the brain. The findings provide a new advance for mimicking human brain plasticity.
In this study, controlling the polarity of gate field, positive/negative correlations of the An/A1 index arising from the substrate‐trapping events, reflected the weight change of neuroplasticity, are realized under the same stimulations for the emulation of drug‐dosage‐related addition/relief behaviors in brain (where A1 and An represent the postsynaptic responses triggered by the 1st and nth input spikes, respectively).
The amplitude modulated (AM) neural oscillation is an essential feature of neural dynamics to coordinate distant brain areas. The AM transcranial alternating current stimulation (tACS) has recently ...been adopted to examine various cognitive functions, but its neural mechanism remains unclear. The current study utilized the phosphene phenomenon to investigate whether, in an AM‐tACS, the AM frequency could modulate or even override the carrier frequency in phosphene percept. We measured the phosphene threshold and the perceived flash rate/pattern from 12 human subjects (four females, aged from 20–44 years old) under tACS that paired carrier waves (10, 14, 18, 22 Hz) with different envelope conditions (0, 2, 4 Hz) over the mid‐occipital and left facial areas. We also examined the phosphene source by adopting a high‐density stimulation montage. Our results revealed that (1) phosphene threshold was higher for AM‐tACS than sinusoidal tACS and demonstrated different carrier frequency functions in two stimulation montages. (2) AM‐tACS slowed down the phosphene flashing and abolished the relation between the carrier frequency and flash percept in sinusoidal tACS. This effect was independent of the intensity change of the stimulation. (3) Left facial stimulation elicited phosphene in the upper‐left visual field, while occipital stimulation elicited equally distributed phosphene. (4) The near‐eye electrodermal activity (EDA) measured under the threshold‐level occipital tACS was greater than the lowest power sufficient to elicit retinal phosphene. Our results show that AM frequency may override the carrier frequency and determine the perceived flashing frequency of AM‐tACS‐induced phosphene.
The current study examined the effect of amplitude‐modulated tACS on phosphene perception. The results showed that the amplitude‐modulating frequency increased the phosphene threshold and overrode the carrier frequency by changing the frequency function of flashing perception. This study, therefore, suggests amplitude modulation as a critical neural cross‐frequency‐coupling format in visual perception.
Aims
Spindle cell/sclerosing rhabdomyosarcomas (SC/SRMS) feature spindled and/or rounded rhabdomyosarcomatous cells within variably hyalinised stroma. Only 30–67% of SC/SRMSs harbour neomorphic MYOD1 ...p.L122R mutations, indicating heterogeneity in this RMS type. We compared MYOD1‐mutant and non‐mutant cases to characterise the histological and genetic spectrum of mutated SC/SRMS.
Methods and results
Seventeen RMSs with spindled, sclerosing or hybrid histology were sequenced to identify MYOD1 and PIK3CA mutations and reappraised to assess histological features and myogenic immunophenotypes. Twelve SC/SRMSs harboured MYOD1 mutations, including homozygous p.L122R (n = 8), heterozygous p.L122R (n = 3) and heterozygous p.E118K (n = 1). MYOD1‐mutant tumours affected nine females and three males aged 8–64 years (median = 22.5), had a median size of 4.2 cm (range = 2–22) and involved the head and neck (n = 7), extremities (n = 4) and mediastinum (n = 1). Fascicular/spindle histology was predominant in four cases, including one with heterologous lipoblasts in focally myxoid stroma. Four sclerosing cases mainly comprised rounded cells, including one with multinucleated tumour cells. Four cases were histologically hybrid. The only PIK3CA (p.H1047R) mutation was detected in a predominantly spindled MYOD1‐p.L122R‐mutated case, but not in its laser‐microdissected lipoblast‐containing area. All MYOD1‐mutant cases exhibited diffuse MYOD1 expression but patchy myogenin reactivity. At final follow‐up (median = 13.5 months), recurrences (n = 4), metastases (n = 2) or both (n = 1) occurred in seven MYOD1‐mutant cases; one had died of disease. Five non‐mutated cases were reclassified as spindle embryonal (n = 3), dense embryonal (n = 1) and unclassifiable (n = 1) RMSs.
Conclusion
MYOD1‐mutant RMSs are uncommonly mutated with PIK3CA and behave aggressively with an expanded morphological and genetic spectrum, including lipoblastic differentiation, multinucleated cells and the alternative p.E118K mutation.
The treatment of cancer cells obtained by blocking cellular metabolism has received a lot of attention recently. Previous studies have demonstrated that Kras mutation-mediated abnormal glucose ...metabolism would lead to an aberrant cell proliferation in human pancreatic ductal adenocarcinoma (PDAC) cells. Previous literature has suggested that consumption of fish oil is associated with lower risk of pancreatic cancer. In this study, we investigated the anti-cancer effects of docosahexaenoic acid (DHA) in human PDAC cells in vitro and in vivo. Omega-3 polyunsaturated fatty acids (PUFAs) such as DHA and eicosapentaenoic acid (EPA) significantly inhibited the proliferation of human PDAC cells. The actions of DHA were evaluated through an induction of cell cycle arrest at G1 phase and noticed a decreased expression of cyclin A, cyclin E and cyclin B proteins in HPAF-II cells. Moreover, it was found that co-treatment of DHA and gemcitabine (GEM) effectively induced oxidative stress and cell death in HPAF-II cells. Interestingly, DHA leads to an increased oxidative glutathione /reduced glutathione (GSSG/GSH) ratio and induced cell apoptosis in HPAF-II cells. The findings in the study showed that supplementation of GSH or N-Acetyl Cysteine (NAC) could reverse DHA-mediated cell death in HPAF-II cells. Additionally, DHA significantly increased cellular level of cysteine, cellular NADP/NADPH ratio and the expression of cystathionase (CTH) and SLCA11/xCT antiporter proteins in HPAF-II cells. The action of DHA was, in part, associated with the inactivation of STAT3 cascade in HPAF-II cells. Treatment with xCT inhibitors, such as erastin or sulfasalazine (SSZ), inhibited the cell survival ability in DHA-treated HPAF-II cells. DHA also inhibited nucleotide synthesis in HPAF-II cells. It was demonstrated in a mouse-xenograft model that consumption of fish oil significantly inhibited the growth of pancreatic adenocarcinoma and decreased cellular nucleotide level in tumor tissues. Furthermore, fish oil consumption induced an increment of GSSG/GSH ratio, an upregulation of xCT and CTH proteins in tumor tissues. In conclusion, DHA significantly inhibited survival of PDAC cells both in vitro and in vivo through its recently identified novel mode of action, including an increment in the ratio of GSSG/GSH and NADP/NADPH respectively, and promoting reduction in the levels of nucleotide synthesis.
Urothelial carcinoma of the bladder (UCB) is the second most common genitourinary cancer. This study aims to assess the diagnostic accuracy of CA125 in advanced UCB.
We searched prevalent studies in ...PubMed, the Cochrane Library, Scopus, Embase, the Web of Science China National Knowledge Infrastructure database, and Wanfang data before October 2022. Pooled sensitivity, specificity, and summary receiver operating characteristics were used to assess the diagnostic value of CA125.
One thousand six hundred forty-one patients from 14 studies were analyzed. UCB stage T3-4N1 was defined as advanced UCB in ten studies; T2-4 was used in three studies; and N1M1 in one study. Patients' age was between 21 to 92, and 21% to 48.6% of patients were female. The pooled sensitivity was 0.695 (95% confidence interval (CI): 0.426-0.875). The pooled specificity was 0.846 (95% CI: 0.713-0.924). The diagnostic odds ratio was 8.138 (95% CI: 4.559-14.526). The AUC was 0.797.
CA125 may provide significant diagnostic accuracy in identifying muscle-invasive, lymph node-involved, and distant metastatic tumors in patients with urothelial carcinoma of the bladder. Limited studies have been conducted on the prognostic role of CA125. More studies are needed for a meta-analysis on the prognostic role of CA125 in UCB.
Cytomegalovirus (CMV) can cause infection and critical diseases in hematopoietic stem cell transplantation (HSCT) recipients. This study aimed to explore the cumulative incidence and risk factors for ...CMV infection and disease among HSCT recipients in Taiwan.
This retrospective cohort study using the Taiwan Blood and Marrow Transplantation Registry (TBMTR) included HSCT recipients between 2009 and 2018 in Taiwan. The primary outcome was cumulative incidence of CMV infection or disease at day 100 after HSCT. Secondary outcomes included day 180 cumulative incidence of CMV infection or disease, infection sites, risk factors for CMV infection or disease, survival analysis, and overall survival after CMV infection and disease.
There were 4394 HSCT recipients included in the study (2044 auto-HSCT and 2350 allo-HSCT). The cumulative incidence of CMV infection and disease was significantly higher in allo-HSCT than in auto-HSCT patients at day 100 (53.7% vs. 6.0%, P < 0.0001 and 6.1% vs. 0.9%, P < 0.0001). Use of ATG (HR 1.819, p < 0.0001), recipient CMV serostatus positive (HR 2.631, p < 0.0001) and acute GVHD grades ≥ II (HR 1.563, p < 0.0001) were risk factors for CMV infection, while matched donor (HR 0.856, p = 0.0180) and myeloablative conditioning (MAC) (HR 0.674, p < 0.0001) were protective factors.
The study revealed a significant disparity in terms of the incidence, risk factors, and clinical outcomes of CMV infection and disease between auto and allo-HSCT patients. These findings underscore the importance of considering these factors in the management of HSCT recipients to improve outcomes related to CMV infections.
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