Diverse roles of pontine NPS-expressing neurons in sleep regulation.

Neuropeptide S (NPS) was postulated to be a wake-promoting neuropeptide with unknown mechanism, and a mutation in its receptor (NPSR1) causes the short sleep duration trait in humans. We investigated the role of different NPS+ nuclei in sleep/wake regulation. Loss-of-function and chemogenetic studies revealed that NPS+ neurons in the parabrachial nucleus (PB) are wake-promoting, whereas peri-locus coeruleus (peri-LC) NPS+ neurons are not important for sleep/wake modulation. Further, we found that a NPS+ nucleus in the central gray of the pons (CGPn) strongly promotes sleep. Fiber photometry recordings showed that NPS+ neurons are wake-active in the CGPn and wake/REM-sleep active in the PB and peri-LC. Blocking NPS-NPSR1 signaling or knockdown of Nps supported the function of the NPS-NPSR1 pathway in sleep/wake regulation. Together, these results reveal that NPS and NPS+ neurons play dichotomous roles in sleep/wake regulation at both the molecular and circuit levels.

An excitatory peri-tegmental reticular nucleus circuit for wake maintenance.

Sleep is a necessity for our survival, but its regulation remains incompletely understood. Here, we used a human sleep duration gene to identify a population of cells in the peri-tegmental reticular nucleus (pTRNADRB1) that regulate sleep-wake, uncovering a role for a poorly understood brain area. Although initial ablation in mice led to increased wakefulness, further validation revealed that pTRNADRB1 neuron stimulation strongly promotes wakefulness, even after stimulation offset. Using combinatorial genetics, we found that excitatory pTRNADRB1 neurons promote wakefulness. pTRN neurons can be characterized as anterior- or posterior-projecting neurons based on multiplexed analysis of projections by sequencing (MAPseq) analysis. Finally, we found that pTRNADRB1 neurons promote wakefulness, in part, through projections to the lateral hypothalamus. Thus, human genetic information from a human sleep trait allowed us to identify a role for the pTRN in sleep-wake regulation.

Selection on Visual Opsin Genes in Diurnal Neotropical Frogs and Loss of the SWS2 Opsin in Poison Frogs.

Amphibians are ideal for studying visual system evolution because their biphasic (aquatic and terrestrial) life history and ecological diversity expose them to a broad range of visual conditions. Here, we evaluate signatures of selection on visual opsin genes across Neotropical anurans and focus on three diurnal clades that are well-known for the concurrence of conspicuous colors and chemical defense (i.e., aposematism): poison frogs (Dendrobatidae), Harlequin toads (Bufonidae: Atelopus), and pumpkin toadlets (Brachycephalidae: Brachycephalus). We found evidence of positive selection on 44 amino acid sites in LWS, SWS1, SWS2, and RH1 opsin genes, of which one in LWS and two in RH1 have been previously identified as spectral tuning sites in other vertebrates. Given that anurans have mostly nocturnal habits, the patterns of selection revealed new sites that might be important in spectral tuning for frogs, potentially for adaptation to diurnal habits and for color-based intraspecific communication. Furthermore, we provide evidence that SWS2, normally expressed in rod cells in frogs and some salamanders, has likely been lost in the ancestor of Dendrobatidae, suggesting that under low-light levels, dendrobatids have inferior wavelength discrimination compared to other frogs. This loss might follow the origin of diurnal activity in dendrobatids and could have implications for their behavior. Our analyses show that assessments of opsin diversification in across taxa could expand our understanding of the role of sensory system evolution in ecological adaptation.

Reclaiming the Lost Conformality in a Non-Hermitian Quantum 5-State Potts Model.

Conformal symmetry, emerging at critical points, can be lost when renormalization group fixed points collide. Recently, it was proposed that after collisions, real fixed points transition into the complex plane, becoming complex fixed points described by complex conformal field theories (CFTs). Although this idea is compelling, directly demonstrating such complex conformal fixed points in microscopic models remains highly demanding. Furthermore, these concrete models are instrumental in unraveling the mysteries of complex CFTs and illuminating a variety of intriguing physical problems, including weakly first-order transitions in statistical mechanics and the conformal window of gauge theories. In this work, we have successfully addressed this complex challenge for the (1+1)-dimensional quantum 5-state Potts model, whose phase transition has long been known to be weakly first order. By adding an additional non-Hermitian interaction, we successfully identify two conjugate critical points located in the complex parameter space, where the lost conformality is restored in a complex manner. Specifically, we unambiguously demonstrate the radial quantization of the complex CFTs and compute the operator spectrum, as well as new operator product expansion coefficients that were previously unknown.

Floquet Flux Attachment in Cold Atomic Systems.

Flux attachment provides a powerful conceptual framework for understanding certain forms of topological order, including most notably the fractional quantum Hall effect. Despite its ubiquitous use as a theoretical tool, directly realizing flux attachment in a microscopic setting remains an open challenge. Here, we propose a simple approach to realizing flux attachment in a periodically driven (Floquet) system of either spins or hard-core bosons. We demonstrate that such a system naturally realizes correlated hopping interactions and provides a sharp connection between such interactions and flux attachment. Starting with a simple, nearest-neighbor, free boson model, we find evidence-from both a coupled-wire analysis and large-scale density matrix renormalization group simulations-that Floquet flux attachment stabilizes the bosonic integer quantum Hall state at 1/4 filling (on a square lattice), and the Halperin-221 fractional quantum Hall state at 1/6 filling (on a honeycomb lattice). At 1/2 filling on the square lattice, time-reversal symmetry is instead spontaneously broken and bosonic integer quantum Hall states with opposite Hall conductances are degenerate. Finally, we propose an optical-lattice-based implementation of our model on a square lattice and discuss prospects for adiabatic preparation as well as effects of Floquet heating.

Non-invasive prediction of the chronic degree of lupus nephropathy based on ultrasound radiomics.

OBJECTIVE: Through machine learning (ML) analysis of the radiomics features of ultrasound extracted from patients with lupus nephritis (LN), this attempt was made to non-invasively predict the chronicity index (CI)of LN. METHODS: A retrospective collection of 136 patients with LN who had renal biopsy was retrospectively collected, and the patients were randomly divided into training set and validation set according to 7:3. Radiomics features are extracted from ultrasound images, independent factors are obtained by using LASSO dimensionality reduction, and then seven ML models were used to establish predictive models. At the same time, a clinical model and an US model were established. The diagnostic efficacy of the model is evaluated by analysis of the receiver operating characteristics (ROC) curve, accuracy, specificity, and sensitivity. The performance of the seven machine learning models was compared with each other and with clinical and US models. RESULTS: A total of 1314 radiomics features are extracted from ultrasound images, and 5 features are finally screened out by LASSO for model construction, and the average ROC of the seven ML is 0.683, among which the Xgboost model performed the best, and the AUC in the test set is 0.826 (95% CI: 0.681-0.936). For the same test set, the AUC of clinical model constructed based on eGFR is 0.560 (95% CI: 0.357-0.761), and the AUC of US model constructed based on Ultrasound parameters is 0.679 (95% CI: 0.489-0.853). The Xgboost model is significantly more efficient than the clinical and US models. CONCLUSION: ML model based on ultrasound radiomics features can accurately predict the chronic degree of LN, which can provide a valuable reference for clinicians in the treatment strategy of LN patients.

Clinical features and immune memory of breakthrough infection in children after age-appropriate 13-valent pneumococcal conjugate vaccination in Taiwan.

PURPOSE: As certain vaccine serotypes are still circulating within the community during the PCV13 era, we aimed to delineate the clinical features and assess the immunity following breakthrough infections in children. METHODS: 101 PCVs-vaccinated children < 18 years with culture confirmed PCV13 serotype breakthrough infection (25/101, invasive pneumococcal disease [IPD]) was identified in Taiwan in 2015-2019. Immunoglobulin G (IgG) antibody levels, IgM+ memory B cells (MBCs), and isotype-switched immunoglobulin (sIg+) MBC specific to serotypes 3, 14, 19 A were assessed prior to and one month after an additional PCV13 booster in 9 patients. A cohort of 89 previously vaccinated, healthy children were enrolled as controls. RESULTS: The majority (88%) of the breakthrough infection occurred in children under 7 years old. Infection by serotypes 3 and 19 A increased in children aged 5-17 years in 2018-2019. The pre-booster serotype 3- and 19 A-specific IgG in both children with breakthrough infection and controls were lower than the IPD protective thresholds (2.83 µg/mL for 3; 1.00 µg/mL for 19 A). Breakthrough infected children showed higher geometric mean ratio in serotype-specific IgG, IgM+ MBCs and sIg+ MBC after an additional PCV13 booster, compared to the controls. CONCLUSIONS: Most breakthrough infections occurred in previously healthy preschool-aged children, but such infections may still occur in school-aged children due to waning immunity. Breakthrough infections may also enhance the anamnestic response elicited by PCV13.

Interpretable machine learning model for new-onset atrial fibrillation prediction in critically ill patients: a multi-center study.

BACKGROUND: New-onset atrial fibrillation (NOAF) is the most common arrhythmia in critically ill patients admitted to intensive care and is associated with poor prognosis and disease burden. Identifying high-risk individuals early is crucial. This study aims to create and validate a NOAF prediction model for critically ill patients using machine learning (ML). METHODS: The data came from two non-overlapping datasets from the Medical Information Mart for Intensive Care (MIMIC), with MIMIC-IV used for training and subset of MIMIC-III used as external validation. LASSO regression was used for feature selection. Eight ML algorithms were employed to construct the prediction model. Model performance was evaluated based on identification, calibration, and clinical application. The SHapley Additive exPlanations (SHAP) method was used for visualizing model characteristics and individual case predictions. RESULTS: Among 16,528 MIMIC-IV patients, 1520 (9.2%) developed AF post-ICU admission. A model with 23 variables was built, with XGBoost performing best, achieving an AUC of 0.891 (0.873-0.888) in validation and 0.769 (0.756-0.782) in external validation. Key predictors included age, mechanical ventilation, urine output, sepsis, blood urea nitrogen, percutaneous arterial oxygen saturation, continuous renal replacement therapy and weight. A risk probability greater than 0.6 was defined as high risk. A friendly user interface had been developed for clinician use. CONCLUSION: We developed a ML model to predict the risk of NOAF in critically ill patients without cardiac surgery and validated its potential as a clinically reliable tool. SHAP improves the interpretability of the model, enables clinicians to better understand the causes of NOAF, helps clinicians to prevent it in advance and improves patient outcomes.

Operator Product Expansion Coefficients of the 3D Ising Criticality via Quantum Fuzzy Spheres.

Conformal field theory (CFT) plays a crucial role in the study of various critical phenomena. While much attention has been paid to the critical exponents of different universalities, which correspond to the conformal dimensions of CFT primary fields, other important and intricate data such as operator product expansion (OPE) coefficients governing the fusion of two primary fields, have remained largely unexplored, especially in dimensions higher than 2D (or equivalently, 1+1D). Motivated by the recently proposed fuzzy sphere regularization, we investigate the operator content of 3D Ising criticality from a microscopic perspective. We first outline the procedure for extracting OPE coefficients on the fuzzy sphere and then compute 13 OPE coefficients of low-lying CFT primary fields. Our results are highly accurate and in agreement with the numerical conformal bootstrap data of 3D Ising CFT. Moreover, we were able to obtain 4 OPE coefficients, including f_{T_{µν}T_{ρη}ε}, which were previously unknown, thus demonstrating the superior capabilities of our scheme. Expanding the horizon of the fuzzy sphere regularization from the state perspective to the operator perspective opens up new avenues for exploring a wealth of new physics.

Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) associated with TAR DNA-binding protein 43 (TDP-43) aggregation has been considered as a lethal and progressive motor neuron disease. Recent studies have shown that both C-terminal TDP-43 (C-TDP-43) aggregates and oligomers were neurotoxic and pathologic agents in ALS and frontotemporal lobar degeneration (FTLD). However, misfolding protein has long been considered as an undruggable target by applying conventional inhibitors, agonists, or antagonists. To provide this unmet medical need, we aim to degrade these misfolding proteins by designing a series of proteolysis targeting chimeras (PROTACs) against C-TDP-43. METHODS: By applying filter trap assay, western blotting, and microscopy imaging, the degradation efficiency of C-TDP-43 aggregates was studied in Neuro-2a cells overexpressing eGFP-C-TDP-43 or mCherry-C-TDP-43. The cell viability was characterized by alarmarBlue assay. The beneficial and disaggregating effects of TDP-43 PROTAC were examined with the YFP-C-TDP-43 transgenic C. elegans by motility assay and confocal microscopy. The impact of TDP-43 PROTAC on C-TDP-43 oligomeric intermediates was monitored by fluorescence lifetime imaging microscopy and size exclusion chromatography in the Neuro-2a cells co-expressing eGFP-C-TDP-43 and mCherry-C-TDP-43. RESULTS: Four PROTACs with different linker lengths were synthesized and characterized. Among these chimeras, PROTAC 2 decreased C-TDP-43 aggregates and relieved C-TDP-43-induced cytotoxicity in Neuro-2a cells without affecting endogenous TDP-43. We showed that PROTAC 2 bound to C-TDP-43 aggregates and E3 ligase to initiate ubiquitination and proteolytic degradation. By applying advanced microscopy, it was further shown that PROTAC 2 decreased the compactness and population of C-TDP-43 oligomers. In addition to cellular model, PROTAC 2 also improved the motility of transgenic C. elegans by reducing the C-TDP-43 aggregates in the nervous system. CONCLUSIONS: Our study demonstrated the dual-targeting capacity of the newly-designed PROTAC 2 against both C-TDP-43 aggregates and oligomers to reduce their neurotoxicity, which shed light on the potential drug development for ALS as well as other neurodegenerative diseases.

Predictors of technical success of percutaneous transhepatic common bile duct stone removal: is it only a matter of stone size?

OBJECTIVES: The common practice is to remove symptomatic common bile duct (CBD) stones in patients. This study aimed to investigate the factors affecting the percutaneous transhepatic removal of CBD stones. METHODS: We retrospectively analyzed the data of 100 patients (66 men and 34 women; age: 25-105 years, mean 79.1 years) with symptomatic CBD stones who underwent percutaneous transhepatic stone removal (PTSR) from January 2010 through October 2019. After balloon dilation of the ampulla of Vater or bilioenteric anastomosis, the stones were pushed out of the CBD into the small bowel with a balloon catheter. If failed, basket lithotripsy was performed. Technical success was defined as complete clearance of the bile ducts on a cholangiogram. RESULTS: The technical success rate was 83%, and achieved 90.2% in patients with altered gastroduodenal/pancreatobiliary anatomy. Multivariable analysis revealed that CBD diameter (odds ratio [OR]: 506.460, p = 0.015), failed ERCP (OR: 16.509, p = 0.004), Tokyo guidelines TG18/TG13 severity (grade III; OR: 60.467, p = 0.006), and left-sided transhepatic approach (OR: 21.621, p = 0.012) were risk factors for technical failure. The appropriate cutoff CBD size was 15.5 mm (area under the curve: 0.91). CBD stone size, radiopacity of stones, and CBD angle between retroduodenal and pancreatic portion did not influence technical success. CONCLUSIONS: PTSR is effective for CBD stone removal in older adults and individuals with altered gastrointestinal tract anatomy. The aforementioned risk factors for technical failure should be considered in preoperative evaluation before PTSR to improve the success rate. KEY POINTS: • PTSR is effective in symptomatic CBD stone management among older adults and individuals with altered anatomy. Investigating clinical /anatomic factors can guide radiologists toward a more comprehensive preoperative evaluation to maximize the success rate. • Our data indicate that dilated CBD (diameter ≥ 15.5 mm) and left-sided PTBDs reduce the technical success rate by 506-fold and 22-fold, respectively. • Clinical factors such as previous failed ERCP for stone removal and higher severity of acute cholangitis lessen the technical success rate.

One-Shot Synthesis of B/N-Doped Calix[4]arene Exhibiting Narrowband Multiple Resonance Fluorescence.

A novel macrocycle of B/N-doped calix[4]arene (C-BN) was synthesized by a one-shot double boronation. Owing to the structural tension and electron-donating properties of the nitrogen atoms in the macrocycle, reaction selectively proceeds between the adjacent benzene rings outside the macrocycle. C-BN shows a highly centrosymmetric structure with two multiple resonance (MR) fragments bridged by tertiary amine groups at the 1,3 positions of the benzene ring. Benefiting from the large intermolecular distance (>4.6 Å) between adjacent MR-emitting cores, C-BN also exhibits excellent narrowband emitting features against aggregation-induced quenching and spectrum broadening. Optimized organic light-emitting diode devices based on C-BN exhibit high maximum external quantum efficiencies of 24.7-26.6 % and small full width at half maximums of 25-28 nm over a wide doping range of 1-12 wt %.

Sterically Wrapped Multiple Resonance Fluorophors for Suppression of Concentration Quenching and Spectrum Broadening.

Multiple resonance (MR) emitters are promising for highly efficient organic light-emitting diodes (OLEDs) with narrowband emission; however, they still face intractable challenges with concentration-caused emission quenching, exciton annihilation, and spectral broadening. In this study, sterically wrapped MR dopants with a fluorescent MR core sandwiched by bulk substituents were developed to address the intractable challenges by reducing intermolecular interactions. Consequently, high photo-luminance quantum yields of ≥90 % and small full width at half maximums (FWHMs) of ≤25 nm over a wide range of dopant concentrations (1-20 wt %) were recorded. In addition, we demonstrated that the sandwiched MR emitter can effectively suppress Dexter interaction when doped in a thermally activated delayed fluorescence sensitizer, eliminating exciton loss through dopant triplet. Within the above dopant concentration range, the optimal emitter realizes remarkably high maximum external quantum efficiencies of 36.3-37.2 %, identical small FWHMs of 24 nm, and alleviated efficiency roll-offs in OLEDs.

Amine-Directed Formation of B-N Bonds for BN-Fused Polycyclic Aromatic Multiple Resonance Emitters with Narrowband Emission.

Despite the remarkable multiple resonance (MR) optoelectronic properties of organic nanographenes with boron and nitrogen atoms disposed para to each other, the synthetic procedures are sophisticated with low yields and the molecular skeletons are limited. Here, a new paradigm of easy-to-access MR emitter is constructed by simplifying the multiborylation through amine-directed formation of B-N bonds while introducing an additional para-positioned nitrogen atom to trigger the MR effect. The proof-of-concept molecules exhibit narrowband emissions at 480 and 490 nm, with full width at half maxima (FWHMs) of only 29 and 34 nm. The devices based on them showed external quantum efficiencies (EQE) of >33.0 %, which remained above 24.0 % even at a high brightness of 5000 cd m-2 . This is the first example of MR emitters with a B-N covalent bond, not only decreasing the synthesis difficulty but also increasing the diversity of MR skeletons for emerging new optoelectronic properties.

[Formula: see text]: ComplexOme-Structural Network Interpreter used to study spatial enrichment in metazoan ribosomes.

BACKGROUND: Upon environmental stimuli, ribosomes are surmised to undergo compositional rearrangements due to abundance changes among proteins assembled into the complex, leading to modulated structural and functional characteristics. Here, we present the ComplexOme-Structural Network Interpreter ([Formula: see text]), a computational method to allow testing whether ribosomal proteins (rProteins) that exhibit abundance changes under specific conditions are spatially confined to particular regions within the large ribosomal complex. RESULTS: [Formula: see text] translates experimentally determined structures into graphs, with nodes representing proteins and edges the spatial proximity between them. In its first implementation, [Formula: see text] considers rProteins and ignores rRNA and other objects. Spatial regions are defined using a random walk with restart methodology, followed by a procedure to obtain a minimum set of regions that cover all proteins in the complex. Structural coherence is achieved by applying weights to the edges reflecting the physical proximity between purportedly contacting proteins. The weighting probabilistically guides the random-walk path trajectory. Parameter tuning during region selection provides the option to tailor the method to specific biological questions by yielding regions of different sizes with minimum overlaps. In addition, other graph community detection algorithms may be used for the [Formula: see text] workflow, considering that they yield different sized, non-overlapping regions. All tested algorithms result in the same node kernels under equivalent regions. Based on the defined regions, available abundance change information of proteins is mapped onto the graph and subsequently tested for enrichment in any of the defined spatial regions. We applied [Formula: see text] to the cytosolic ribosome structures of Saccharomyces cerevisiae, Oryctolagus cuniculus, and Triticum aestivum using datasets with available quantitative protein abundance change information. We found that in yeast, substoichiometric rProteins depleted from translating polysomes are significantly constrained to a ribosomal region close to the tRNA entry and exit sites. CONCLUSIONS: [Formula: see text] offers a computational method to partition multi-protein complexes into structural regions and a statistical approach to test for spatial enrichments of any given subsets of proteins. [Formula: see text] is applicable to any multi-protein complex given appropriate structural and abundance-change data. [Formula: see text] is publicly available as a GitHub repository https://github.com/MSeidelFed/COSNet_i and can be installed using the python installer pip.

Early prediction of 1-year tumor response of hepatocellular carcinoma with lipiodol deposition pattern through post-embolization cone-beam computed tomography during conventional transarterial chemoembolization.

OBJECTIVE: To evaluate whether parenchyma-to-lipiodol ratio (PLR) and lesion-to-lipiodol ratio (LLR) on C-arm cone-beam computed tomography (CBCT) can predict 1-year tumor response in patients with hepatocellular carcinoma (HCC) treated with conventional transcatheter arterial chemoembolization (cTACE). METHODS: This retrospective analysis included 221 HCC target lesions within up-to-seven criteria in 80 patients who underwent cTACE with arterial-phase CBCT and unenhanced CBCT after cTACE from 2015 to 2018. PLR and LLR of every tumor slice were obtained through mean density division of liver parenchyma and tumor enhancement with intratumoral lipiodol deposition. The cutoff values (COVs) of maximal PLR and LLR of every tumor were analyzed using Youden's index. The reliability of COV, correlations between the related parameters, and 1-year progression were assessed through interobserver agreement and multivariate analysis. COV validity was verified using the chi-square test and Cramer's V coefficient (V) in the validation cohort. RESULTS: Standard COVs of PLR and LLR were 0.149 and 1.4872, respectively. Interobserver agreement of COV for PLR and LLR was near perfect (kappa > 0.9). Multivariate analysis suggested that COV of PLR is an independent predictor (odds ratio = 1.23532×1014, p = 4.37×10-7). COV of PLR showed strong consistency, correlation with 1-year progression in prediction model (V = 0.829-0.776; p < 0.0001), and presented as an effective predictor in the validation cohort (V = 0.766; p < 0.0001). CONCLUSION: The COV of PLR (0.149) assessed through immediate post-embolization CBCT is an objective, effective, and approachable predictor of 1-year HCC progression after cTACE. KEY POINTS: • The maximal PLR value indicates the least lipiodol-distributed region in an HCC tumor. The maximal LLR value indicates the least lipiodol-deposited region in the tumor due to incomplete lipiodol delivery. PLR and LLR are concepts like signal-to-noise ratio to characterize the lipiodol retention pattern objectively to predict 1-year tumor progression immediately without any quantification software for 3D image analysis immediately after cTACE treatment. • COV of PLR can facilitate the early prediction of tumor progression/recurrence and indicate the section of embolized HCC, providing the operator's good targets for sequential cTACE or combined ablation. • The validation cohort in our study verified standard COVs of PLR and LLR. The validation process was more convincing and delicate than that of previous retrospective studies.

Genistein enhances the effects of L-asparaginase on inducing cell apoptosis in human leukemia cancer HL-60 cells.

Genistein (GEN) has been shown to induce apoptotic cell death in various human cancer cells. L-asparaginase (Asp), a clinical drug for leukemia, has been shown to induce cell apoptosis in leukemia cells. No available information concerning GEN combined with Asp increased the cell apoptosis compared to GEN or Asp treatment alone. The objective of this study is to evaluate the anti-leukemia activity of GEN combined with Asp on human leukemia HL-60 cells in vitro. The cell viability, the distribution of cell cycle, apoptotic cell death, and the level of ΔΨm were examined by flow cytometric assay. The expressions of apoptosis-associated proteins were measured by western blotting. GEN combined with Asp revealed a more significant decrease in total viable cells and induced a higher percentage of G2/M phase arrest, DNA damage, and cell apoptosis than that of GEN or Asp treatment only in HL-60 cells. Furthermore, the combined treatments (GEN and Asp) showed a higher decrease in the level of ΔΨm than that of GEN or Asp treatment only. These results indicated that GEN combined with Asp induced mitochondria dysfunction by disrupting the mitochondrial membrane potential. The results from western blotting demonstrated that the treatment of GEN combined with Asp showed a higher increase in the levels of Bax and Bak (pro-apoptotic proteins) and an active form of caspase-3 and a higher decrease in Bcl-2 (anti-apoptotic protein) than that of GEN or Asp treatment alone. GEN significantly enhances the efficiency of Asp on cytotoxic effects (the induction of apoptosis) in HL-60 cells.

Characterization of the Survival Influential Genes in Carcinogenesis.

The genes influencing cancer patient mortality have been studied by survival analysis for many years. However, most studies utilized them only to support their findings associated with patient prognosis: their roles in carcinogenesis have not yet been revealed. Herein, we applied an in silico approach, integrating the Cox regression model with effect size estimated by the Monte Carlo algorithm, to screen survival-influential genes in more than 6000 tumor samples across 16 cancer types. We observed that the survival-influential genes had cancer-dependent properties. Moreover, the functional modules formed by the harmful genes were consistently associated with cell cycle in 12 out of the 16 cancer types and pan-cancer, showing that dysregulation of the cell cycle could harm patient prognosis in cancer. The functional modules formed by the protective genes are more diverse in cancers; the most prevalent functions are relevant for immune response, implying that patients with different cancer types might develop different mechanisms against carcinogenesis. We also identified a harmful set of 10 genes, with potential as prognostic biomarkers in pan-cancer. Briefly, our results demonstrated that the survival-influential genes could reveal underlying mechanisms in carcinogenesis and might provide clues for developing therapeutic targets for cancers.

Spatially Enriched Paralog Rearrangements Argue Functionally Diverse Ribosomes Arise during Cold Acclimation in Arabidopsis.

Ribosome biogenesis is essential for plants to successfully acclimate to low temperature. Without dedicated steps supervising the 60S large subunits (LSUs) maturation in the cytosol, e.g., Rei-like (REIL) factors, plants fail to accumulate dry weight and fail to grow at suboptimal low temperatures. Around REIL, the final 60S cytosolic maturation steps include proofreading and assembly of functional ribosomal centers such as the polypeptide exit tunnel and the P-Stalk, respectively. In consequence, these ribosomal substructures and their assembly, especially during low temperatures, might be changed and provoke the need for dedicated quality controls. To test this, we blocked ribosome maturation during cold acclimation using two independent reil double mutant genotypes and tested changes in their ribosomal proteomes. Additionally, we normalized our mutant datasets using as a blank the cold responsiveness of a wild-type Arabidopsis genotype. This allowed us to neglect any reil-specific effects that may happen due to the presence or absence of the factor during LSU cytosolic maturation, thus allowing us to test for cold-induced changes that happen in the early nucleolar biogenesis. As a result, we report that cold acclimation triggers a reprogramming in the structural ribosomal proteome. The reprogramming alters the abundance of specific RP families and/or paralogs in non-translational LSU and translational polysome fractions, a phenomenon known as substoichiometry. Next, we tested whether the cold-substoichiometry was spatially confined to specific regions of the complex. In terms of RP proteoforms, we report that remodeling of ribosomes after a cold stimulus is significantly constrained to the polypeptide exit tunnel (PET), i.e., REIL factor binding and functional site. In terms of RP transcripts, cold acclimation induces changes in RP families or paralogs that are significantly constrained to the P-Stalk and the ribosomal head. The three modulated substructures represent possible targets of mechanisms that may constrain translation by controlled ribosome heterogeneity. We propose that non-random ribosome heterogeneity controlled by specialized biogenesis mechanisms may contribute to a preferential or ultimately even rigorous selection of transcripts needed for rapid proteome shifts and successful acclimation.

Exploration of the experiences of working stressors and coping strategies associated with menstrual symptoms among nurses with shifting schedules: a Q methodology investigation.

BACKGROUND: The essence and workload of nursing can easily lead to burdens associated with female nurses' menstrual symptoms, and consequently, result in decreased working performance. Without effective support this can lead to resignation due to maladaptation. This study adopted Q methodology to explore the experience of working stressors and coping strategies associated with menstrual symptoms among nurses with shifting schedules. METHODS: Data were collected in two stages. First, in-depth interviews were conducted to collect nurses' experiences. Sentences that best fit the study's purpose were extracted for the construction of Q statements. Second, nurses were allowed to subjectively rank these Q statements by using Q-sorts. A total of 90 participants ranked the designed Q statements. The Q factor analysis revealed a five-factor solution that accounted for 48.90% of the total variance. RESULTS: The five evident factors included: menstrual symptoms interfering in collaboration with colleagues, deficiency of professional function and stress due to symptoms burden, diverse experiences without a clear pattern, adapted self-management with and without medication use, and stress due to symptoms burden and using medication for self-management. CONCLUSIONS: The identification of these five groups may facilitate the development of responsive strategies to meet nurses' preferences. Furthermore, identifying workplace factors that are associated with the adverse effects of menstrual symptoms on nurses will be helpful for nursing supervisors and hospital managers. Additionally, strategies that can be implemented to create supportive work environments are discussed.