Prolonged sleep deprivation induces a cytokine-storm-like syndrome in mammals.

Most animals require sleep, and sleep loss induces serious pathophysiological consequences, including death. Previous experimental approaches for investigating sleep impacts in mice have been unable to persistently deprive animals of both rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS). Here, we report a "curling prevention by water" paradigm wherein mice remain awake 96% of the time. After 4 days of exposure, mice exhibit severe inflammation, and approximately 80% die. Sleep deprivation increases levels of prostaglandin D2 (PGD2) in the brain, and we found that elevated PGD2 efflux across the blood-brain-barrier-mediated by ATP-binding cassette subfamily C4 transporter-induces both accumulation of circulating neutrophils and a cytokine-storm-like syndrome. Experimental disruption of the PGD2/DP1 axis dramatically reduced sleep-deprivation-induced inflammation. Thus, our study reveals that sleep-related changes in PGD2 in the central nervous system drive profound pathological consequences in the peripheral immune system.

Inefficient SRP interaction with a nascent chain triggers a mRNA quality control pathway.

Misfolded proteins are often cytotoxic, unless cellular systems prevent their accumulation. Data presented here uncover a mechanism by which defects in secretory proteins lead to a dramatic reduction in their mRNAs and protein expression. When mutant signal sequences fail to bind to the signal recognition particle (SRP) at the ribosome exit site, the nascent chain instead contacts Argonaute2 (Ago2), and the mutant mRNAs are specifically degraded. Severity of signal sequence mutations correlated with increased proximity of Ago2 to nascent chain and mRNA degradation. Ago2 knockdown inhibited degradation of the mutant mRNA, while overexpression of Ago2 or knockdown of SRP54 promoted degradation of secretory protein mRNA. The results reveal a previously unappreciated general mechanism of translational quality control, in which specific mRNA degradation preemptively regulates aberrant protein production (RAPP).

A signalling pathway for transcriptional regulation of sleep amount in mice.

In mice and humans, sleep quantity is governed by genetic factors and exhibits age-dependent variation1-3. However, the core molecular pathways and effector mechanisms that regulate sleep duration in mammals remain unclear. Here, we characterize a major signalling pathway for the transcriptional regulation of sleep in mice using adeno-associated virus-mediated somatic genetics analysis4. Chimeric knockout of LKB1 kinase-an activator of AMPK-related protein kinase SIK35-7-in adult mouse brain markedly reduces the amount and delta power-a measure of sleep depth-of non-rapid eye movement sleep (NREMS). Downstream of the LKB1-SIK3 pathway, gain or loss-of-function of the histone deacetylases HDAC4 and HDAC5 in adult brain neurons causes bidirectional changes of NREMS amount and delta power. Moreover, phosphorylation of HDAC4 and HDAC5 is associated with increased sleep need, and HDAC4 specifically regulates NREMS amount in posterior hypothalamus. Genetic and transcriptomic studies reveal that HDAC4 cooperates with CREB in both transcriptional and sleep regulation. These findings introduce the concept of signalling pathways targeting transcription modulators to regulate daily sleep amount and demonstrate the power of somatic genetics in mouse sleep research.

Kinase signalling in excitatory neurons regulates sleep quantity and depth.

Progress has been made in the elucidation of sleep and wakefulness regulation at the neurocircuit level1,2. However, the intracellular signalling pathways that regulate sleep and the neuron groups in which these intracellular mechanisms work remain largely unknown. Here, using a forward genetics approach in mice, we identify histone deacetylase 4 (HDAC4) as a sleep-regulating molecule. Haploinsufficiency of Hdac4, a substrate of salt-inducible kinase 3 (SIK3)3, increased sleep. By contrast, mice that lacked SIK3 or its upstream kinase LKB1 in neurons or with a Hdac4S245A mutation that confers resistance to phosphorylation by SIK3 showed decreased sleep. These findings indicate that LKB1-SIK3-HDAC4 constitute a signalling cascade that regulates sleep and wakefulness. We also performed targeted manipulation of SIK3 and HDAC4 in specific neurons and brain regions. This showed that SIK3 signalling in excitatory neurons located in the cerebral cortex and the hypothalamus positively regulates EEG delta power during non-rapid eye movement sleep (NREMS) and NREMS amount, respectively. A subset of transcripts biased towards synaptic functions was commonly regulated in cortical glutamatergic neurons through the expression of a gain-of-function allele of Sik3 and through sleep deprivation. These findings suggest that NREMS quantity and depth are regulated by distinct groups of excitatory neurons through common intracellular signals. This study provides a basis for linking intracellular events and circuit-level mechanisms that control NREMS.

Biochemical principles of small RNA pathways.

The discovery of RNA interference (RNAi) is among the most significant biomedical breakthroughs in recent history. Multiple classes of small RNA, including small-interfering RNA (siRNA), micro-RNA (miRNA), and piwi-interacting RNA (piRNA), play important roles in many fundamental biological and disease processes. Collective studies in multiple organisms, including plants, Drosophila, Caenorhabditis elegans, and mammals indicate that these pathways are highly conserved throughout evolution. Thus, scientists across disciplines have found novel pathways to unravel, new insights in probing pathology, and nascent technologies to develop. The field of RNAi also provides a clear framework for understanding fundamental principles of biochemistry. The current review highlights elegant, reason-based experimentation in discovering RNA-directed biological phenomena and the importance of robust assay development in translating these observations into mechanistic understanding. This biochemical template also provides a conceptual framework for overcoming emerging challenges in the field and for understanding an expanding small RNA world.

Enhancing the Electrocatalytic Hydrogenation of Furfural via Anion-Induced Molecular Activation and Adsorption.

The electrocatalytic hydrogenation (ECH) of furfural (FF) to furfuryl alcohol, which does not require additional hydrogen or high pressure, is a green and promising production route. In this study, we explore the effects of anions on FF ECH in two buffer electrolytes (KHCO3 and phosphate-buffered saline [PBS]). Anions influence the yield of furfuryl alcohol through molecular activation and adsorption. Molecular dynamics simulations show that bicarbonate is present in the first shell layer of the FF molecule and induces strong hydrogen bonding interactions. In contrast, hydrogen phosphate is present only in the second shell layer, resulting in weak hydrogen bonding interactions. Owing to the interfacial anions and hydrogen bonding, FF molecules exhibit strong flat adsorption on the electrode surface in the KHCO3 solution, while weak adsorption is observed in the PBS solution, as confirmed by operando synchrotron-radiation Fourier-transform infrared spectroscopy and in situ Raman spectroscopy. Density-functional theory calculations reveal that the overall anionic hydrogen bonding network promotes the activation of the carbonyl group in the FF molecule in KHCO3, whereas electrophilic activity is inhibited in PBS. Consequently, FF ECH demonstrates much faster kinetics in KHCO3, while it exhibits sluggish ECH kinetics and a severe hydrogen evolution reaction in PBS. This work introduces a new strategy to optimize the catalytic process through the modulation of the microenvironment.

Electrocatalytic Coupling of Nitrate and Formaldehyde for Hexamethylenetetramine Synthesis via C-N Bond Construction and Ring Formation.

Hexamethylenetetramine (HMTA) is extensively used in the defense industry, medicines, food, plastics, rubber, and other applications. Traditional organic synthesis of HMTA relies on ammonia derived from the Haber process at high temperatures and pressures. In contrast, electrochemical methods enable a safe and green one-pot synthesis of HMTA from waste NO3-. However, HMTA synthesis through the electrochemical method is challenging owing to the complex reaction pathways involving C-N bond construction and ring formation. In this study, HMTA was efficiently synthesized over electrochemical oxidation-derived copper (e-OD-Cu), with a yield of 76.8% and a Faradaic efficiency of 74.9% at -0.30 VRHE. The catalytic mechanism and reaction pathway of HMTA synthesis on e-OD-Cu were investigated through a series of in situ characterization methods and density-functional theory calculations. The results demonstrated that the electrocatalytic synthesis of HMTA involved a tandem electrochemical-chemical reaction. Additionally, the results indicated that the presence of Cu vacancies enhanced substrate adsorption and inhibited the further hydrogenation of C═N. Overall, this study provides an electrocatalytic method for HMTA synthesis and an electrochemical strategy for constructing multiple C-N bonds.

Aqueous Electrocatalytic Hydrogenation Depolymerization of Lignin ß-O-4 Linkage via Selective Caryl-O(C) Bond Cleavage: The Regulation of Adsorption.

The cleavage of the benzene-oxygen (Caryl-O(C)) bond of the lignin ß-O-4 linkage is expected to relieve condensation of the degradation product and improve the product value. Nevertheless, the electrochemical breaking of the Caryl-O(C) bond has not been achieved yet due to the high dissociation energy (∼409 kJ mol-1) and the easy over-reduction of aromatic compounds. Here, we report an aqueous electrochemical reduction strategy for breaking Caryl-O(C) bonds via the regulation of molecular adsorption. The density functional theory (DFT) calculations and quartz crystal microbalance (QCM) measurements reveal that the residual Cu(I) in the CuO electrocatalyst enhances the adsorption of the 2-phenoxy-1-phenylethyl alcohol (PPE) by the Caryl-O(C) bond and lowers the energy barrier of the protons attacking the oxygen atom in the ß-O-4 linkage. Thus, compared to the Cu electrocatalyst (with a hydroquinone yield of 47.4% and a benzyl alcohol yield of 24.8%), the CuO nanorod exhibits a much higher yield of hydroquinone (95.3%) and benzyl alcohol (88.6%) at a potential of -0.4 V vs reversible hydrogen electrode (RHE) in an undivided cell. Moreover, the reaction pathway and the cleavage of the Caryl-O(C) bond are identified through a combination of in situ synchrotron-radiation Fourier transformed infrared spectroscopy (SR-FTIR) and DFT calculations. This effective method is utilized for poplar lignin electrolysis, yielding 10.9 wt % of guaiacylglycerol, with an outstanding selectivity of >63.0%. This work provides an efficient and mild method of cleavage of Caryl-O(C) bonds in lignin valorization.

Catalyst Selection over an Electrochemical Reductive Coupling Reaction toward Direct Electrosynthesis of Oxime from NOx and Aldehyde.

Aqueous electrochemical coupling reactions, which enable the green synthesis of complex organic compounds, will be a crucial tool in synthetic chemistry. However, a lack of informed approaches for screening suitable catalysts is a major obstacle to its development. Here, we propose a pioneering electrochemical reductive coupling reaction toward direct electrosynthesis of oxime from NOx and aldehyde. Through integrating experimental and theoretical methods, we screen out the optimal catalyst, i.e., metal Fe catalyst, that facilitates the enrichment and C-N coupling of key reaction intermediates, all leading to high yields (e.g., ∼99% yield of benzaldoxime) for the direct electrosynthesis of oxime over Fe. With a divided flow reactor, we achieve a high benzaldoxime production of 22.8 g h-1 gcat-1 in ∼94% isolated yield. This work not only paves the way to the industrial mass production of oxime via electrosynthesis but also offers references for the catalyst selection of other electrochemical coupling reactions.

The glycolytic enzyme PFKFB3 drives kidney fibrosis through promoting histone lactylation-mediated NF-κB family activation.

Persistently elevated glycolysis in kidney has been demonstrated to promote chronic kidney disease (CKD). However, the underlying mechanism remains largely unclear. Here, we observed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, was remarkably induced in kidney proximal tubular cells (PTCs) following ischemia-reperfusion injury (IRI) in mice, as well as in multiple etiologies of patients with CKD. PFKFB3 expression was positively correlated with the severity of kidney fibrosis. Moreover, patients with CKD and mice exhibited increased urinary lactate/creatine levels and kidney lactate, respectively. PTC-specific deletion of PFKFB3 significantly reduced kidney lactate levels, mitigated inflammation and fibrosis, and preserved kidney function in the IRI mouse model. Similar protective effects were observed in mice with heterozygous deficiency of PFKFB3 or those treated with a PFKFB3 inhibitor. Mechanistically, lactate derived from PFKFB3-mediated tubular glycolytic reprogramming markedly enhanced histone lactylation, particularly H4K12la, which was enriched at the promoter of NF-κB signaling genes like Ikbkb, Rela, and Relb, activating their transcription and facilitating the inflammatory response. Further, PTC-specific deletion of PFKFB3 inhibited the activation of IKKß, I κ B α, and p65 in the IRI kidneys. Moreover, increased H4K12la levels were positively correlated with kidney inflammation and fibrosis in patients with CKD. These findings suggest that tubular PFKFB3 may play a dual role in enhancing NF-κB signaling by promoting both H4K12la-mediated gene transcription and its activation. Thus, targeting the PFKFB3-mediated NF-κB signaling pathway in kidney tubular cells could be a novel strategy for CKD therapy.

Electronic Structure Regulation by Fe Doped Ni-Phosphides for Long-term Overall Water Splitting at Large Current Density.

Acquiring a highly efficient electrocatalyst capable of sustaining prolonged operation under high current density is of paramount importance for the process of electrocatalytic water splitting. Herein, Fe-doped phosphide (Fe-Ni5P4) derived from the NiFc metal-organic framework (NiFc-MOF) (Fc: 1,1'-ferrocene dicarboxylate) shows high catalytic activity for overall water splitting (OWS). Fe-Ni5P4||Fe-Ni5P4 exhibits a low voltage of 1.72 V for OWS at 0.5 A cm-2 and permits stable operation for 2700 h in 1.0 m KOH. Remarkably, Fe-Ni5P4||Fe-Ni5P4 can sustain robust water splitting at an extra-large current density of 1 A cm-2 for 1170 h even in alkaline seawater. Theoretical calculations confirm that Fe doping simultaneously reduces the reaction barriers of coupling and desorption (O*→OOH*, OOH*→O2 *) in the oxygen evolution reaction (OER) and regulates the adsorption strength of the intermediates (H2O*, H*) in the hydrogen evolution reaction (HER), enabling Fe-Ni5P4 to possess excellent dual functional activity. This study offers a valuable reference for the advancement of highly durable electrocatalysts through the regulation derived from coordination frameworks, with significant implications for industrial applications and energy conversion technologies.

In situ Activation of Molecular Oxygen at Intermetallic Spacing-Optimized Iron Network-Like Sites for Boosting Electrocatalytic Oxygen Reduction.

The oxygen reduction reaction (ORR) catalyzed by transition-metal single-atom catalysts (SACs) is promising for practical applications in energy-conversion devices, but great challenges still remain due to the sluggish kinetics of O═O cleavage. Herein, a kind of high-density iron network-like sites catalysts are constructed with optimized intermetallic distances on an amino-functionalized carbon matrix (Fe-HDNSs). Quasi-in situ soft X-ray absorption spectroscopy and in situ synchrotron infrared characterizations demonstrate that the optimized intermetallic distances in Fe-HDNSs can in situ activate the molecular oxygen by fast electron compensation through the hybridized Fe 3d‒O 2p, which efficiently facilitates the cleavage of the O═O bond to *O species and highly suppresses the side reactions for an accelerated kinetics of the 4e- ORR. As a result, the well-designed Fe-HDNSs catalysts exhibit superior performances with a half-wave potential of 0.89 V versus reversible hydrogen electrode (RHE) and a kinetic current density of 72 mA cm-2@0.80 V versus RHE, exceeding most of the noble-metal-free ORR catalysts. This work offers some new insights into the understanding of 4e- ORR kinetics and reaction pathways to boost electrochemical performances of SACs.

PmHs1pro-1 monitors Bsursaphelenchus xylophilus infection and activates defensive response in resistant Pinus massoniana.

Plant resistance (R) genes play a crucial role in the detection of effector proteins secreted by pathogens, either directly or indirectly, as well as in the subsequent activation of downstream defence mechanisms. However, little is known about how R genes regulate the defence responses of conifers, particularly Pinus massoniana, against the destructive pine wood nematode (PWN; Bursaphelenchus xylophilus). Here, we isolated and characterised PmHs1pro-1, a nematode-resistance gene of P. massoniana, using bioinformatics, molecular biology, histochemistry and transgenesis. Tissue-specific expressional pattern and localisation of PmHs1pro-1 suggested that it was a crucial positive regulator in response to PWN attack in resistant P. massoniana. Meanwhile, overexpression of PmHs1pro-1 was found to activate reactive oxygen species (ROS) metabolism-related enzymes and the expressional level of their key genes, including superoxide dismutase, peroxidase and catalase. In addition, we showed that PmHs1pro-1 directly recognised the effector protein BxSCD1of PWN, and induced the ROS burst responding to PWN invasion in resistant P. massoniana. Our findings illustrated the molecular framework of R genes directly recognising the effector protein of pathology in pine, which offered a novel insight into the plant-pathogen arms race.

Nomogram incorporating preoperative pan-immune-inflammation value and monocyte to high-density lipoprotein ratio for survival prediction in patients with colorectal cancer: a retrospective study.

OBJECTIVE: Using the preoperative pan-immune-inflammation value (PIV) and the monocyte to high-density lipoprotein ratio (MHR) to reflect inflammation, immunity, and cholesterol metabolism, we aim to develop and visualize a novel nomogram model for predicting the survival outcomes in patients with colorectal cancer (CRC). METHODS: A total of 172 patients with CRC who underwent radical resection were retrospectively analyzed. Survival analysis was conducted after patients were grouped according to the optimal cut-off values of PIV and MHR. Univariate and multivariate analyses were performed using Cox proportional hazards regression to screen the independent prognostic factors. Based on these factors, a nomogram was constructed and validated. RESULTS: The PIV was significantly associated with tumor location (P < 0.001), tumor maximum diameter (P = 0.008), and T stage (P = 0.019). The MHR was closely related to gender (P = 0.016), tumor maximum diameter (P = 0.002), and T stage (P = 0.038). Multivariate analysis results showed that PIV (Hazard Ratio (HR) = 2.476, 95% Confidence Interval (CI) = 1.410-4.348, P = 0.002), MHR (HR = 3.803, 95%CI = 1.609-8.989, P = 0.002), CEA (HR = 1.977, 95%CI = 1.121-3.485, P = 0.019), and TNM stage (HR = 1.759, 95%CI = 1.010-3.063, P = 0.046) were independent prognostic indicators for overall survival (OS). A nomogram incorporating these variables was developed, demonstrating robust predictive accuracy for OS. The area under the curve (AUC) values of the predictive model for 1-, 2-, and 3- year are 0.791,0.768,0.811, respectively. The calibration curves for the probability of survival at 1-, 2-, and 3- year presented a high degree of credibility. Furthermore, Decision curve analysis (DCA) for the probability of survival at 1-, 2-, and 3- year demonstrate the significant clinical utility in predicting survival outcomes. CONCLUSION: Preoperative PIV and MHR are independent risk factors for CRC prognosis. The novel developed nomogram demonstrates a robust predictive ability, offering substantial utility in facilitating the clinical decision-making process.

Deep Learning Radiomic Analysis of MRI Combined with Clinical Characteristics Diagnoses Placenta Accreta Spectrum and its Subtypes.

BACKGROUND: Different placenta accreta spectrum (PAS) subtypes pose varying surgical risks to the parturient. Machine learning model has the potential to diagnose PAS disorder. PURPOSE: To develop a cascaded deep semantic-radiomic-clinical (DRC) model for diagnosing PAS and its subtypes based on T2-weighted MRI. STUDY TYPE: Retrospective. POPULATION: 361 pregnant women (mean age: 33.10 ± 4.37 years), suspected of PAS, divided into segment training cohort (N = 40), internal training cohort (N = 139), internal testing cohort (N = 60), and external testing cohort (N = 122). FIELD STRENGTH/SEQUENCE: Coronal T2-weighted sequence at 1.5 T and 3.0 T. ASSESSMENT: Clinical characteristics such as history of uterine surgery and the presence of placenta previa, complete placenta previa and dangerous placenta previa were extracted from clinical records. The DRC model (incorporating radiomics, deep semantic features, and clinical characteristics), a cumulative radiological score method performed by radiologists, and other models (including a radiomics and clinical, the clinical, radiomics and deep learning models) were developed for PAS disorder diagnosing (existence of PAS and its subtypes). STATISTICAL TESTS: AUC, ACC, Student's t-test, the Mann-Whitney U test, chi-squared test, dice coefficient, intraclass correlation coefficients, least absolute shrinkage and selection operator regression, receiver operating characteristic curve, calibration curve with the Hosmer-Lemeshow test, decision curve analysis, DeLong test, and McNemar test. P < 0.05 indicated a significant difference. RESULTS: In PAS diagnosis, the DRC-1 outperformed than other models (AUC = 0.850 and 0.841 in internal and external testing cohorts, respectively). In PAS subtype classification (abnormal adherent placenta and abnormal invasive placenta), DRC-2 model performed similarly with radiologists (P = 0.773 and 0.579 in the internal testing cohort and P = 0.429 and 0.874 in the external testing cohort, respectively). DATA CONCLUSION: The DRC model offers efficiency and high diagnostic sensitivity in diagnosis, aiding in surgical planning. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Pregnancy-related intracranial venous sinus thrombosis secondary to cryptococcal meningoencephalitis: a case report and literature review.

BACKGROUND: Cerebral venous sinus thrombosis (CVST), a serious cerebrovascular and neurological emergency, is common in pregnant individuals and accounts for approximately 0.5-1.0% of all cerebrovascular diseases. However, CVST with cryptococcal meningoencephalitis in immunocompetent pregnant patients is rare. CASE PRESENTATION: A 30-year-old woman who was 33 weeks pregnant presented with recurrent dizziness, headache, and vomiting as the main clinical manifestations, all of which were initially nonspecific. After assessment of the cerebrospinal fluid, skull computerized tomography, magnetic resonance imaging, and other laboratory and imaging examinations, the patient was diagnosed with secondary pregnancy-related CVST with cryptococcal meningoencephalitis. Despite receiving potent anticoagulant and antifungal treatment, the patient's condition deteriorated, and the patient's family opted to cease treatment. CONCLUSIONS: We present a rare case of CVST with cryptococcal meningoencephalitis in an immunocompetent pregnant patient. The difficulty of diagnosing and treating secondary pregnancy-related CVST caused by cryptococcal meningoencephalitis, as well as the great challenges faced at present are highlighted. One crucial lesson from the present case is that when clinical and imaging signs are unusual for CVST during pregnancy, it is essential to account for the possibility of other central nervous system (CNS) diseases, such as CNS infections with Cryptococcus, which may cause CVST.

Phosphorylation of the human microRNA-generating complex mediates MAPK/Erk signaling.

MicroRNAs (miRNAs) govern an expanding number of biological and disease processes. Understanding the mechanisms by which the miRNA pathway is regulated, therefore, represents an important area of investigation. We determined that the human miRNA-generating complex is comprised of Dicer and phospho-TRBP isoforms. Phosphorylation of TRBP is mediated by the mitogen-activated protein kinase (MAPK) Erk. Expression of phospho-mimic TRBP and TRBP phosphorylation enhanced miRNA production by increasing stability of the miRNA-generating complex. Mitogenic signaling in response to serum and the tumor promoter PMA was dependent on TRBP phosphorylation. These effects were accompanied by a coordinated increase in levels of growth-promoting miRNA and reduced expression of let-7 tumor suppressor miRNA. Conversely, pharmacological inhibition of MAPK/Erk resulted in an anti-growth miRNA profile. Taken together, these studies indicate that the MAPK/Erk pathway regulates the miRNA machinery and suggest a general principle, wherein signaling systems target the miRNA pathway to achieve biological responses.

Quantitative phosphoproteomic analysis of the molecular substrates of sleep need.

Sleep and wake have global effects on brain physiology, from molecular changes1-4 and neuronal activities to synaptic plasticity3-7. Sleep-wake homeostasis is maintained by the generation of a sleep need that accumulates during waking and dissipates during sleep8-11. Here we investigate the molecular basis of sleep need using quantitative phosphoproteomic analysis of the sleep-deprived and Sleepy mouse models of increased sleep need. Sleep deprivation induces cumulative phosphorylation of the brain proteome, which dissipates during sleep. Sleepy mice, owing to a gain-of-function mutation in the Sik3 gene 12 , have a constitutively high sleep need despite increased sleep amount. The brain proteome of these mice exhibits hyperphosphorylation, similar to that seen in the brain of sleep-deprived mice. Comparison of the two models identifies 80 mostly synaptic sleep-need-index phosphoproteins (SNIPPs), in which phosphorylation states closely parallel changes of sleep need. SLEEPY, the mutant SIK3 protein, preferentially associates with and phosphorylates SNIPPs. Inhibition of SIK3 activity reduces phosphorylation of SNIPPs and slow wave activity during non-rapid-eye-movement sleep, the best known measurable index of sleep need, in both Sleepy mice and sleep-deprived wild-type mice. Our results suggest that phosphorylation of SNIPPs accumulates and dissipates in relation to sleep need, and therefore SNIPP phosphorylation is a molecular signature of sleep need. Whereas waking encodes memories by potentiating synapses, sleep consolidates memories and restores synaptic homeostasis by globally downscaling excitatory synapses4-6. Thus, the phosphorylation-dephosphorylation cycle of SNIPPs may represent a major regulatory mechanism that underlies both synaptic homeostasis and sleep-wake homeostasis.

HP1BP3, a Chromatin Retention Factor for Co-transcriptional MicroRNA Processing.

Recent studies suggest that the microprocessor (Drosha-DGCR8) complex can be recruited to chromatin to catalyze co-transcriptional processing of primary microRNAs (pri-miRNAs) in mammalian cells. However, the molecular mechanism of co-transcriptional miRNA processing is poorly understood. Here we find that HP1BP3, a histone H1-like chromatin protein, specifically associates with the microprocessor and promotes global miRNA biogenesis in human cells. Chromatin immunoprecipitation (ChIP) studies reveal genome-wide co-localization of HP1BP3 and Drosha and HP1BP3-dependent Drosha binding to actively transcribed miRNA loci. Moreover, HP1BP3 specifically binds endogenous pri-miRNAs and facilitates the Drosha/pri-miRNA association in vivo. Knockdown of HP1BP3 compromises pri-miRNA processing by causing premature release of pri-miRNAs from the chromatin. Taken together, these studies suggest that HP1BP3 promotes co-transcriptional miRNA processing via chromatin retention of nascent pri-miRNA transcripts. This work significantly expands the functional repertoire of the H1 family of proteins and suggests the existence of chromatin retention factors for widespread co-transcriptional miRNA processing.

Corticosteroid in IgA nephropathy with moderate proteinuria: A retrospective cohort study.

BACKGROUND: Corticosteroids remain contentious as a therapeutic option for IgA nephropathy. We conducted a retrospective cohort study to explore whether corticosteroid therapy is efficient and safe for IgAN patients with moderate proteinuria. METHODS: A total of 336 patients with renal biopsy-confirmed IgAN, estimated glomerular filtration (eGFR) over 15 mL/min/1.73 m2 and urine protein levels of 0.75-3.5 g/d were enrolled. According to the treatment protocol, we classified the enrolled patients into two groups: one receiving corticosteroids and the other receiving supportive care. Complete remission, partial remission, and no remission were applied to describe the efficacy assessments. The endpoint was defined as a 40% reduction in eGFR, the onset of ESRD, or renal disease-related death. RESULTS: Clinical and pathological progression risk factors were higher in corticosteroid-treated individuals. Logistic regression analysis revealed that the corticosteroid group was considerably related to a higher remission rate after adjustment for confounding factors. The occurrence of serious adverse events between the two groups was not found to be statistically significantly different. Then, we matched 95 couples of patients with similar baseline levels in both groups by propensity score matching. The results showed that corticosteroid-treated patients showed higher overall and complete remission rates than untreated patients. However, due to the relatively short follow-up period, no significant differences in the incidence of endpoint and survival analyses have been observed thus far. CONCLUSION: Corticosteroid therapy may benefit IgAN patients with moderate proteinuria via proteinuria reduction and renal function preservation.