One- and 2-year outcomes of lumbar facet arthroplasty versus spinal fusion in young (<65 years) and old (≥65 years) patients for the treatment of degenerative spondylolisthesis and stenosis.

Background: Facet arthroplasty, an alternative to lumbar fusion, offers stabilization and preserves range of motion. This subanalysis of the TOPS IDE trial (FDA #G160168) compared facet arthroplasty, using the TOPS device, with a standard single-level transforaminal lumbar interbody fusion (TLIF) in patients stratified by age (<65 and ≥65 years) with symptomatic grade 1 degenerative spondylolisthesis with moderate to severe spinal stenosis at L2-5. Methods: Patient-reported outcomes (PROMS), including Oswestry disability index (ODI), visual analog pain scales (VAS), and Zurich claudication questionnaires (ZCQ), were assessed at baseline and multiple postoperative timepoints. Radiographic evaluation of flexion/extension range of motion (ROM) occurred at baseline, 12 months, and 24 months. Data were analyzed following an intention-to-treat model. Significance was defined as p<.05. Results: About 299 patients were included (TOPS=206, TLIF=93). The groups were similar at baseline. At 2 years, the TOPS group had a greater proportion of patients report ≥15-point improvement for ODI (93.8% versus 77.1%, p=.011) and ≥20-point improvement for VAS back (84.4% versus 61.8%, p=.014). At 1 year, TOPS group had a greater proportion of patients report clinically significant improvements in all ZCQ categories (91.6% versus 78.5%, p=.012). In patients <65 years, the TOPS group had improved PROMS compared to TLIF at 2 years; however, these differences were less pronounced in patients ≥65 years old. The TOPS groups preserved more ROM at 12 (2.8° 95%CI [1.87; 3.74], p<.0001) and 24 (2.99° 95%CI [1.82; 4.15], p<.0001) months compared to TLIF. ROM was similarly preserved in patients aged <65 and ≥65. The rate of adverse events did not differ significantly between treatment groups. Conclusions: Facet arthroplasty preserves more ROM in all ages and leads to improved PROMS compared to TLIF, particularly in younger patients.

Timeless noncoding DNA contains cell-type preferential enhancers important for proper Drosophila circadian regulation.

To address the contribution of transcriptional regulation to Drosophila clock gene expression and to behavior, we generated a series of CRISPR-mediated deletions within two regions of the circadian gene timeless (tim), an intronic E-box region and an upstream E-box region that are both recognized by the key transcription factor Clock (Clk) and its heterodimeric partner Cycle. The upstream deletions but not an intronic deletion dramatically impact tim expression in fly heads; the biggest upstream deletion reduces peak RNA levels and tim RNA cycling amplitude to about 15% of normal, and there are similar effects on tim protein (TIM). The cycling amplitude of other clock genes is also strongly reduced, in these cases due to increases in trough levels. These data underscore the important contribution of the upstream E-box enhancer region to tim expression and of TIM to clock gene transcriptional repression in fly heads. Surprisingly, tim expression in clock neurons is only modestly affected by the biggest upstream deletion and is similarly affected by a deletion of the intronic E-box region. This distinction between clock neurons and glia is paralleled by a dramatically enhanced accessibility of the intronic enhancer region within clock neurons. This distinctive feature of tim chromatin was revealed by ATAC-seq (assay for transposase-accessible chromatin with sequencing) assays of purified neurons and glia as well as of fly heads. The enhanced cell type-specific accessibility of the intronic enhancer region explains the resilience of clock neuron tim expression and circadian behavior to deletion of the otherwise more prominent upstream tim E-box region.

A novel PDPN antagonist peptide CY12-RP2 inhibits melanoma growth via Wnt/ß-catenin and modulates the immune cells.

BACKGROUND: Podoplanin (PDPN) is a highly conserved, mucin-type protein specific to the lymphatic system. Overexpression of PDPN is associated with the progression of various solid tumors, and plays an important roles in the tumor microenvironment by regulating the immune system. However, the role of PDPN-mediated signal activation in the progression of melanoma is still unknown. METHODS: PDPN expression was first analyzed in 112 human melanoma tissue microarrays and melanoma cell lines. Functional experiments including proliferation, clone formation, migration, and metastasis were utilized to identify the suppressive effects of PDPN. The Ph.D.TM-12 Phage Display Peptide Library was used to obtain a PDPN antagonist peptide, named CY12-RP2. The immunofluorescence, SPR assay, and flow cytometry were used to identify the binding specificity of CY12-RP2 with PDPN in melanoma cells. Functional and mechanistic assays in vivo and in vitro were performed for discriminating the antitumor and immune activation effects of CY12-RP2. RESULTS: PDPN was overexpressed in melanoma tissue and cells, and inhibited melanoma cells proliferation, migration, and metastasis by blocking the EMT and Wnt/ß-catenin pathway. PDPN antagonistic peptide, CY12-RP2, could specifically bind with PDPN, suppressing melanoma various functions inducing apoptosis in both melanoma cells and 3D spheroids. CY12-RP2 also enhanced the anti-tumor capacity of PBMC, and inhibited melanoma cells growth both in xenografts and allogeneic mice model. Moreover, CY12-RP2 could inhibit melanoma lung metastasis, and abrogated the immunosuppressive effects of PDPN by increasing the proportion of CD3 + CD4 + T cells, CD3 + CD8 + T cells, CD49b + Granzyme B + NK cells, and CD11b + CD86 + M1-like macrophages and the levels of IL-1ß, TNF-α, and IFN-γ. CONCLUSIONS: This study has demonstrated the important role of PDPN in the progression of melanoma and formation of immunosuppressive environment, and provided a potential approach of treating melanoma using the novel CY12-RP2 peptide. In melanoma, PDPN is overexpressed in the cancer cells, and promotes melanoma cells growth and metastasis through activating the Wnt/ß-catenin pathway. Treatment with the PDPN antagonistic peptide CY12-RP2 could not only inhibit the melanoma growth and metastasis both in vitro and in vivo through Wnt/ß-catenin pathway blockade, but also abrogate the immunosuppressive effects of PDPN through modulating immune cells.

The neurosurgeon workforce: a geographical gender-focused analysis of the trends in representation of neurosurgeons and choices in training over 70 years.

OBJECTIVE: Neurosurgeons frequently move throughout their careers, with moves driven by personal and professional factors. In this study, the authors analyzed these migration trends through a dynamic migratory map and statistical review, with a particular focus on differences in education and practice patterns between male and female neurosurgeons. METHODS: A list containing all board-certified and -affiliated US neurosurgeons practicing in 2019 was obtained from the American Association of Neurological Surgeons. The list was augmented to include demographic and location information for medical school, residency, fellowship(s), and current practice for all neurosurgeons with publicly available data. Migration heatmaps were generated, and migration patterns over 10-year intervals were plotted. A web tool was additionally created to allow for dynamic visualization of this database. RESULTS: The database included 5307 neurosurgeons with a mean age of 57.2 ± 11.3 years. The female population made up 8.93% of all neurosurgeons, and were found to be more likely to complete fellowships than their male counterparts, at 54.2% and 39.1%, respectively (p < 0.0001). A total of 39.5% of all neurosurgeons completed at least one fellowship. A large proportion of currently practicing US neurosurgeons completed medical school internationally in the 1990s. Recently, there has been a trend in neurosurgeons choosing to practice in the South, emigrating from the Northeast and the Western US Census regions. By population, the Western US region trained the fewest neurosurgeons at 1 per 115,000 residents, and the Northeastern US region trained the most at 1 per 49,000. The web tool provides a simple interface to visualize the database on a world map. CONCLUSIONS: Diversity, equity, and inclusion in neurosurgery have been a strong point of discussion in recent literature, with neurosurgeons comprising one of the most gender-disparate workforces in the US medical system. This study provides additional metrics to assess these disparities to help motivate further action toward a larger, more diverse neurosurgical community.

Loss of the Novel Myelin Protein CMTM5 in Multiple Sclerosis Lesions and Its Involvement in Oligodendroglial Stress Responses.

This study comprehensively addresses the involvement of the protein CKLF-like Marvel transmembrane domain-containing family member 5 (CMTM5) in the context of demyelination and cytodegenerative autoimmune diseases, particularly multiple Sclerosis (MS). An observed reduction in CMTM5 expression in post-mortem MS lesions prompted further investigations in both in vitro and in vivo animal models. In the cuprizone animal model, we detected a decrease in CMTM5 expression in oligodendrocytes that is absent in other members of the CMTM protein family. Our findings also confirm these results in the experimental autoimmune encephalomyelitis (EAE) model with decreased CMTM5 expression in both cerebellum and spinal cord white matter. We also examined the effects of a Cmtm5 knockdown in vitro in the oligodendroglial Oli-neu mouse cell line using the CRISPR interference technique. Interestingly, we found no effects on cell response to thapsigargin-induced endoplasmic reticulum (ER) stress as determined by Atf4 activity, an indicator of cellular stress responses. Overall, these results substantiate previous findings suggesting that CMTM5, rather than contributing to myelin biogenesis, is involved in maintaining axonal integrity. Our study further demonstrates that the knockdown of Cmtm5 in vitro does not modulate oligodendroglial responses to ER stress. These results warrant further investigation into the functional role of CMTM5 during axonal degeneration in the context of demyelinating conditions.

FANCI is Associated with Poor Prognosis and Immune Infiltration in Liver Hepatocellular Carcinoma.

Objective: This study aimed to validate FANCI as a potential marker for both prognosis and therapy in liver hepatocellular carcinoma. Method: FANCI expression data were acquired from GEPIA, HPA, TCGA, and GEO databases. The impact of clinicopathological features was analyzed by UALCAN. The prognosis of Liver Hepatocellular Carcinoma (LIHC) patients with highly expressed FANCI was constructed utilizing Kaplan-Meier Plotter. GEO2R was employed to identify differentially expressed genes (DEGs). Metascape was used to analyze functional pathways correlations. Protein-Protein interaction (PPI) networks were generated by Cytoscape. Furthermore, molecular complex detection (MCODE) was utilized to recognize Hub genes, which were selected to establish a prognostic model. Lastly, the relationship between FANCI and immune cell infiltration in LIHC was examined. Results: Compared to adjacent tissues, FANCI expression levels were significantly higher in LIHC tissues and were positively correlated to the cancer grade, stage, and prior hepatitis B virus (HBV) infection. High expression of FANCI was found to be associated with poor prognosis in LIHC (HR=1.89, p<0.001). DEGs that were positively correlated with FANCI were involved in various processes, including the cell cycle, VEGF pathway, immune system processes, and biogenesis of ribonucleoproteins. MCM10, TPX2, PRC1, and KIF11 were identified as key genes closely related to FANCI and poor prognosis. A reliable five-variable prognostic model was constructed with strong predictive capability. Lastly, a positive correlation was observed between FANCI expression and tumor-infiltration levels of CD8+ T cells, B cells, regulatory T (Tregs), CD4+ T helper 2 (Th2), and macrophage M2 cells. Conclusion: FANCI may hold promise as a potential biomarker for predicting prognostic outcomes, and a valuable therapeutic target for LIHC patients, with a focus on anti-proliferation, anti-chemoresistance, and combination with immunotherapy.

Widespread posttranscriptional regulation of cotransmission.

While neurotransmitter identity was once considered singular and immutable for mature neurons, it is now appreciated that one neuron can release multiple neuroactive substances (cotransmission) whose identities can even change over time. To explore the mechanisms that tune the suite of transmitters a neuron releases, we developed transcriptional and translational reporters for cholinergic, glutamatergic, and GABAergic signaling in Drosophila. We show that many glutamatergic and GABAergic cells also transcribe cholinergic genes, but fail to accumulate cholinergic effector proteins. Suppression of cholinergic signaling involves posttranscriptional regulation of cholinergic transcripts by the microRNA miR-190; chronic loss of miR-190 function allows expression of cholinergic machinery, reducing and fragmenting sleep. Using a "translation-trap" strategy, we show that neurons in these populations have episodes of transient translation of cholinergic proteins, demonstrating that suppression of cotransmission is actively modulated. Posttranscriptional restriction of fast transmitter cotransmission provides a mechanism allowing reversible tuning of neuronal output.

All-Cause and Cardiovascular-Related Mortality in CKD Patients With and Without Heart Failure: A Population-Based Cohort Study in Kaiser Permanente Southern California.

Rationale & Objective: Heart failure and chronic kidney disease (CKD) frequently coexist reflective of the strong interplay between these organ systems. A better understanding of the prevalence of different types of heart failure (preserved and reduced ejection fraction) and their subsequent mortality risks among advanced CKD patients would provide important epidemiologic insights and may pave the way for more focused and proactive management strategies. Study Design: Retrospective cohort study. Setting & Population: Patients aged ≥18 years with incident CKD (estimated glomerular filtration rate ≤45 mL/min/1.73 m2) with and without heart failure in a large integrated health care system in Southern California. Exposure: Heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF). Outcomes: All-cause and cardiovascular-related mortality within one year of CKD identification. Analytical Approach: HRs were estimated using Cox proportional-hazards model for risk of all-cause mortality and Fine-Gray subdistribution hazard model for risk of cardiovascular-related mortality within 1 year. Results: The study cohort included 76,688 patients with incident CKD between 2007 and 2017, of which 14,249 (18.6%) had prevalent heart failure. Among these patients, 8,436 (59.2%) had HFpEF and 3,328 (23.3%) had HFrEF. Compared with patients without heart failure, the HR for 1-year all-cause mortality was 1.70 (95% CI, 1.60-1.80) among patients with heart failure. The HRs were 1.59 (95% CI, 1.48-1.70) for patients with HFpEF and 2.43 (95% CI, 2.23-2.65) for patients with HFrEF. Compared with patients without heart failure, the 1-year cardiovascular-related mortality HR for patients with heart failure was 6.69 (95% CI, 5.93-7.54). Cardiovascular-related mortality HR was even higher among those with HFrEF (HR, 11.47; 95% CI, 9.90-13.28). Limitations: Retrospective design with a short 1-year follow-up period. Additional variables including medication adherence, medication changes, and time-varying variables were not accounted for in this intention-to-treat analysis. Conclusions: Among patients with incident CKD, heart failure was highly prevalent with HFpEF accounting for over 70% among patients with known ejection fraction. Although the presence of heart failure was associated with higher 1-year all-cause and cardiovascular-related mortality, patients with HFrEF were the most vulnerable.

Butt-seq: a new method for facile profiling of transcription.

A wide range of sequencing methods has been developed to assess nascent RNA transcription and resolve the single-nucleotide position of RNA polymerase genome-wide. These techniques are often burdened with high input material requirements and lengthy protocols. We leveraged the template-switching properties of thermostable group II intron reverse transcriptase (TGIRT) and developed Butt-seq (bulk analysis of nascent transcript termini sequencing), which can produce libraries from purified nascent RNA in 6 h and from as few as 10,000 cells-an improvement of at least 10-fold over existing techniques. Butt-seq shows that inhibition of the superelongation complex (SEC) causes promoter-proximal pausing to move upstream in a fashion correlated with subnucleosomal fragments. To address transcriptional regulation in a tissue, Butt-seq was used to measure the circadian regulation of transcription from fly heads. All the results indicate that Butt-seq is a simple and powerful technique to analyze transcription at a high level of resolution.

Widespread post-transcriptional regulation of co-transmission.

While neurotransmitter identity was once considered singular and immutable for mature neurons, it is now appreciated that one neuron can release multiple neuroactive substances (co-transmission) whose identities can even change over time. To explore the mechanisms that tune the suite of transmitters a neuron releases, we developed transcriptional and translational reporters for cholinergic, glutamatergic, and GABAergic signaling in Drosophila . We show that many glutamatergic and GABAergic cells also transcribe cholinergic genes, but fail to accumulate cholinergic effector proteins. Suppression of cholinergic signaling involves posttranscriptional regulation of cholinergic transcripts by the microRNA miR-190; chronic loss of miR-190 function allows expression of cholinergic machinery, reducing and fragmenting sleep. Using a "translation-trap" strategy we show that neurons in these populations have episodes of transient translation of cholinergic proteins, demonstrating that suppression of co-transmission is actively modulated. Posttranscriptional restriction of fast transmitter co-transmission provides a mechanism allowing reversible tuning of neuronal output. One-Sentence Summary: Cholinergic co-transmission in large populations of glutamatergic and GABAergic neurons in the Drosophila adult brain is controlled by miR-190.

Nano-LYTACs for Degradation of Membrane Proteins and Inhibition of CD24/Siglec-10 Signaling Pathway.

Lysosome-targeting chimeras (LYTACs) are an emerging therapeutic modality that effectively degrade cancer cell membranes and extracellular target proteins. In this study, a nanosphere-based LYTAC degradation system is developed. The amphiphilic peptide-modified N-acetylgalactosamine (GalNAc) can self-assemble into nanospheres with a strong affinity for asialoglycoprotein receptor targets. They can degrade different membranes and extracellular proteins by linking with the relevant antibodies. CD24, a heavily glycosylated glycosylphosphatidylinositol-anchored surface protein, interacts with Siglec-10 to modulate the tumor immune response. The novel Nanosphere-AntiCD24, synthesized by linking nanospheres with CD24 antibody, accurately regulates the degradation of CD24 protein and partially restores the phagocytic function of macrophages toward tumor cells by blocking the CD24/Siglec-10 signaling pathway. When Nanosphere-AntiCD24 is combined with glucose oxidase, an enzyme promoting the oxidative decomposition of glucose, the combination not only effectively restores the function of macrophages in vitro but also suppresses tumor growth in xenograft mouse models without detectable toxicity to normal tissues. The results indicate that GalNAc-modified nanospheres, as a part of LYTACs, can be successfully internalized and are an effective drug-loading platform and a modular degradation strategy for the lysosomal degradation of cell membrane and extracellular proteins, which can be broadly applied in the fields of biochemistry and tumor therapeutics.

Correction: Yu et al. Recent Advances of Mesoporous Silica as a Platform for Cancer Immunotherapy. Biosensors 2022, 12, 109.

In the published publication [...].

Peptide-based PROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and PD-L1 expression.

BACKGROUND: Peptide proteolysis-targeting chimeras (p-PROTACs) with advantages of high specificity and low toxicity have emerged as a powerful technology of targeted protein degradation for biomedical applications. FOXM1, a proliferation-associated transcription factor, is overexpressed in a variety of human tumors as a key driver of tumorigenesis and cancer progression, and is a potential anticancer therapeutic target. However, FOXM1-targeting p-PROTACs has not been researched. METHODS: Here, we first analyzed the expression of FOXM1, GLUT1 and PD-L1 in liver cancer through database and clinical samples of patients. FOXM1-targeting peptides, selected by screening phage display library, are verified its targeting effect by immunofluorescence and CCK-8 test. The novel p-PROTAC degrader of FOXM1 is chemically synthesis, named FOXM1-PROTAC, by linking a FOXM1-binding antagonistic peptide, with the E3 ubiquitin ligase recruitment ligand Pomalidomide and with the cell membrane penetrating peptide TAT. Its degradation effect on FOXM1 was detected by Western blotting, qPCR, and we verified its effect on the behavior of cancer cells by flow cytometry, scratch assay, and Transwell in vitro. The tumor xenografted mice model was used for evaluating FOXM1-PROTAC therapeutic response in vivo. Finally, we detected the expression of GLUT1 and PD-L1 after FOXM1-PROTAC degraded FOXM1 by using Western Blotting and hippocampal detectors and dual immunofluorescence. RESULTS: We found that the novel FOXM1-PROTAC efficiently entered cells and induced degradation of FOXM1 protein, which strongly inhibits viability as well as migration and invasion in various cancer cell lines, and suppressed tumor growth in HepG2 and MDA-MB-231 cells xenograft mouse models, without detected toxicity in normal tissues. Meanwhile, FOXM1-PROTAC decreased the cancer cells glucose metabolism via downregulating the protein expression levels of glucose transporter GLUT1 and the immune checkpoint PD-L1, which suggests involvement of FOXM1 in cancer cell metabolism and immune regulation. CONCLUSIONS: Our results indicate that biologically targeted degradation of FOXM1 is an attractive therapeutic strategy, and antagonist peptide-containing FOXM1-PROTACs as both degrader and inhibitor of FOXM1 could be developed as a safe and promising drug for FOXM1-overexpressed cancer therapy.

Disease-Specific Factors Associated with Readmissions or Mortality After Hospital Discharge in COVID-19 Patients: a Retrospective Cohort Study.

BACKGROUND: Understanding the implications of disease-specific factors beyond baseline patient characteristics for coronavirus disease 2019 (COVID-19) may allow for identification of indicators for safe hospital discharge. OBJECTIVE: Assess whether disease-specific factors are associated with adverse events post-discharge using a data-driven approach. DESIGN: Retrospective cohort study. SETTING: Fifteen medical centers within Kaiser Permanente Southern California. PARTICIPANTS: Adult patients (n=3508) discharged alive following hospitalization for COVID-19 between 05/01/2020 and 09/30/2020. INTERVENTIONS: None. MAIN MEASURES: Adverse events defined as all-cause readmission or mortality within 14 days of discharge. Least absolute shrinkage and selection operator (LASSO) was used for variable selection and logistic regression was performed to estimate odds ratio (OR) and 95% confidence interval (CI). KEY RESULTS: Four variables including age, Elixhauser index, treatment with remdesivir, and symptom duration at discharge were selected by LASSO. Treatment with remdesivir was inversely associated with adverse events (OR: 0.46 [95%CI: 0.36-0.61]), while symptom duration ≤ 10 days was associated with adverse events (OR: 2.27 [95%CI: 1.79-2.87]) in addition to age (OR: 1.02 [95%CI: 1.01-1.03]) and Elixhauser index (OR: 1.15 [95%CI: 1.11-1.20]). A significant interaction between remdesivir and symptom duration was further observed (p=0.01). The association of remdesivir was stronger among those with symptom duration ≤10 days vs >10 days at discharge (OR: 0.30 [95%CI: 0.19-0.47] vs 0.62 [95%CI: 0.44-0.87]), while the association of symptom duration ≤ 10 days at discharge was weaker among those treated with remdesivir vs those not treated (OR: 1.31 [95%CI: 0.79-2.17] vs 2.71 [95%CI 2.05-3.59]). CONCLUSIONS: Disease-specific factors including treatment with remdesivir, symptom duration, and their interplay may help guide clinical decision making at time of discharge.

Real-world use patterns of angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) among patients with heart failure within a large integrated health system.

BACKGROUND: Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that is now preferred in guidelines over angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for patients with heart failure with reduced ejection fraction (HFrEF). However, it has not been broadly adopted in clinical practice. OBJECTIVE: To characterize ARNI use within a large diverse real-world population and assess for any racial disparities. METHODS: We conducted a cross-sectional study within Kaiser Permanente Southern California. Adult patients with HFrEF who received ARNIs, ACEIs, or ARBs between January 1, 2014, and November 30, 2020, were identified. The prevalence of ARNI use among the cohort and patient characteristics by ARNIs vs ACEIs/ARBs use were described. Multivariable regression was performed to estimate odds ratios and 95% CIs of receiving ARNI by race and ethnicity. RESULTS: Among 12,250 patients with HFrEF receiving ACEIs, ARBs, or ARNIs, 556 (4.54%) patients received ARNIs. ARNI use among this cohort increased from 0.02% in 2015 to 7.48% in 2020. Patients receiving ARNIs were younger (aged 62 vs 69 years) and had a lower median ejection fraction (27% vs 32%) compared with patients receiving ACEIs/ARBs. They also had higher use of mineralocorticoid antagonists (24.1% vs 19.8%) and automatic implantable cardioverterdefibrillators (17.4% vs 13.3%). There were no significant differences in rate of ARNI use by race and ethnicity. CONCLUSIONS: Within a large diverse integrated health system in Southern California, the rate of ARNI use has risen over time. Patients given ARNIs were younger with fewer comorbidities, while having worse ejection fraction. Racial minorities were no less likely to receive ARNIs compared with White patients. DISCLOSURES: Dr Huang had stock ownership in Gilead and Pfizer. Dr Liang received support for article processing and medical writing.

The Water Transport System in Astrocytes-Aquaporins.

Astrocytes have distinctive morphological and functional characteristics, and are found throughout the central nervous system. Astrocytes are now known to be far more than just housekeeping cells in the brain. Their functions include contributing to the formation of the blood-brain barrier, physically and metabolically supporting and communicating with neurons, regulating the formation and functions of synapses, and maintaining water homeostasis and the microenvironment in the brain. Aquaporins (AQPs) are transmembrane proteins responsible for fast water movement across cell membranes. Various subtypes of AQPs (AQP1, AQP3, AQP4, AQP5, AQP8 and AQP9) have been reported to be expressed in astrocytes, and the expressions and subcellular localizations of AQPs in astrocytes are highly correlated with both their physiological and pathophysiological functions. This review describes and summarizes the recent advances in our understanding of astrocytes and AQPs in regard to controlling water homeostasis in the brain. Findings regarding the features of different AQP subtypes, such as their expression, subcellular localization, physiological functions, and the pathophysiological roles of astrocytes are presented, with brain edema and glioma serving as two representative AQP-associated pathological conditions. The aim is to provide a better insight into the elaborate "water distribution" system in cells, exemplified by astrocytes, under normal and pathological conditions.

Statin Use and Mortality among Patients Hospitalized with Sepsis: A Retrospective Cohort Study within Southern California, 2008-2018.

Background: Despite early goal-directed therapy, sepsis mortality remains high. Statins exhibit pleiotropic effects. Objective: We sought to compare mortality outcomes among statin users versus nonusers who were hospitalized with sepsis. Methods: Retrospective cohort study of patients (age ≥18 years) during 1/1/2008-9/30/2018. Mortality was compared between statin users and nonusers and within statin users (hydrophilic versus lipophilic, fungal versus synthetic derivation, and individual statins head-to-head). Multivariable Cox regression models were used to estimate hazard ratios (HR) for 30-day and 90-day mortality. Inverse probability treatment weighting (IPTW) analysis was performed to account for indication bias. Results: Among 128,161 sepsis patients, 34,088 (26.6%) were prescribed statin drugs prior to admission. Statin users compared to nonusers had a 30-day and 90-day mortality HR (95% CI) of 0.80 (0.77-0.83) and 0.79 (0.77-0.81), respectively. Synthetic derived statin users compared to fungal derived users had a 30- and 90-day mortality HR (95% CI) of 0.86 (0.81-0.91) and 0.85 (0.81-0.89), respectively. Hydrophilic statin users compared to lipophilic users had a 30-day and 90-day mortality HR (95% CI) of 0.90 (0.81-1.01) and 0.86 (0.78-0.94), respectively. Compared to simvastatin, 30-day mortality HRs (95% CI) were 0.85 (0.66-1.10), 0.87 (0.82-0.92), 0.87 (0.76-0.98), and 1.22 (1.10-1.36) for rosuvastatin, atorvastatin, pravastatin, and lovastatin, respectively. Conclusion: Statin use was associated with lower mortality in patients hospitalized with sepsis. Hydrophilic and synthetic statins were associated with better outcomes than lipophilic and fungal-based preparations.

TRPM2 deficiency in mice protects against atherosclerosis by inhibiting TRPM2-CD36 inflammatory axis in macrophages.

Atherosclerosis is the major cause of ischemic heart disease and stroke, the leading causes of mortality worldwide. The central pathological features of atherosclerosis include macrophage infiltration and foam cell formation. However, the detailed mechanisms regulating these two processes remain unclear. Here we show that oxidative stress-activated Ca2+-permeable transient receptor potential melastatin 2 (TRPM2) plays a critical role in atherogenesis. Both global and macrophage-specific Trpm2 deletion protect Apoe -/- mice against atherosclerosis. Trpm2 deficiency reduces oxidized low-density lipoprotein (oxLDL) uptake by macrophages, thereby minimizing macrophage infiltration, foam cell formation and inflammatory responses. Activation of the oxLDL receptor CD36 induces TRPM2 activity, and vice versa. In cultured macrophages, TRPM2 is activated by CD36 ligands oxLDL and thrombospondin-1 (TSP1), and deleting Trpm2 or inhibiting TRPM2 activity suppresses the activation of CD36 signaling cascade induced by oxLDL and TSP1. Our findings establish the TRPM2-CD36 axis as a molecular mechanism underlying atherogenesis, and suggest TRPM2 as a potential therapeutic target for atherosclerosis.