A Translation-Activating Function of MIWI/piRNA during Mouse Spermiogenesis.

Spermiogenesis is a highly orchestrated developmental process during which chromatin condensation decouples transcription from translation. Spermiogenic mRNAs are transcribed earlier and stored in a translationally inert state until needed for translation; however, it remains largely unclear how such repressed mRNAs become activated during spermiogenesis. We previously reported that the MIWI/piRNA machinery is responsible for mRNA elimination during late spermiogenesis in preparation for spermatozoa production. Here we unexpectedly discover that the same machinery is also responsible for activating translation of a subset of spermiogenic mRNAs to coordinate with morphological transformation into spermatozoa. Such action requires specific base-pairing interactions of piRNAs with target mRNAs in their 3' UTRs, which activates translation through coupling with cis-acting AU-rich elements to nucleate the formation of a MIWI/piRNA/eIF3f/HuR super-complex in a developmental stage-specific manner. These findings reveal a critical role of the piRNA system in translation activation, which we show is functionally required for spermatid development.

The Alazami Syndrome-Associated Protein LARP7 Guides U6 Small Nuclear RNA Modification and Contributes to Splicing Robustness.

The La-related protein 7 (LARP7) forms a complex with the nuclear 7SK RNA to regulate RNA polymerase II transcription. It has been implicated in cancer and the Alazami syndrome, a severe developmental disorder. Here, we report a so far unknown role of this protein in RNA modification. We show that LARP7 physically connects the spliceosomal U6 small nuclear RNA (snRNA) with a distinct subset of box C/D small nucleolar RNAs (snoRNAs) guiding U6 2'-O-methylation. Consistently, these modifications are severely compromised in the absence of LARP7. Although general splicing remains largely unaffected, transcriptome-wide analysis revealed perturbations in alternative splicing in LARP7-depleted cells. Importantly, we identified defects in 2'-O-methylation of the U6 snRNA in Alazami syndrome siblings carrying a LARP7 mutation. Our data identify LARP7 as a bridging factor for snoRNA-guided modification of the U6 snRNA and suggest that alterations in splicing fidelity contribute to the etiology of the Alazami syndrome.

LARP7-Mediated U6 snRNA Modification Ensures Splicing Fidelity and Spermatogenesis in Mice.

U6 snRNA, as an essential component of the catalytic core of the pre-mRNA processing spliceosome, is heavily modified post-transcriptionally, with 2'-O-methylation being most common. The role of these modifications in pre-mRNA splicing as well as their physiological function in mammals have remained largely unclear. Here we report that the La-related protein LARP7 functions as a critical cofactor for 2'-O-methylation of U6 in mouse male germ cells. Mechanistically, LARP7 promotes U6 loading onto box C/D snoRNP, facilitating U6 2'-O-methylation by box C/D snoRNP. Importantly, ablation of LARP7 in the male germline causes defective U6 2'-O-methylation, massive alterations in pre-mRNA splicing, and spermatogenic failure in mice, which can be rescued by ectopic expression of wild-type LARP7 but not an U6-loading-deficient mutant LARP7. Our data uncover a novel role of LARP7 in regulating U6 2'-O-methylation and demonstrate the functional requirement of such modification for splicing fidelity and spermatogenesis in mice.

Loss of FUT8 in renal tubules ameliorates ischemia-reperfusion injury-induced renal interstitial inflammation transition to fibrosis via the TLR3-NF-κB pathway.

Renal ischemia-reperfusion injury (IRI) is a common reason of acute kidney injury (AKI). AKI can progress to chronic kidney disease (CKD) in some survivors. Inflammation is considered the first-line response to early-stage IRI. We previously reported that core fucosylation (CF), specifically catalyzed by α-1,6 fucosyltransferase (FUT8), exacerbates renal fibrosis. However, the FUT8 characteristics, role, and mechanism in inflammation and fibrosis transition remain unclear. Considering renal tubular cells are the trigger cells that initiate the fibrosis in the AKI-to-CKD transition in IRI, we targeted CF by generating a renal tubular epithelial cell (TEC)-specific FUT8 knockout mouse and measured FUT8-driven and downstream signaling pathway expression and AKI-to-CKD transition. During the IRI extension phase, specific FUT8 deletion in the TECs ameliorated the IRI-induced renal interstitial inflammation and fibrosis mainly via the TLR3 CF-NF-κB signaling pathway. The results firstly indicated the role of FUT8 in the transition of inflammation and fibrosis. Therefore, the loss of FUT8 in TECs may be a novel potential strategy for treating AKI-CKD transition.

Topological Microlaser with a Non-Hermitian Topological Bulk.

Bulk-edge correspondence, with quantized bulk topology leading to protected edge states, is a hallmark of topological states of matter and has been experimentally observed in electronic, atomic, photonic, and many other systems. While bulk-edge correspondence has been extensively studied in Hermitian systems, a non-Hermitian bulk could drastically modify the Hermitian topological band theory due to the interplay between non-Hermiticity and topology, and its effect on bulk-edge correspondence is still an ongoing pursuit. Importantly, including non-Hermicity can significantly expand the horizon of topological states of matter and lead to a plethora of unique properties and device applications, an example of which is a topological laser. However, the bulk topology, and thereby the bulk-edge correspondence, in existing topological edge-mode lasers is not well defined. Here, we propose and experimentally probe topological edge-mode lasing with a well-defined non-Hermitian bulk topology in a one-dimensional (1D) array of coupled ring resonators. By modeling the Hamiltonian with an additional degree of freedom (referred to as synthetic dimension), our 1D structure is equivalent to a 2D non-Hermitian Chern insulator with precise mapping. Our Letter may open a new pathway for probing non-Hermitian topological effects and exploring non-Hermitian topological device applications.

Energetic eruptions leading to a peculiar hydrogen-rich explosion of a massive star.

Every supernova so far observed has been considered to be the terminal explosion of a star. Moreover, all supernovae with absorption lines in their spectra show those lines decreasing in velocity over time, as the ejecta expand and thin, revealing slower-moving material that was previously hidden. In addition, every supernova that exhibits the absorption lines of hydrogen has one main light-curve peak, or a plateau in luminosity, lasting approximately 100 days before declining. Here we report observations of iPTF14hls, an event that has spectra identical to a hydrogen-rich core-collapse supernova, but characteristics that differ extensively from those of known supernovae. The light curve has at least five peaks and remains bright for more than 600 days; the absorption lines show little to no decrease in velocity; and the radius of the line-forming region is more than an order of magnitude bigger than the radius of the photosphere derived from the continuum emission. These characteristics are consistent with a shell of several tens of solar masses ejected by the progenitor star at supernova-level energies a few hundred days before a terminal explosion. Another possible eruption was recorded at the same position in 1954. Multiple energetic pre-supernova eruptions are expected to occur in stars of 95 to 130 solar masses, which experience the pulsational pair instability. That model, however, does not account for the continued presence of hydrogen, or the energetics observed here. Another mechanism for the violent ejection of mass in massive stars may be required.

Laparoscopic antireflux surgery or PPIs in the management of reflux-related esophageal stricture.

BACKGROUND: Gastroesophageal reflux disease (GERD) is often associated with esophageal stricture, particularly benign esophageal stricture. We aimed to evaluate the effects of balloon catheter dilation (BD) combined with laparoscopic fundoplication (LF) surgery and proton pump inhibitors (PPIs) in patients with reflux-induced esophageal strictures. METHODS: We retrospectively analyzed 116 patients with reflux-induced benign esophageal strictures who underwent balloon dilatation therapy combined with PPIs (BD-PPIs group, n = 58) and balloon dilatation combined with LF (BD-LF group, n = 58). Patients were followed up for 24 months. The outcomes of the patients were monitored, including clinical success, symptom improvement, adverse events, and the frequency of esophagitis. RESULTS: At the latest follow-up, the rate of clinical success was higher in BD-LF group than in BD-PPIs group (80.4% vs. 57.7%, P = 0.011). The patients in the BD-PPIs group required more dilation sessions to achieve successful dilation, as compared to those in the BD-LF group (2.1 ± 1.2 vs. 0.7 ± 0.8, P < 0.001). The DeMeester score, number of reflux episodes for which pH was < 4, and lower esophageal sphincter pressure were significantly better in the BD-LF group than in the BD-PPIs group (all P < 0.001). The incidence of reflux esophagitis was higher in the BD-PPIs group than in the BD-LF group, at 24 months (58.8% vs. 18.2%, P = 0.003). CONCLUSIONS: Balloon dilatation with concomitant LF is effective and safe for esophageal stricture secondary to GERD. Moreover, antireflux surgery techniques, such as Nissen or Toupet procedure, should be added for reflux-induced benign esophageal stricture.

Bone marrow mesenchymal stem cell-derived exosomal miR-34c-5p ameliorates RIF by inhibiting the core fucosylation of multiple proteins.

Renal interstitial fibrosis (RIF) is an incurable pathological lesion in chronic kidney diseases. Pericyte activation is the major pathological characteristic of RIF. Fibroblast and macrophage activation are also involved in RIF. Studies have revealed that core fucosylation (CF), an important post-translational modification of proteins, plays a key role in pericyte activation and RIF by regulating multiple profibrotic signaling pathways as a hub-like target. Here, we reveal that mesenchymal stem cell (MSC)-derived exosomes reside specifically in the injured kidney and deliver microRNA (miR)-34c-5p to reduce cellular activation and RIF by inhibiting CF. Furthermore, we showed that the CD81-epidermal growth factor receptor (EGFR) ligand-receptor complex aids the entry of exosomal miR-34c-5p into pericytes, fibroblasts, and macrophages. Altogether, our findings reveal a novel role of MSC-derived exosomes in inhibiting multicellular activation via CF and provide a potential intervention strategy for renal fibrosis.

Time series RNA-seq analysis identifies MAPK10 as a critical gene in diabetes mellitus-induced atrial fibrillation in mice.

Atrial fibrillation (AF) is a major complication of type 2 diabetes mellitus (T2DM) and plays critical roles in the pathogenesis of atrial remodeling. However, the differentially expressed genes in atria during the development of AF induced by hyperglycemia have rarely been reported. Here, we showed time-dependent increased AF incidence and duration, atrial enlargement, inflammation, fibrosis, conduction time and action potential duration in db/db mice, a model of T2DM. RNA sequencing analysis showed that 2256 genes were differentially expressed in the atria at 12, 14 and 16 weeks. Gene Ontology analysis showed that these genes participate primarily in cell adhesion, cellular response to interferon-beta, immune system process, positive regulation of cell migration, ion transport and cellular response to interferon-gamma. Analysis of significant pathways revealed the IL-17 signaling pathway, TNF signaling pathway, MAPK signaling pathway, chemokine signaling pathway, and cAMP receptor signaling. Additionally, these differentially expressed genes were classified into 50 profiles by hierarchical clustering analysis. Twelve of these profiles were significant and comprised 1115 genes. Gene coexpression network analysis identified that mitogen-activated protein kinase 10 (MAPK10) was localized in the core of the gene network and was the most highly expressed gene at different time points. Knockdown of MAPK10 markedly attenuated DM-induced AF incidence, atrial inflammation, fibrosis, electrical disorder and apoptosis in db/db mice. In summary, the present findings revealed that many genes are involved in DM-induced AF and that MAPK10 plays a central role in this disease, indicating that strategies targeting MAPK10 may represent a potential therapeutic approach to treat DM-induced AF.

Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice.

Recent studies have demonstrated that hyperglycemia is a major risk factor for the development and exacerbation of cardiovascular disease (CVD). However, the molecular mechanisms involved in diabetic cardiomyopathy (DCM) have not been fully elucidated. In this study, we focused on the underlying mechanism of DCM. Leptin receptor-deficient db/db mice were used to model a type 2 diabetes mellitus (T2DM) model in our study. WT mice and db/db mice received 4-phenylbutyric acid (4-PBA) (25 mg/kg/day) and saline by intraperitoneal injection every other day for 4 weeks. WT and db/db mice were given tail vein injections of 100 µL of rAAV9-Sh-MAPK10 and rAAV9-Sh-GFP at the age of 6-8 weeks. Echocardiography was performed to measure cardiac function, histological examinations were used to evaluate ventricular hypertrophy and fibrosis. Quantitative RT-qPCR was used to assess the mRNA expression of Jun N-terminal kinase 3 (JNK3, MAPK10), atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and collagen I and III. Immunoblotting was performed to measure the levels of cardiac hypertrophy-related proteins, fibrosis-related proteins, endoplasmic reticulum stress (ERS)-related proteins and apoptosis-related proteins. TUNEL staining was performed to examine cardiomyocyte apoptosis. In contrast to 12-week-old db/db mice, 16-week-old db/db mice showed the most severe myocardial dysfunction. The DCM induced by hyperglycemia was largely alleviated by 4-PBA (25 mg/kg/day, intraperitoneal injection). Similarly, tail vein injection of rAAV9-Sh-MAPK10 reversed the phenotype of the heart in db/db mice including cardiac hypertrophy and apoptosis in db/db mice. The mechanistic findings suggested that hyperglycemia initiated the ERS response through the negative regulation of sirtuin 1 (SIRT1), leading to the occurrence of myocardial dysfunction, and specific knockdown of MAPK10 in the heart directly reversed myocardial dysfunction induced by hyperglycemia. We demonstrated that hyperglycemia promotes DCM in db/db mice through the ERS-MAPK10 signaling pathway in diabetic mice.

Endoscopic cardial constriction with band ligation in the treatment of refractory gastroesophageal reflux disease: a preliminary feasibility study.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common digestive disease, could cause extra-esophageal symptoms. Peroral endoscopic cardial constriction with band ligation (PECC-b) is a minimally invasive method for the treatment of GERD in recent years. The goals of this study were to evaluate the clinical efficacy of PECC-b to treat gastroesophageal reflux-related symptoms. METHODS: A retrospective study of patients undergoing PECC-b between January 2017 and December 2018 at a single institution was conducted. All patients confirmed GERD by endoscopy, esophageal PH-impedance monitoring, esophageal manometry and symptom questionnaires. The outcome measures included reflux-related scores, patients' satisfaction and drug independence after 12 months following surgery. RESULTS: A total of 68 patients, with follow-up of 12 months post surgery, were included in the final analysis. The symptom scores were all significantly decreased as compared with preoperation (P < 0.05). The esophageal symptom scores showed a better improvement than extra-esophageal symptoms (P < 0.001). Fifty-three (77.9%) patients achieved complete drug therapy independence and 52 (76.5%) patients were completely or partially satisfied with the symptom relief following surgery. CONCLUSIONS: The PECC-b is a safe, effective and recommended approach for the control of GERD-related symptoms. Further multicenter prospective studies are required to confirm these outcomes.

Topological Bands and Triply Degenerate Points in Non-Hermitian Hyperbolic Metamaterials.

Hyperbolic metamaterials (HMMs), an unusual class of electromagnetic metamaterials, have found important applications in various fields due to their distinctive properties. A surprising feature of HMMs is that even continuous HMMs can possess topological edge modes. However, previous studies based on equal-frequency surface (analogy of Fermi surface) may not correctly capture the topology of entire bands. Here we develop a topological band description for continuous HMMs that can be described by a non-Hermitian Hamiltonian formulated from Maxwell's equations. We find two types of three-dimensional non-Hermitian triply degenerate points with complex linear dispersions and topological charges ±2 and 0 induced by chiral and gyromagnetic effects. Because of the photonic nature, the vacuum band plays an important role for topological edge states and bulk-edge correspondence in HMMs. The topological band results are numerically confirmed by direct simulation of Maxwell's equations. Our work presents a general non-Hermitian topological band treatment of continuous HMMs, paving the way for exploring interesting topological phases in photonic continua and device implementations of topological HMMs.

Transcriptome analysis reveals benzotriazole ultraviolet stabilizers regulate networks related to inflammation in juvenile zebrafish (Danio rerio) brain.

Benzotriazole ultraviolet stabilizers (BUVSs) are widely applied ultraviolet absorbing compounds in industrial materials and personal care products. Due to their ubiquitous use and reports of bio-accumulation in aquatic organisms, these compounds are significant environmental pollutants; however, data are limited for BUVSs toxicity. In this study, juvenile zebrafish (Danio rerio) were exposed to 4 commonly used BUVSs (UV-234, UV-326, UV-329, and UV-P) at one dose of 10 or 100 µg/L for 28 days. To characterize the underlying mechanisms of different BUVSs-induced toxicities, we performed global transcriptome sequencing (RNA-Seq) in the brain (100 µg/L). There were 390, 575, 483, and 470 differentially expressed genes (DEGs) detected following UV-234, UV-326, UV-329, and UV-P exposure at 100 µg/L, respectively. Only 59 genes were identified as DEGs following exposure to each of the BUVSs, suggesting that these chemicals can induce unique responses in fish. Noteworthy was that there were 81 common gene networks (~10%) identified following exposure to BUVSs, many of which were related to inflammation and immune function. Uniquely regulated pathways affected by different BUVSs included those related to mitochondrial respiration, interleukin 1/brain-damaging signaling, dopaminergic signaling, and adrenergic receptor cascades. Furthermore, quantitative PCR (qPCR) results revealed that mgst1 levels were increased in fish from the 100 µg/L UV-329 treatment, while the expression of pck2 was significantly down-regulated in fish from both the 10 and 100 µg/L UV-P treatment. Transcriptomic data suggest that BUVSs can alter mitochondrial bioenergetics, alter expression of a broad range of genes in the oxidative stress response, and can induce pathways related to the immune system in zebrafish brain.

Inhibiting core fucosylation attenuates glucose-induced peritoneal fibrosis in rats.

Ultrafiltration failure is a major complication of long-term peritoneal dialysis, resulting in dialysis failure. Peritoneal fibrosis induced by continuous exposure to high glucose dialysate is the major contributor of ultrafiltration failure, for which there is no effective treatment. Overactivation of several signaling pathways, including transforming growth factor-ß1 (TGF-ß1) and platelet-derived growth factor (PDGF) pathways, contribute to the development of peritoneal fibrosis. Therefore, simultaneously blocking multiple signaling pathways might be a potential novel method of treating peritoneal fibrosis. Previously, we showed that core fucosylation, an important posttranslational modification of the TGF-ß1 receptors, can regulate the activation of TGF-ß1 signaling in renal interstitial fibrosis. However, it remains unclear whether core fucosylation affects the progression of peritoneal fibrosis. Herein, we show that core fucosylation was enriched in the peritoneal membrane of rats accompanied by peritoneal fibrosis induced by a high glucose dialysate. Blocking core fucosylation dramatically attenuated peritoneal fibrosis in the rat model achieved by simultaneously inactivating the TGF-ß1 and PDGF signaling pathways. Next the protective effects of blocking core fucosylation and imatinib (a selective PDGF receptor inhibitor) on peritoneal fibrosis were compared and found to exhibit a greater inhibitory effect over imatinib alone, suggesting that blocking activation of multiple signaling pathways may have superior inhibitory effects on the development of peritoneal fibrosis. Thus, core fucosylation is essential for the development of peritoneal fibrosis by regulating the activation of multiple signaling pathways. This may be a potential novel target for drug development to treat peritoneal fibrosis.

Continuous-wave operation in directly patterned perovskite distributed feedback light source at room temperature.

We report a directly patterned perovskite distributed feedback (DFB) resonator and show narrow amplified spontaneous emission (ASE) at pump powers as low as 0.1 W/cm2 under continuous-wave (CW) optical pumping conditions at room temperature. Compared to the pristine thin film photoluminescence spectrum, a 16-fold reduction in emission linewidth in the MAPbI3 DFB cavity was observed. The direct nanostructuring of perovskites was achieved by thermal nanoimprint lithography. Our findings pave the way toward realizing CW pumped perovskite lasers at room temperature and energy-efficient perovskite light sources.

The Role of Gastroesophageal Reflux in Provoking High Blood Pressure Episodes in Patients With Hypertension.

GOALS: We assessed the relationship between gastroesophageal reflux disease (GERD) and hypertension and whether antiacid therapy could be used to control blood pressure (BP) on hypertension in patients with GERD. BACKGROUND: Gastroesophageal reflux disease (GERD) may provoke cardiovascular disease. Many factors are involved in the development of essential hypertension, but whether GERD has a role needs further study. STUDY: Patients with essential hypertension (n=86) were studied by 24-hour continuous BP monitoring and esophageal impedance and pH monitoring. Patients fulfilling the GERD criteria received 14-day therapy with omeprazole (20 mg twice a day), and the effect on BP was studied. RESULTS: Of the 86 essential hypertension patients, 38 (44.2%) had GERD. Among these 38 patients, 494 episodes of pathologic reflux (PR), and 684 episodes of high BP were recorded. PR was significantly more common at nighttime especially when supine. Of the 684 episodes of hypertension, 102 (14.9%) were synchronous with PR. GERD patients had significantly higher nocturnal BP than non-GERD patients. Antiacid therapy brought about significant reduction in all esophageal monitoring parameters as well as in BP parameters in GERD patients. CONCLUSIONS: This study demonstrated that there is significant correlation between hypertension and GERD. Antiacid therapy can restore normal esophageal pH and help maintain normal BP.

Nanoimprinted perovskite metasurface for enhanced photoluminescence.

Recently, solution-processed hybrid halide perovskite has emerged as promising materials for advanced optoelectronic devices such as photovoltaics, photodetectors, light emitting diodes and lasers. In the mean time, all-dielectric metasurfaces with high-index materials have attracted attention due to their low-loss and high-efficient optical resonances. Because of its tunable by composition band gap in the visible frequencies, organolead halide perovskite could serve as a powerful platform for realizing high-index, low-loss metasurfaces. However, direct patterning of perovskite by lithography-based technique is not feasible due to material instability under moisture. Here we report novel organolead halide perovskite metasurfaces created by the cost-effective thermal nanoimprint technology. The nanoimprinted perovskite metasurface showed improved surface morphology and enhanced optical absorption properties. Significantly enhanced optical emission with an eight-fold enhancement in photoluminescence (PL) intensity was observed under room temperature. Temperature-dependent PL of perovskite nanograting metasurface was also investigated. Based on our results, we believe that thermal nanoimprint is a simple and cost-effective technique to fabricate perovskite-based metasurfaces, which could have broad impact on optoelectronic and photonic applications.

Near perfect light trapping in a 2D gold nanotrench grating at oblique angles of incidence and its application for sensing.

A two-dimensional nanotrench cavity grating on a thick gold film was fabricated by using e-beam lithography. Optical reflection spectra from the fabricated device were measured at oblique angles of incidence for TE and TM polarizations. Near perfect light absorption was observed at different wavelengths for TE and TM polarizations at oblique angles of incidence. The peak absorption wavelength of TM polarization red-shifts significantly as angle of incidence increases. The peak absorption wavelength of TE polarization blue-shifts slightly as incident angle increases. Using finite-difference time-domain (FDTD) simulations, two orders of magnitude magnetic field enhancement was revealed inside nanotrenches, indicating strong light trapping inside the nanostructure. The fabricated device was investigated as a refractive index chemical sensor. It was found that sensitivity increases for TM polarization and decreases for TE polarization when angle of incidence increases from zero.

A multi-layer reduced graphene oxide catalyst encapsulating a high-entropy alloy for rechargeable zinc-air batteries.

A reduced graphene oxide encapsulating Fe6Ni20Co2Mn2Cu1.5@rGO catalyst is prepared using a Joule heating strategy. The graphene-coated layer with high crystallinity enhances the stability of the crystal structure, resulting in superior OER activity. Rechargeable zinc-air batteries with Fe6Ni20Co2Mn2Cu1.5@rGO demonstrate remarkable performance, boasting a high specific capacity of 800 mA h gZn-1, an impressive peak power density of 154.612 mW cm-2, and a cycle life of 300 hours at a current density of 10 mA cm-2.