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.

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.

Broadband transparent and high-Q resonant polarization meta-grating enabled by a non-local geometric-phase metasurface.

Spatial wavefront control and high-Q spectral filtering are both of great importance for various optical applications, such as eye-tracking for eyewear, planar optical modulators, and optical sensing. However, it is a great challenge to simultaneously satisfy these two functionalities in a metasurface due to the inevitable conflicts of local and non-local modes, where local modes of a single meta-atom manipulate the wavefront in a broadband range, while non-local collective modes of extended meta-atoms only support high-Q resonances at certain characteristic wavelengths. Here, we demonstrate a low-contrast dielectric non-local meta-grating that provides both spatial and spectral control of light in a broadband range of 700-1600 nm, offering elaborate wavefront shaping only for narrow-band resonances. Such counterintuitive functionality is supported by spatially tailored dark modes (quasi-bound states in the continuum) encoding with spatially varying geometric phases, while low-contrast dielectric provides broadband non-resonant transmission. Moreover, a broadband transparent polarization meta-grating with two resonance wavelengths is presented. Non-local geometric-phase metasurfaces open an exciting avenue for wavefront shaping and spectral manipulation, and may have potential applications in sensing, lasing, and spectral filtering.

Topology-optimized catenary-like metasurface for wide-angle and high-efficiency deflection: from a discrete to continuous geometric phase.

We investigate the topology optimization of geometric phase metasurfaces for wide-angle and high-efficiency deflection, where adjoint-based multi-object optimization approach is adopted to improve the absolute efficiency while maintaining the polarization conversion characteristic of geometric phase metasurfaces. We show that, for the initially discrete geometric phase metasurfaces with different materials and working wavelengths, the topology shapes gradually evolve from discrete structures to quasi-continuous arrangements with the increment of optimization iteration operations. More importantly, the finally optimized metasurfaces manifest as catenary-like structure, providing significant improvements of absolute efficiency. Furthermore, for the initial structure with catenary distribution, the corresponding optimized metasurface also has a catenary-like topology shape. Our results on the topology-optimized geometric phase metasurfaces reveal that, from the perspective of numerical optimization, the continuous catenary metasurfaces is superior to the discrete geometric phase metasurfaces.

Molecular Features and Expression Patterns of Vitellogenin Receptor in Calliptamus italicus (Orthoptera: Acrididae).

Vitellogenin receptor (VgR) mediates the intake of vitellin via oocytes, thus exerting an important role in vitellogenesis. In this study, reverse transcription-polymerase chain reaction (RT-PCR) and rapid-amplification of cDNA ends techniques were adopted to clone the CiVgR gene, namely the VgR gene of Calliptamus italicus, i.e., Orthopteran. The full length of CiVgR was 5,589 bp, and the open reading frame was estimated to be 5,265 bp, which encoded 1,754 amino acids (aa). Sequence alignment analysis showed that CiVgR belonged to the superfamily of low-density lipoprotein receptor genes, which contained several conserved domains, including ligand-binding domains, epidermal growth factor precursor homology domains, transmembrane domains, and cytoplasmic domains. However, no O-linked sugar domain was identified. Phylogenetic analysis showed that CiVgR had the closest genetic relationship to Blattarias. RT-PCR showed that CiVgR was only specifically expressed in the ovarian tissue of females. quantitative real time polymerase chain reaction showed that the transcription of CiVgR already appeared in the fourth-instar nymph of C. italicus, which gradually increased after adult emergence, peaked at the previtellogenesis stage, and then started to decrease. The expression pattern of CiVgR was closely associated with vitellogenesis. The findings of this study further our understanding of the molecular mechanisms involved in the reproduction of C. italicus, and provide new ideas to control this insect.

Sustainable asymmetric synthesis of diltiazem precursor enabled by recombinant Escherichia coli whole cells co-expressing an engineered ketoreductase and glucose dehydrogenase.

As a key synthetic intermediate of the cardiovascular drug diltiazem, methyl (2R,3S)-3-(4-methoxyphenyl) glycidate ((2R,3S)-MPGM) (1) is accessible via the ring closure of chlorohydrin (3S)-methyl 2-chloro-3-hydroxy-3-(4-methoxyphenyl)propanoate ((3S)-2). We report the efficient reduction of methyl 2-chloro-3-(4-methoxyphenyl)-3-oxo-propanoate (3) to (3S)-2 using an engineered enzyme SSCRM2 possessing 4.5-fold improved specific activity, which was obtained through the structure-guided site-saturation mutagenesis of the ketoreductase SSCR by reliving steric hindrance and undesired interactions. With the combined use of the co-expression fine-tuning strategy, a recombinant E. coli (pET28a-RBS-SSCRM2 /pACYCDuet-GDH), co-expressing SSCRM2 and glucose dehydrogenase, was constructed and optimized for protein expression. After optimizing the reaction conditions, whole-cell-catalyzed complete reduction of industrially relevant 300 g L-1 of 3 was realized, affording (3S)-2 with 99% ee and a space-time yield of 519.1 g∙L-1 ∙d-1 , representing the highest record for the biocatalytic synthesis of (3S)-2 reported to date. The E-factor of this biocatalytic synthesis was 24.5 (including water). Chiral alcohol (3S)-2 generated in this atom-economic synthesis was transformed to (2R,3S)-MPGM in 95% yield with 99% ee.

A randomized controlled trial investigating the impact of a single flash cupping session on patients with chronic lower back pain using multichannel surface electromyographic assessment.

BACKGROUND: Chronic lower back pain (CLBP) is one of the most common disorders worldwide. Flash cupping has the ability to relieve CLBP; nevertheless, its impact on CLBP and the likely mechanism of action have not been studied. OBJECTIVE: The goal of this study was to assess the impact of a single, brief cupping session on CLBP and low back muscle activity using multichannel surface electromyography (sEMG). METHODS: In this randomized controlled trial, 24 patients with CLBP were enrolled and randomly assigned to the control group (treated by acupuncture) and cupping group (treated by acupuncture and flash cupping). Acupuncture was applied on the shen shu (BL23), dachang shu (BL25), and wei zhong (BL40) acupoints in both the groups. A brief cupping treatment was applied to the shen shu (BL23), qihai shu (BL24), dachang shu (BL25), guanyuan shu (BL26), and xiaochang shu (BL27) acupoints on both sides of the lower back in the cupping group. The numeric rating scale (NRS) was used to assess therapy efficacy for lower back pain (LBP) before and after treatment. Surface EMG data collected during symmetrical trunk flexion-extension movements were utilized to measure lower back muscle activity and the effectiveness of LBP therapy. RESULTS: There was no statistically significant difference (P= 0.63) in pain intensity between the two groups before and after treatment. There was a statistically significant difference (P= 0.04) between the control group and the cupping group in the sEMG topographic map parameter CoGx-To-Midline. CONCLUSION: This study established a connection between the action mechanism of flash cupping and enhanced horizontal synchronization of lower back muscular activity.

Systematic Evaluation of the Efficacy of Acupuncture Associated with Physical and Mental Intervention when Treating Idiopathic Tinnitus and the Improvement of Tinnitus Symptoms.

Objective: To systematically evaluate the efficacy of acupuncture associated with physical and mental intervention when treating idiopathic tinnitus and the improvement of tinnitus symptoms, so as to supply evidence-based medicine for its popularization and adoption. Methods: PubMed, EMBASE, ScienceDirect, Cochrane Library, China knowledge Network Database (CNKI), China VIP Database, Wanfang Database, and China Biomedical Literature Database (CBM) online database were searched for the controlled trial of acupuncture associated with physical and mental intervention when treating idiopathic tinnitus. The retrieval time limit is from January 2010 to March 2022. Separately, two researchers extracted the data, and according to the Cochrane Handbook 5.3, the bias risk of each piece of literature was assessed. The collected data were measured using RevMan5.3 statistical software. Results: Finally, 5 CT articles were included in this study, with a total sample size of 282. Meta-analysis showed that the effective rate of the study group was significantly higher than that of the control group (P < 0.05). The scores of tinnitus disorder scale (THI) after treatment were analyzed by Meta. The THI scores of the study group after treatment were significantly lower than those before treatment. Meta-analysis of the severity of tinnitus after treatment showed that the severity of tinnitus in the observation group after treatment was significantly lower than that before treatment. There is a certain publication deviation in the literature, which may be related to the heterogeneity of the research and the small number of literatures. Conclusion: On the basis of acupuncture treatment, associated with physical and mental intervention is helpful to the recovery of patients with idiopathic tinnitus, can effectively improve their clinical symptoms, and is suitable for clinical application. A popularization of this concept in clinical practice is worth considering, but further research and follow-up with a higher methodological quality and longer intervention time are needed to confirm its efficacy.

Biocatalytic dynamic reductive kinetic resolution of aryl α-chloro ß-keto esters: divergent, stereocontrolled synthesis of diltiazem, clentiazem, and siratiazem.

The first systematic study of ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) on aryl α-chloro ß-keto esters was performed, and 15 structurally diverse chiral anti-aryl α-chloro ß-hydroxy esters were synthesized in 74-98% isolated yields, along with moderate-to-excellent diastereoselectivity (up to >99 : 1 dr) and good-to-excellent enantioselectivity (mostly >99% ee). LfSDR1-catalyzed complete reduction of 100 g L-1 of substrate 6b at a ten-gram scale was achieved with a continuous fed-batch strategy, affording anti-(2S,3S)-1b, the key intermediate of diltiazem, in a record-breaking space-time yield of 96 g L-1 d-1. An eight-step synthesis of diltiazem, clentiazem, and siratiazem was accomplished in 32-45% overall yields, featuring this versatile biocatalytic reduction reaction as well as an efficient, green chlorination reaction in flow.

Emerging Long-Range Order from a Freeform Disordered Metasurface.

Recently, disordered metasurfaces have attracted considerable interest due to their potential applications in imaging, holography, and wavefront shaping. However, how to emerge long-range ordered phase distribution in disordered metasurfaces remains an outstanding problem. Here, a general framework is proposed to generate a spatially homogeneous in-plane phase distribution from a disordered metasurface, by engineering disorder parameters together with topology optimization. As a proof-of-concept demonstration, an all-dielectric disordered supercell metasurface with relatively homogeneous in-plane phase fluctuation is designed by disorder parameter engineering, manifesting as polarization conversion-dependent random scattering or unidirectional transmission. Then, a topology optimization approach is utilized to overcome the lattice coupling effect and to further improve the homogeneity of complex electric field fluctuation. In comparison with the initial supercell metasurface, both the phase fluctuation range and the relative efficiency of the topology-optimized freeform metasurface are significantly improved, leading to a long-range ordered electric field distribution. Moreover, three experimental realizations are performed, all of which agree well with the theoretical results. This methodology may inspire more exotic optical phenomena and find more promising applications in disordered metasurfaces and disordered optics.

A highland-adaptation mutation of the Epas1 protein increases its stability and disrupts the circadian clock in the plateau pika.

The Qinghai-Tibet Plateau (QTP) harbors hundreds of species well adapted to its extreme conditions, including its low-oxygen (hypoxic) atmosphere. Here, we show that the plateau pika-a keystone mammal of the QTP-lacks robust circadian rhythms. The major form of the plateau pika Epas1 protein includes a 24-residue insert caused by a point mutation at the 5' juncture site of Intron14 and is more stable than other mammalian orthologs. Biochemical studies reveal that an Epas1-Bmal1 complex with lower trans-activation activity occupies the E1/E2 motifs at the promoter of the core-clock gene Per2, thus explaining how an Epas1 mutation-selected in the hypoxic conditions of the QTP-disrupts the molecular clockwork. Importantly, experiments with hypoxic chambers show that mice expressing the plateau pika Epas1 ortholog in their suprachiasmatic nucleus have dysregulated central clocks, and pika Epas1 knockin mice reared in hypoxic conditions exhibit dramatically reduced heart damage compared with wild-type animals.