Phase Transition in Postsynaptic Densities Underlies Formation of Synaptic Complexes and Synaptic Plasticity.

Postsynaptic densities (PSDs) are membrane semi-enclosed, submicron protein-enriched cellular compartments beneath postsynaptic membranes, which constantly exchange their components with bulk aqueous cytoplasm in synaptic spines. Formation and activity-dependent modulation of PSDs is considered as one of the most basic molecular events governing synaptic plasticity in the nervous system. In this study, we discover that SynGAP, one of the most abundant PSD proteins and a Ras/Rap GTPase activator, forms a homo-trimer and binds to multiple copies of PSD-95. Binding of SynGAP to PSD-95 induces phase separation of the complex, forming highly concentrated liquid-like droplets reminiscent of the PSD. The multivalent nature of the SynGAP/PSD-95 complex is critical for the phase separation to occur and for proper activity-dependent SynGAP dispersions from the PSD. In addition to revealing a dynamic anchoring mechanism of SynGAP at the PSD, our results also suggest a model for phase-transition-mediated formation of PSD.

Enhanced Thermoelectric Properties of Ti2CO2-Bismuthene-Ti2CO2: Optimized Power Factor and Reduced Thermal Conductivity.

In this study, bismuthene was intercalated between bilayer Ti2CTx to induce significant modifications in its electronic and phonon structures, thereby enhancing its thermoelectric properties. First-principles calculations reveal that the insertion of bismuthene transforms the Ti2CO2 system from a semiconductor into a metal and optimizes the thermoelectric properties of bilayer Ti2CO2 by enhancing its power factor and reducing its lattice thermal conductivity. Under the first-principles calculation parameters used in this study, the ZT of the Ti2CO2 system increased from 0.12 to 0.55. Conversely, for metallic bilayer MXenes, the introduction of bismuthene led to a substantial decrease in ZT (from 0.53 to 0.11 in the Ti2C system and from 0.07 to 0.05 in the Ti2CCl2 system). This study investigates the physical mechanisms underlying the enhancement of thermoelectric properties from both electronic and phononic perspectives and provides theoretical insights into the development and application of MXene-based thermoelectric materials.

Association between sleep regularity and arterial stiffness among middle-age adults in Southwestern China.

BACKGROUND: Sleep regularity has been linked to a risk of arterial stiffness (AS). However, the association between sleep regularity indicators, which reflect 24-hour sleep variability, and AS has not yet been examined. METHODS: We analyzed data from 516 adults, aged 40-65 years (the median age of 51 years), from the 'Follow-up Study of Sleep Characteristics and Chronic Diseases in the Middle-aged and Elderly Population in Guizhou Province'. Participants underwent assessments of AS (OMRON HBP-8000, baPWV ≥ 1400 cm/s) and sleep (wrist smart band (Honor band 5i) for ≥ 7 days). Logistic regression was utilized to evaluate the odds ratio (OR) and 95% confidence interval (CI) of the association between sleep regularity and AS. RESULTS: A total of 516 people were included in this study, of which 279 (54.07%) were in the AS group. The univariate results showed that the AS group (Median 71.18) had lower SRI compared to the No-AS group (Median 75.00) (p < 0.001). The multifactorial results showed participants with higher SRI scores were more likely to have a lower risk of AS compared to those with lower SRI scores (ORQ4 VS. Q1=0.46, 95%CI: 0.25-0.85, p = 0.013). The SRI effect was more pronounced in male (ORQ4 VS. Q1=0.28, 95%CI: 0.12-0.69, p = 0.005), snoring populations (ORQ4 VS. Q1=0.13, 95%CI: 0.04-0.48, p = 0.002), and non-retired populations (ORQ4 VS. Q1=0.45, 95%CI: 0.22-0.92, p = 0.028). CONCLUSIONS: The present findings indicated that the effect between SRI and AS may be more sensitive than the standard deviation of sleep duration as well as the standard deviation of sleep onset.

Hyperbaric oxygen therapy promotes the browning of white fat and contributes to the healing of diabetic wounds.

Non-healing wounds are one of the chronic complications of diabetes and have remained a worldwide challenge as one of the major health problems. Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic wound treatment, for which the molecular basis is not understood. Adipocytes regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes. Endothelial cell-derived extracellular vesicles could promote wound healing in diabetes. To study the mechanism by which HBO promotes wound healing in diabetes, we investigated the effect of HBO on fat cells in diabetic mice. A diabetic wound mouse model was established and treated with HBO. Haematoxylin and eosin (H&E) staining and immunofluorescence were used for the analysis of wound healing. To further explore the mechanism, we performed whole-genome sequencing on extracellular vesicles (EVs). Furthermore, we conducted in vitro experiments. Specifically, exosomes were collected from human umbilical vein endothelial cell (HUVEC) cells after HBO treatment, and then these exosomes were co-incubated with adipose tissue. The wound healing rate in diabetic mice treated with HBO was significantly higher. HBO therapy promotes the proliferation of adipose precursor cells. HUVEC-derived exosomes treated with HBO significantly promoted fat cell browning. These data clarify that HBO therapy may promote vascular endothelial cell proliferation and migration, and promote browning of fat cells through vascular endothelial cells derived exosomes, thereby promoting diabetic wound healing. This provides new ideas for the application of HBO therapy in the treatment of diabetic trauma.

Mixed-Valence CuI /CuIII Metal-Organic Frameworks with Non-innocent Ligand for Multielectron Transfer.

We report two novel three-dimensional copper-benzoquinoid metal-organic frameworks (MOFs), [Cu4 L3 ]n and [Cu4 L3 ⋅ Cu(iq)3 ]n (LH4 =1,4-dicyano-2,3,5,6-tetrahydroxybenzene, iq=isoquinoline). Spectroscopic techniques and computational studies reveal the unprecedented mixed valency in MOFs, formal Cu(I)/Cu(III). This is the first time that formally Cu(III) species are witnessed in metal-organic extended solids. The coordination between the mixed-valence metal and redox-non-innocent ligand L, which promotes through-bond charge transfer between Cu metal sites, allows better metal-ligand orbital overlap of the d-π conjugation, leading to strong long-range delocalization and semiconducting behavior. Our findings highlight the significance of the unique mixed valency between formal Cu(I) and highly-covalent Cu(III), non-innocent ligand, and pore environments of these bench stable Cu(III)-containing frameworks on multielectron transfer and electrochemical properties.

CIDEC: A Potential Factor in Diabetic Vascular Inflammation.

Cell death-inducing DFF45-like effector C (CIDEC) is involved in diet-induced adipose inflammation. Whether CIDEC plays a role in diabetic vascular inflammation remains unclear. A type 2 diabetic rat model was induced by high-fat diet and low-dose streptozotocin. We evaluated its characteristics by metabolic tests, Western blot analysis of CIDEC and C1q/tumor necrosis factor-related protein-3 (CTRP3) expression, and histopathological analysis of aortic tissues. The diabetic group exhibited elevated CIDEC expression, aortic inflammation, and remodeling. To further investigate the role of CIDEC in the pathogenesis of aortic inflammation, gene silencing was used. With CIDEC gene silencing, CTRP3 expression was restored, accompanied with amelioration of insulin resistance, aortic inflammation, and remodeling in diabetic rats. Thus, the silencing of CIDEC is potent in mediating the reversal of aortic inflammation and remodeling, indicating that CIDEC may be a potential therapeutic target for vascular complications in diabetes.

Cell death-inducing DFFA-like effector C/CIDEC gene silencing alleviates diabetic cardiomyopathy via upregulating AMPKa phosphorylation.

Cell death-inducing DFFA-like effector C (CIDEC) is responsible for metabolic disturbance and insulin resistance, which are considered to be important triggers in the development of diabetic cardiomyopathy (DCM). To investigate whether CIDEC plays a critical role in DCM, DCM rat model was induced by a high-fat diet and a single injection of low-dose streptozotocin (27.5 mg/kg). DCM rats showed severe metabolic disturbance, insulin resistance, myocardial hypertrophy, interstitial fibrosis, ectopic lipid deposition, inflammation and cardiac dysfunction, accompanied by CIDEC elevation. With CIDEC gene silencing, the above pathophysiological characteristics were significantly ameliorated accompanied by significant improvements in cardiac function in DCM rats. Enhanced AMP-activated protein kinase (AMPK) α activation was involved in the underlying pathophysiological molecular mechanisms. To further explore the underlying mechanisms that CIDEC facilitated collagen syntheses in vitro, insulin-resistant cardiac fibroblast (CF) model was induced by high glucose (15.5 mmol/L) and high insulin (104  µU/mL). We observed that insulin-resistant stimulation dramatically raised CIDEC expression and promoted CIDEC nuclear translocation in CFs. Meanwhile, AMPKα2 was observed to distribute almost completely inside CF nucleus. The results further proved that CIDEC biochemically interacted and co-localized with AMPKα2 rather than AMPKα1 in CF nucleus, which provided a novel mechanism of CIDEC in promoting collagen syntheses. This study suggested that CIDEC gene silencing alleviates DCM via AMPKα signaling both in vivo and in vitro, implicating CIDEC may be a promising target for treatment of human DCM.

Mechanistic basis of MAGUK-organized complexes in synaptic development and signalling.

Membrane-associated guanylate kinases (MAGUKs) are a family of scaffold proteins that are highly enriched in synapses and are responsible for organizing the numerous protein complexes required for synaptic development and plasticity. Mutations in genes encoding MAGUKs and their interacting proteins can cause a broad spectrum of human psychiatric disorders. Here, we review MAGUK-mediated synaptic protein complex formation and regulation by focusing on findings from recent biochemical and structural investigations. These mechanistic-based studies show that the formation of MAGUK-organized complexes is often directly regulated by protein phosphorylation, suggesting a close connection between neuronal activity and the assembly of dynamic protein complexes in synapses.

BGSA: a bit-parallel global sequence alignment toolkit for multi-core and many-core architectures.

MOTIVATION: Modern bioinformatics tools for analyzing large-scale NGS datasets often need to include fast implementations of core sequence alignment algorithms in order to achieve reasonable execution times. We address this need by presenting the BGSA toolkit for optimized implementations of popular bit-parallel global pairwise alignment algorithms on modern microprocessors. RESULTS: BGSA outperforms Edlib, SeqAn and BitPAl for pairwise edit distance computations and Parasail, SeqAn and BitPAl when using more general scoring schemes for pairwise alignments of a batch of sequence reads on both standard multi-core CPUs and Xeon Phi many-core CPUs. Furthermore, banded edit distance performance of BGSA on a Xeon Phi-7210 outperforms the highly optimized NVBio implementation on a Titan X GPU for the seed verification stage of a read mapper by a factor of 4.4. AVAILABILITY AND IMPLEMENTATION: BGSA is open-source and available at https://github.com/sdu-hpcl/BGSA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Deep-Ultraviolet Emissive Carbon Nanodots.

Deep-ultraviolet (DUV) emissive carbon nanodots (CNDs) have been designed theoretically and demonstrated experimentally based on the results of first-principles calculations using the density functional theory method. The emission of the CNDs is located in the range from 280 to 300 nm, which coincides well with the results of theoretical calculation results. The photoluminescence (PL) quantum yield (QY) of the CNDs is up to 31.6%, and the strong emission of the CNDs originates from core-state (π-π*) carriers' radiative recombination and surface passivation. Benefiting from the core-state emission and surface group passivation, the emission of the CNDs is independent of the excitation wavelength and ambient solvent. DUV light-emitting diodes (LEDs) have been fabricated based on the DUV emissive CNDs, and the LEDs can be used as the excitation source to excite blue, green, and red CNDs, indicating their potential application in DUV light sources. This work may provide a clue for the designing and realizing of DUV emissive CNDs, thus promising the potential application of CNDs in DUV light-emitting sources.

Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex.

The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.

LGN/mInsc and LGN/NuMA complex structures suggest distinct functions in asymmetric cell division for the Par3/mInsc/LGN and Gαi/LGN/NuMA pathways.

Asymmetric cell division requires the establishment of cortical cell polarity and the orientation of the mitotic spindle along the axis of cell polarity. Evidence from invertebrates demonstrates that the Par3/Par6/aPKC and NuMA/LGN/Gαi complexes, which are thought to be physically linked by the adaptor protein mInscuteable (mInsc), play indispensable roles in this process. However, the molecular basis for the binding of LGN to NuMA and mInsc is poorly understood. The high-resolution structures of the LGN/NuMA and LGN/mInsc complexes presented here provide mechanistic insights into the distinct and highly specific interactions of the LGN TPRs with mInsc and NuMA. Structural comparisons, together with biochemical and cell biology studies, demonstrate that the interactions of NuMA and mInsc with LGN are mutually exclusive, with mInsc binding preferentially. Our results suggest that the Par3/mInsc/LGN and NuMA/LGN/Gαi complexes play sequential and partially overlapping roles in asymmetric cell division.

A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function.

Shank and SAPAP (synapse-associated protein 90/postsynaptic density-95-associated protein) are two highly abundant scaffold proteins that directly interact with each other to regulate excitatory synapse development and plasticity. Mutations of SAPAP, but not other reported Shank PDZ domain binders, share a significant overlap on behavioral abnormalities with the mutations of Shank both in patients and in animal models. The molecular mechanism governing the exquisite specificity of the Shank/SAPAP interaction is not clear, however. Here we report that a sequence preceding the canonical PDZ domain of Shank, together with the elongated PDZ BC loop, form another binding site for a sequence upstream of the SAPAP PDZ-binding motif, leading to a several hundred-fold increase in the affinity of the Shank/SAPAP interaction. We provide evidence that the specific interaction afforded by this newly identified site is required for Shank synaptic targeting and the Shank-induced synaptic activity increase. Our study provides a molecular explanation of how Shank and SAPAP dosage changes due to their gene copy number variations can contribute to different psychiatric disorders.

Structural Basis of Highly Specific Interaction between Nephrin and MAGI1 in Slit Diaphragm Assembly and Signaling.

BACKGROUND: The slit diaphragm is a specialized adhesion junction between opposing podocytes, establishing the final filtration barrier that prevents passage of proteins from the capillary lumen into the urinary space. Nephrin, the key structural and signaling adhesion molecule expressed in the slit diaphragm, contains an evolutionally conserved, atypical PDZ-binding motif (PBM) reported to bind to a variety of proteins in the slit diaphragm. Several mutations in NPHS1 (the gene encoding nephrin) that result in nephrin lacking an intact PBM are associated with glomerular diseases. However, the molecular basis of nephrin-PBM-mediated protein complexes is still unclear. METHODS: Using a combination of biochemic, biophysic, and cell biologic approaches, we systematically investigated the interactions between nephrin-PBM and PDZ domain-containing proteins in the slit diaphragm. RESULTS: We found that nephrin-PBM specifically binds to one member of the membrane-associated guanylate kinase family of scaffolding proteins, MAGI1, but not to another, MAGI2. The complex structure of MAGI1-PDZ3/nephrin-PBM reveals that the Gly at the -3 position of nephrin-PBM is the determining feature for MAGI1-PDZ3 recognition, which sharply contrasts with the typical PDZ/PBM binding mode. A single gain-of-function mutation within MAGI2 enabled nephrin-PBM binding. In addition, using our structural analysis, we developed a highly efficient inhibitory peptide capable of specifically blocking the nephrin/MAGI1 interaction. CONCLUSIONS: MAGI1 interacts with nephrin-PBM with exquisite specificity. A newly developed, potent inhibitory peptide that blocks this interaction may be useful for future functional investigations in vivo. Our findings also provide possible explanations for the diseases caused by NPHS1 mutations.

Use of Multi-Agent Theory to Resolve Complex Indoor Air Quality Control Problems.

Taiwan has suffered from widespread haze and poor air quality during recent years, and the control of indoor air quality has become an important topic. This study relies on Multi-Agent theory in which collected air quality was used in calculations and after agents make decisions in accordance with pre-written rules to construct and indoor air quality control system and conflict resolution mechanism, which will serve to maintain a healthy and comfortable indoor environment. As for implementation, the simulated system used the Arduino open source microcontroller system to collect air quality data and turn on building equipment in order to improve indoor air quality. This study also used the graphic control program LabVIEW to write a control program and user interface. The implementation verifies the feasibility of applying multi-agent theory to air quality control systems, and an Individual intelligent agent has the basic ability to resolve their own conflicts autonomously. However, when there are multiple factors and user status are simultaneously involved in the decision-making, it is difficult for the system to exhaust all conflict conditions, and when context control surpassing the restrictions of binary logic rule-based reasoning, it is necessary to change the algorithm and redesign the system.

Structure of the PSD-95/MAP1A complex reveals a unique target recognition mode of the MAGUK GK domain.

The PSD-95 family of membrane-associated guanylate kinases (MAGUKs) are major synaptic scaffold proteins and play crucial roles in the dynamic regulation of dendritic remodelling, which is understood to be the foundation of synaptogenesis and synaptic plasticity. The guanylate kinase (GK) domain of MAGUK family proteins functions as a phosphor-peptide binding module. However, the GK domain of PSD-95 has been found to directly bind to a peptide sequence within the C-terminal region of neuronal-specific microtubule-associated protein 1A (MAP1A), although the detailed molecular mechanism governing this phosphorylation-independent interaction at the atomic level is missing. In the present study, we determine the crystal structure of PSD-95 GK in complex with the MAP1A peptide at 2.6-Å resolution. The complex structure reveals that, unlike a linear and elongated conformation in the phosphor-peptide/GK complexes, the MAP1A peptide adopts a unique conformation with a stretch of hydrophobic residues far from each other in the primary sequence clustering and interacting with the 'hydrophobic site' of PSD-95 GK and a highly conserved aspartic acid of MAP1A (D2117) mimicking the phosphor-serine/threonine in binding to the 'phosphor-site' of PSD-95 GK. We demonstrate that the MAP1A peptide may undergo a conformational transition upon binding to PSD-95 GK. Further structural comparison of known DLG GK-mediated complexes reveals the target recognition specificity and versatility of DLG GKs.

[Surfaced-Enhanced Raman Scattering Spectroscopic Study on Sheng-Di-Dang-Gui Decoction].

To reveal the relationship between the single decoction and prescription, the surface-enhanced Raman scattering (SERS) spectroscopy of Sheng-Di-Dang-Gui decoction (SDDGD), Sheng-Di decoction (SDD) and Dang-Gui decoction (DGD) were tested and analyzed. Mainly seventeen Raman signals (538, 622, 732, 761, 835, 876, 959, 1 145, 1 245, 1 276, 1 326, 1 402, 1 456, 1 470, 1 518, 1 546 and 1 605 cm(-1)) in three decoctions were discussed. The characteristic Raman bands of three decoctions were tentatively assigned. Fifteen obvious Raman bands (538, 732, 761, 835, 876, 959, 1 145, 1 245, 1 276, 1 326, 1 402, 1 456, 1 470, 1 518 and 1 605 cm(-1)) were observed in the SERS spectroscopy of SDDGD, thirteen obvious Raman bands (538, 761, 835, 876, 959, 1 145, 1 245, 1 276, 1 326, 1 402, 1 470, 1 518 and 1 546 cm(-1)) were observed in the SERS spectroscopy of SDD, ten obvious Raman bands (538, 622, 732, 761, 835, 876, 959, 1 245, 1 326 and 1 402 cm(-1)) were observed in the SERS spectroscopy of DGD. Some Raman bands in SERS spectra of SDD and DGD were retained in the SDDGD, however some Raman bands in two kinds of decoctions never appeared in the SDDGD. And new Raman bands (1 456 and 1 605 cm(-1)) were generated in the SDDGD, resulted in the fact that new chemical compositions were created. Medical ingredients in the SDDGD were not the simple addition of SDD and DGD. The results showed that the SERS spectroscopy might provide a new kind of novel, effective and simple detecting method for the prescription research.

[Advances in Raman Spectroscopy for Nasopharyngeal Carcinoma Tissue].

Nasopharyngeal carcinoma is a unique malignant tumor that has a distinct geographic and racial distribution, with a high incidence in southeast Asia and southern China. High degree of malignancy, poor prognosis and difficulty in early diagnosis remain a problem in nasopharyngeal carcinoma. Raman spectroscopy technique based on inelastic scattering is a rapid and nonivasive detection method, which is capable of providing the information of biochemical components at molecular vibration level.This article reviewed the recent research progress of nasopharyngeal carcinoma based on Raman spectroscopy. It mainly introduces the study of detecting nasopharyngeal carcinoma tissue by using Raman spectroscopy as well as surface-enhanced Raman scattering spectroscopy (SERS). The emphasis is put on the latest works by our research group, including high wavenumber Raman spectroscopy of tissue, Raman spectroscopy of tissue smears, and a specially designed endoscopic device combined with Raman spectroscopy for in vivo nasopharyngeal cancerous tissue detection, which was firstly developed by our group. Finally, the prospects of the development of Raman spectroscopy for nasopharyngeal carcinoma were discussed.

[Studies of Male Fertility with Raman Spectroscopy].

Raman spectroscopy which belongs to scattering spectroscopy obtained molecular vibrational and rotational information to achieve detection and analysis of molecular structure and corresponding changes through recording the frequency shift when light interacted with materials. Compared with routine biochemical analysis, Raman spectroscopy has the advantage of non-invasive, label-free and no sample requirement. Raman spectroscopy has been widely applied in biomedical field such as human tissue, organs, cells and human body fluids for disease diagnosis. This article mainly focuses on recent research advances of Raman spectroscopy in human semen. Firstly, Raman spectroscopy(including surface-enhanced Raman spectroscopy, SERS) employed in forensic science for semen analysis, and some related data processing methods were introduced, then Raman spectroscopy involved investigations of male fertility was highlighted, more specifically, the Raman-based qualitative and quantitative analysis which assist the objective detection and evaluation of male fertility. Furthermore, studies of single sperm cell based on micro-Raman system to characterize and evaluate sperm quality and the preliminarily obtained Raman biomarkers which indicate high-quality sperm cell were introduced. Finally, the potential development of Raman spectroscopy involved in reproduction and fertility field was also discussed.

Guanylate kinase domains of the MAGUK family scaffold proteins as specific phospho-protein-binding modules.

Membrane-associated guanylate kinases (MAGUKs) are a large family of scaffold proteins that play essential roles in tissue developments, cell-cell communications, cell polarity control, and cellular signal transductions. Despite extensive studies over the past two decades, the functions of the signature guanylate kinase domain (GK) of MAGUKs are poorly understood. Here we show that the GK domain of DLG1/SAP97 binds to asymmetric cell division regulatory protein LGN in a phosphorylation-dependent manner. The structure of the DLG1 SH3-GK tandem in complex with a phospho-LGN peptide reveals that the GMP-binding site of GK has evolved into a specific pSer/pThr-binding pocket. Residues both N- and C-terminal to the pSer are also critical for the specific binding of the phospho-LGN peptide to GK. We further demonstrate that the previously reported GK domain-mediated interactions of DLGs with other targets, such as GKAP/DLGAP1/SAPAP1 and SPAR, are also phosphorylation dependent. Finally, we provide evidence that other MAGUK GKs also function as phospho-peptide-binding modules. The discovery of the phosphorylation-dependent MAGUK GK/target interactions indicates that MAGUK scaffold-mediated signalling complex organizations are dynamically regulated.