Promiscuous G-protein activation by the calcium-sensing receptor.

The human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca2+ concentration and maintains Ca2+ homeostasis1,2. It also mediates diverse cellular processes not associated with Ca2+ balance3-5. The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes6. We determined structures of CaSR in complex with G proteins from three different subfamilies: Gq, Gi and Gs. We found that the homodimeric CaSR of each complex couples to a single G protein through a common mode. This involves the C-terminal helix of each Gα subunit binding to a shallow pocket that is formed in one CaSR subunit by all three intracellular loops (ICL1-ICL3), an extended transmembrane helix 3 and an ordered C-terminal region. G-protein binding expands the transmembrane dimer interface, which is further stabilized by phospholipid. The restraint imposed by the receptor dimer, in combination with ICL2, enables G-protein activation by facilitating conformational transition of Gα. We identified a single Gα residue that determines Gq and Gs versus Gi selectivity. The length and flexibility of ICL2 allows CaSR to bind all three Gα subtypes, thereby conferring capacity for promiscuous G-protein coupling.

Human TMEFF1 is a restriction factor for herpes simplex virus in the brain.

Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE.

Author Correction: Structure of human GABAB receptor in an inactive state.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Structure of human GABAB receptor in an inactive state.

The human GABAB receptor-a member of the class C family of G-protein-coupled receptors (GPCRs)-mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction1. A unique GPCR that is known to require heterodimerization for function2-6, the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands7,8, while GABAB2 couples with G proteins9-14. Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail15. Although the VFT heterodimer structure has been resolved16, the structure of the full-length receptor and its transmembrane signalling mechanism remain unknown. Here we present a near full-length structure of the GABAB receptor, captured in an inactive state by cryo-electron microscopy. Our structure reveals several ligands that preassociate with the receptor, including two large endogenous phospholipids that are embedded within the transmembrane domains to maintain receptor integrity and modulate receptor function. We also identify a previously unknown heterodimer interface between transmembrane helices 3 and 5 of both subunits, which serves as a signature of the inactive conformation. A unique 'intersubunit latch' within this transmembrane interface maintains the inactive state, and its disruption leads to constitutive receptor activity.

Chiral bisphosphine Ph-BPE ligand: a rising star in asymmetric synthesis.

Chiral 1,2-bis(2,5-diphenylphospholano)ethane (Ph-BPE) is a class of optimal organic bisphosphine ligands with C2-symmetry. Ph-BPE with its excellent catalytic performance in asymmetric synthesis has attracted much attention of chemists with increasing popularity and is growing into one of the most commonly used organophosphorus ligands, especially in asymmetric catalysis. Over two hundred examples have been reported since 2012. This review presents how Ph-BPE is utilized in asymmetric synthesis and how powerful it is as a chiral ligand or even a catalyst in a wide range of reactions including applications in the total synthesis of bioactive molecules.

Structural Fingerprinting of the Frontal Aslant Tract: Predicting Cognitive Control Capacity and Obsessive-Compulsive Symptoms.

White matter of the human brain is influenced by common genetic variations and shaped by neural activity-dependent experiences. Variations in microstructure of cerebral white matter across individuals and even across fiber tracts might underlie differences in cognitive capacity and vulnerabilities to mental disorders. The frontoparietal and cingulo-opercular networks of the brain constitute the central system supporting cognitive functions, and functional connectivity of these networks has been used to distinguish individuals known as "functional fingerprinting." The frontal aslant tract (FAT) that passes through the two networks has been implicated in executive functions. However, whether FAT can be used as a "structural fingerprint" to distinguish individuals and predict an individual's cognitive function and dysfunction is unknown. Here we investigated the fingerprinting property of FAT microstructural profiles using three independent diffusion MRI datasets with repeated scans on human participants including both females and males. We found that diffusion and geometric profiles of FAT can be used to distinguish individuals with a high accuracy. Next, we demonstrated that fractional anisotropy in different FAT segments predicted distinct cognitive functions, including working memory, inhibitory control, and relational reasoning. Finally, we assessed the contribution of altered FAT microstructural profiles to cognitive dysfunction in unmedicated patients with obsessive-compulsive disorders. We found that the altered microstructure in FAT was associated with the severity of obsessive-compulsive symptoms. Collectively, our findings suggest that the microstructural profiles of FAT can identify individuals with a high accuracy and may serve as an imaging marker for predicting an individual's cognitive capacity and disease severity.SIGNIFICANCE STATEMENT The frontoparietal network and cingulo-opercular network of the brain constitute a dual-network architecture for human cognitive functions, and functional connectivity of these two networks can be used as a "functional fingerprint" to distinguish individuals. However, the structural underpinnings of these networks subserving individual heterogeneities in their functional connectivity and cognitive ability remain unknown. We show here that the frontal aslant tract (FAT) that passes through the two networks distinguishes individuals with a high accuracy. Further, we demonstrate that the diffusion profiles of FAT predict distinct cognitive functions in healthy subjects and are associated with the clinical symptoms in patients with obsessive-compulsive disorders. Our findings suggest that the FAT may serve as a unique structural fingerprint underlying individual cognitive capability.

PDGFRß-Antagonistic Affibody-Mediated Tumor-Targeted Tumor Necrosis Factor-Alpha for Enhanced Radiotherapy in Lung Cancer.

The morbidity and mortality of lung cancer are still the highest among all malignant tumors. Radiotherapy plays an important role in clinical treatment of lung cancer. However, the effect of radiotherapy is not ideal due to the radiation resistance of tumor tissues. Abnormalities in tumor vascular structure and function affect blood perfusion, and oxygen transport is impeded, making tumor microenvironment hypoxic. Tumor hypoxia is the major cause of radiotherapy resistance. By promoting tumor vessel normalization and enhancing vascular transport function, tumor hypoxia can be relieved to reduce radiotherapy resistance and increase tumor radiotherapy sensitivity. In our previous study, a pericytes-targeted tumor necrosis factor alpha (named Z-TNFα) was first constructed and produced by genetically fusing the platelet-derived growth factor receptor ß (PDGFRß)-antagonistic affibody (ZPDGFRß) to the TNFα, and the Z-TNFα induced normalization of tumor vessels and improved the delivery of doxorubicin, enhancing tumor chemotherapy. In this study, the tumor vessel normalization effect of Z-TNFα in lung cancer was further clarified. Moreover, the tumor hypoxia improvement and radiosensitizing effect of Z-TNFα were emphatically explored in vivo. Inspiringly, Z-TNFα specifically accumulated in Lewis lung carcinoma (LLC) tumor graft and relieved tumor hypoxia as well as inhibited HIF-1α expression. As expected, Z-TNFα significantly increased the effect of radiotherapy in mice bearing LLC tumor graft. In conclusion, these results demonstrated that Z-TNFα is also a promising radiosensitizer for lung cancer radiotherapy.

Clinical study on the necessity and feasibility of routine MRCP in patients with cholecystolithiasis before LC.

BACKGROUND: In the past quite a long time, intraoperative cholangiography(IOC)was necessary during laparoscopic cholecystectomy (LC). Now magnetic resonance cholangiopancreatography (MRCP) is the main method for diagnosing common bile duct stones (CBDS). Whether MRCP can replace IOC as routine examination before LC is still inconclusive. The aim of this study was to analyze the clinical data of patients undergoing LC for cholecystolithiasis, and to explore the necessity and feasibility of preoperative routine MRCP in patients with cholecystolithiasis. METHODS: According to whether MRCP was performed before operation, 184 patients undergoing LC for cholecystolithiasis in the Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University from January 1, 2017 to December 31, 2018 were divided into non-MRCP group and MRCP group for this retrospective study. The results of preoperative laboratory test, abdominal ultrasound and MRCP, biliary related comorbidities, surgical complications, hospital stay and hospitalization expenses were compared between the two groups. RESULTS: Among the 184 patients, there were 83 patients in non-MRCP group and 101 patients in MRCP group. In MRCP group, the detection rates of cholecystolithiasis combined with CBDS and common bile duct dilatation by MRCP were higher than those by abdominal ultrasound (P < 0.05). The incidence of postoperative complications in non-MRCP group (8.43%) was significantly higher (P < 0.05) than that in MRCP group (0%). There was no significant difference in hospital stay (P > 0.05), but there was significant difference in hospitalization expenses (P < 0.05) between the two groups. According to the stratification of gallbladder stone patients with CBDS, hospital stay and hospitalization expenses were compared, and there was no significant difference between the two groups (P > 0.05). CONCLUSIONS: The preoperative MRCP can detect CBDS, cystic duct stones and anatomical variants of biliary tract that cannot be diagnosed by abdominal ultrasound, which is helpful to plan the surgical methods and reduce the surgical complications. From the perspective of health economics, routine MRCP in patients with cholecystolithiasis before LC does not increase hospitalization costs, and is necessary and feasible.

Long-term outcomes of laparoscopic versus open distal gastrectomy for patients with advanced gastric cancer in North China: a multicenter randomized controlled trial.

BACKGROUND: Laparoscopic distal gastrectomy (LDG) has become a common procedure for treating advanced gastric cancer (AGC) in China. However, there is uncertainty regarding its oncological outcomes compared to open distal gastrectomy (ODG). This study aims to compare the 3-year disease-free survival (DFS) rates among patients who underwent surgery for AGC in northern China. METHODS: A multicenter, non-inferiority, open-label, parallel, randomized clinical trial was conducted to evaluate patients with AGC who were eligible for distal gastrectomy at five tertiary hospitals in North China. In this trial, patients were randomly assigned preoperatively to receive either LDG or ODG in a 1:1 allocation ratio. The primary endpoint was postoperative morbidity and mortality within 30 days and the secondary endpoint was the 3-year DFS rate. This trial has been registered at ClinicalTrials.gov (Identifier: NCT02464215). RESULTS: A total of 446 patients were randomly allocated to LDG (n = 223) or ODG group (n = 223) between March 2014 and August 2017. After screening, a total of 214 patients underwent the open surgical approach, while 216 patients underwent laparoscopic surgery. The 3-year DFS rate was 85.9% for the LDG group and 84.72% for the ODG group, with no significant statistical difference (Hazard ratio 1.12; 95% CI 0.68-1.84, P = 0.65). Body mass index (BMI) < 25 kg/m2, advanced pathologic T4, and pathologic N2-3 category were confirmed as independent risk factors for DFS in the Cox regression. CONCLUSIONS: In comparison to ODG, LDG with D2 lymphadenectomy yielded similar outcomes in terms of 3-year DFS rates among patients diagnosed with AGC.

Pallidum volume as a predictor for the effectiveness of mindfulness-based cognitive therapy and psycho-education in unmedicated patients with obsessive-compulsive disorder.

BACKGROUND: Mindfulness-based cognitive therapy (MBCT) has been documented to be effective in treating obsessive-compulsive disorder (OCD). However, the neurobiological basis of MBCT remains largely elusive, which makes it clinically challenging to predict which patients are more likely to respond poorly. Hence, identifying biomarkers for predicting treatment outcomes holds both scientific and clinical values. This prognostic study aims to investigate whether pre-treatment brain morphological metrics can predict the effectiveness of MBCT, compared with psycho-education (PE) as an active placebo, among patients with OCD. METHODS: A total of 32 patients with OCD were included in this prognostic study. They received magnetic resonance imaging (MRI) brain scans before treatment. Subsequently, 16 patients received 10 weeks of MBCT, while the other 16 patients underwent a 10-week PE program. The effectiveness of the treatments was primarily assessed by the reduction rate of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total score before and after the treatment. We investigated whether several predefined OCD-associated brain morphological metrics, selected based on prior published studies by the ENIGMA Consortium, could predict the treatment effectiveness. RESULTS: Both the MBCT and PE groups exhibited substantial reductions in Y-BOCS scores over 10 weeks of treatment, with the MBCT group showing a larger reduction. Notably, the pallidum total volume was associated with treatment effectiveness, irrespective of the intervention group. Specifically, a linear regression model utilizing the pre-treatment pallidum volume to predict the treatment effectiveness suggested that a one-cubic-centimeter increase in pallidum volume corresponded to a 22.3% decrease in the Y-BOCS total score reduction rate. CONCLUSIONS: Pallidum volume may serve as a promising predictor for the effectiveness of MBCT and PE, and perhaps, other treatments with the shared mechanisms by MBCT and PE, among patients with OCD.

Symmetric activation and modulation of the human calcium-sensing receptor.

The human extracellular calcium-sensing (CaS) receptor controls plasma Ca2+ levels and contributes to nutrient-dependent maintenance and metabolism of diverse organs. Allosteric modulation of the CaS receptor corrects disorders of calcium homeostasis. Here, we report the cryogenic-electron microscopy reconstructions of a near-full-length CaS receptor in the absence and presence of allosteric modulators. Activation of the homodimeric CaS receptor requires a break in the transmembrane 6 (TM6) helix of each subunit, which facilitates the formation of a TM6-mediated homodimer interface and expansion of homodimer interactions. This transformation in TM6 occurs without a positive allosteric modulator. Two modulators with opposite functional roles bind to overlapping sites within the transmembrane domain through common interactions, acting to stabilize distinct rotamer conformations of key residues on the TM6 helix. The positive modulator reinforces TM6 distortion and maximizes subunit contact to enhance receptor activity, while the negative modulator strengthens an intact TM6 to dampen receptor function. In both active and inactive states, the receptor displays symmetrical transmembrane conformations that are consistent with its homodimeric assembly.

Probabilistic human health risk assessment of PCDD/Fs near municipal solid-waste incinerator using Monte Carlo analysis coupled with triangular fuzzy numbers.

PCDD/Fs are dioxins produced by waste incineration and pose risks to human health. We aimed to detail the health risks of airborne and soil PCDD/Fs near a municipal solid-waste incinerator (MSWI) for the surrounding population and develop a new model that improves upon existing methods. Thus, we conducted field sampling and then investigated a MSWI in the Pearl River Delta (2016-2018). Our results showed that the carcinogenic and non-carcinogenic risk values of PCDD/Fs exposed to residents in nearby areas were acceptable, with hazard index (HI) values lower than 1.0 and a total carcinogenic risk lower than 1.0E-6. Notably, the results raised concerns regarding higher non-carcinogenic risks in children than in adults. Comparative analysis of the frequency accumulation diagram, accumulated probability risk, and the absolute value of error (δ) between the 95% confidence interval (CI) and the 90% CI of the Monte Carlo stochastic simulation-triangular fuzzy number (MCSS-TFN) and the MCSS model, respectively, demonstrated that the MCSS-TFN exhibited less uncertainty than the MCSS model, regardless of the health risk value of PCDD/Fs in ambient air or in soil. This observation underscores the superiority of the MCSS-TFN model over other models in assessing the health risks associated with PCDD/Fs in situations with limited data. Our new method overcomes the limited dataset size and high uncertainty in assessing the health risks of dioxin substances, providing a more comprehensive understanding of their associated health risks than MCSS models.

First Report of 'Candidatus Phytoplasma ziziphi'-Related Strains Infecting Peony (Paeonia suffruticosa Andr.) Showing Leaf Yellows Symptoms in China.

Peony (Paeonia suffruticosa Andr.), belonging to family Paeoniaceae, is an important medicinal and ornamental plant. During August of each year from 2016 to 2023, peony plants at Heze city were found to exhibit leaf yellows symptoms. The incidence rate of the symptomatic plant was recorded from 10% to 30% in four peony gardens with about 200 acres. Total DNA was extracted from 0.10 g fresh plant leaf tissues from 24 symptomatic and 8 asymptomatic samples using rapid plant genomic DNA isolation kit (Aidlab Biotechnology, Beijing, China). The extracted DNA was amplified by nested polymerase chain reaction using universal primers R16mF2/R16mR1 followed by R16F2/R16R2 (Lee et al., 1993; Gundersen and Lee, 1996) specific for the 16S rRNA gene and new designed tuf gene specific primers JWB-tuforfF1 (5'-ATGGCTGAAATATTTTCAAGAG-3') and JWB-tuforfR1 (5'-TTATTCTATGATTTTAATAACAG-3') followed by JWB-tuforfF2 (5'-ATGTAAACGTAGGAACTATTGG-3') and JWB-tuforfR2 (5'- TCCGATAGTTCTTCCACCTTCAC-3'). Amplicons of about 1.25 kb and 1.02 kb (16S rRNA gene and tuf gene, respectively) were obtained in 8 symptomatic samples from four peony gardens. However, no amplification was obtained in any of the asymptomatic samples. The representative amplicons of 16S rRNA and tuf genes of three positive samples (Heze-9, -18 and -27) were cloned into a zero background pLB-simple vector (Tiangen Biotechnology, Beijing, China) and sequenced by Taihe Biotechnology, Beijing, China. Sequences obtained in the study were deposited in NCBI GenBank with accession numbers PP504882, PP504883 and PP504884 for the 16S rRNA gene as well as PP530237, PP530238 and PP530239 for the tuf gene. The phytoplasma strain under the study was described as peony yellows (PeY) phytoplasma, PeY-Heze strain. Alignment analysis by DNAMAN software showed that three 16S rRNA gene sequences obtained in the study shared 99.36% to 99.60% sequence identity and three tuf gene sequences obtained in the study were identical. BLAST analysis of the 16S rRNA gene sequences of the PeY-Heze phytoplasma strains showed 99.60%-99.84% sequence identity with 'Candidatus Phytoplasma ziziphi' (GenBank accession: CP025121). And tuf sequences of the strains showed 100% similarity with 'Ca. P. ziziphi' (CP025121). Interestingly, the virtual RFLP patterns derived from three 16Sr RNA gene sequences obtained in the study by iPhyClassifier (Zhao et al., 2009) were different from the reference patterns of all previously established 16Sr groups/subgroups. The most similar are the reference pattern of the 16Sr group VII, subgroup E (AY741531), with a similarity coefficient of 0.72, which is less than 0.85. These phytoplasma strains may represent a new 16Sr group. Phylogenetic analysis based on 16S rRNA genes using MEGA 7.0 by neighbor-joining (NJ) method with 1000 bootstrap value indicated that PeY-Heze strains clustered into one clade with the phytoplasma strains of 'Ca. P. ziziphi' with 68% bootstrap value. Although there are several reports available on 'Ca. P. solani' infecting peony in Shandong Province, China (Gao et al., 2013). To our knowledge, this is the first report of 'Ca. P. ziziphi'-related strains infecting peony in China. The findings in this study will be beneficial to the detection, quarantine, and prevention of peony yellows phytoplasmas in China.

Analysis of correlation between BMI and TWL% outcome following metabolic and bariatric surgery: a retrospective study using restricted cubic spline.

OBJECTIVE: This study aimed to examine the correlation between preoperative body mass index (BMI) and adequate percentage of total weight loss (TWL%) outcome and present evidence of tiered treatment for patients with obesity in different preoperative BMI. METHODS: We included patients with complete follow-up data who underwent metabolic and bariatric surgery (BMS). We termed optimal clinical response as TWL% >20% at one year following MBS. To investigate dose-response association between preoperative BMI and optimal clinical response, preoperative BMI was analyzed in three ways: (1) as quartiles; (2) per 2.5 kg/m2 units (3) using RCS, with 3 knots as recommended. RESULTS: A total of 291 patients with obesity were included in our study. The corresponding quartile odds ratios associated with optimal clinical response and adjusted for potential confounders were 1.00 (reference), 1.434 [95% confidence interval (95%CI)   =  0.589-3.495], 4.926 (95%CI   =  1.538-15.772), and 2.084 (95%CI   =  0.941-1.005), respectively. RCS analysis showed a non-linear inverted U-shaped association between preoperative BMI and optimal clinical response (Nonlinear P   =  0.009). In spline analysis, when preoperative BMI was no less than 42.9 kg/m2, the possibility of optimal clinical response raised as preoperative BMI increased. When preoperative BMI was greater than 42.9 kg/m2, the possibility of optimal clinical response had a tendency to decline as preoperative BMI increased. CONCLUSION: Our research indicated the non-linear inverted U-shaped correlation between preoperative BMI and adequate weight loss. Setting a preoperative BMI threshold of 42.9 is critical to predicting optimal clinical outcomes.

Integrated Assays of Genome-Wide Association Study, Multi-Omics Co-Localization, and Machine Learning Associated Calcium Signaling Genes with Oilseed Rape Resistance to Sclerotinia sclerotiorum.

Sclerotinia sclerotiorum (Ss) is one of the most devastating fungal pathogens, causing huge yield loss in multiple economically important crops including oilseed rape. Plant resistance to Ss pertains to quantitative disease resistance (QDR) controlled by multiple minor genes. Genome-wide identification of genes involved in QDR to Ss is yet to be conducted. In this study, we integrated several assays including genome-wide association study (GWAS), multi-omics co-localization, and machine learning prediction to identify, on a genome-wide scale, genes involved in the oilseed rape QDR to Ss. Employing GWAS and multi-omics co-localization, we identified seven resistance-associated loci (RALs) associated with oilseed rape resistance to Ss. Furthermore, we developed a machine learning algorithm and named it Integrative Multi-Omics Analysis and Machine Learning for Target Gene Prediction (iMAP), which integrates multi-omics data to rapidly predict disease resistance-related genes within a broad chromosomal region. Through iMAP based on the identified RALs, we revealed multiple calcium signaling genes related to the QDR to Ss. Population-level analysis of selective sweeps and haplotypes of variants confirmed the positive selection of the predicted calcium signaling genes during evolution. Overall, this study has developed an algorithm that integrates multi-omics data and machine learning methods, providing a powerful tool for predicting target genes associated with specific traits. Furthermore, it makes a basis for further understanding the role and mechanisms of calcium signaling genes in the QDR to Ss.

A Bibliometric and Visual Analysis of the Current Status and Trends of Forensic Mixed Stain Research.

OBJECTIVES: To explore the context and hotspot changes of forensic mixed stain research through bibliometric approach. METHODS: The literature of forensic mixed stain included in the core collection of Web of Science database from 2011 to 2022 were collected as the study object, and the annual publication number, countrie (region), institution, journal, keywords, etc. were bibliometrically and visually analyzed using the R-based Bibliometrix 1.1.6 package and VOSviewer 1.6.18 software. RESULTS: A total of 732 articles on forensic mixed stain were included from 2011 to 2022, with the annual number of articles published and the annual citation frequency showing a steady increase year by year. Among the 59 countries (regions) with the most published articles, the United States ranked first with 246 articles, followed by China with 153 articles. The literature came from 104 journals, and the total number of articles published in the top 10 journals was 633. FORENSIC SCI INT GENET ranked first with 307 articles. Visual analysis using VOSviewer software showed that keywords could be divided into four research clusters, namely the genetic marker development group (blue), the mixed stain typing analysis theory group (red), the sequencing analysis group (yellow), and the case sample research group (green). It can be divided into four development stages in terms of different time periods: early development (2011-2013), middle development (2014-2016), rapid development (2017-2020) and latest development (2021-2022). CONCLUSIONS: The number of publications by domestic and foreign scholars in the study of mixed stain in forensic science is showing a relatively stable trend. Machine learning, next generation sequencing and other research have been the hottest topics that have attracted the most attention in recent years, which is expected to further develop the theory of mixed stain typing and sequencing analysis in forensic mixed stain research.

Realization of Strong Coupling between Deterministic Single-Atom Arrays and a High-Finesse Miniature Optical Cavity.

We experimentally demonstrate strong coupling between a one-dimensional (1D) single-atom array and a high-finesse miniature cavity. The atom array is obtained by loading single atoms into a 1D optical tweezer array with dimensions of 1×11. Therefore, a deterministic number of atoms is obtained, and the atom number is determined by imaging the atom array on a CCD camera in real time. By precisely controlling the position and spacing of the atom array in the high finesse Fabry-Perot cavity, all the atoms in the array are strongly coupled to the cavity simultaneously. The vacuum Rabi splitting spectra are discriminated for deterministic atom numbers from 1 to 8, and the sqrt[N] dependence of the collective enhancement of the coupling strength on atom number N is validated at the single-atom level.

Hydrogen Peroxide-Activated Nitric Oxide-Releasing Vancomycin-Loaded Electrostatic Complexation for Efficient Elimination of Methicillin-Resistant Staphylococcus aureus Abscesses.

The treatment of subcutaneous abscesses has been greatly hindered due to the spread of drug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA). Thus, alternative strategies are highly desired to complement conventional antibiotic therapies and surgical intervention. As one of such strategies, applications of nitric oxide (NO) have shown great potential in the treatment of bacteria-induced subcutaneous abscesses by improving the efficacy of many therapeutic methods. However, it is extremely challenging to achieve precise delivery and controlled release because of its gaseous nature. In the present study, an effective strategy was reported in which on demand hydrogen peroxide (H2O2)-activated nitric oxide-releasing vancomycin (Van)-loaded electrostatic complexation (Lipo/Van@Arg) was fabricated. In this system, Van was encapsulated into a negative-charged DSPG/Chol liposome (Lipo/Van) and electrostatically bound with the positive-charged l-arginine (l-Arg). As expected, Lipo/Van@Arg exhibited superior bacterial binding and biofilm penetration abilities. After being in the interior of the biofilms, Lipo/Van@Arg could be triggered by the endogenous H2O2 and effectively release NO. The released NO could exhibit combined antibacterial and biofilm eradication effects with Van. Moreover, an in vivo evaluation using a BALB/c mouse model of subcutaneous abscesses indicated that the combination treatment of NO and Van based on Lipo/Van@Arg could effectively eliminate MRSA from the abscesses, thereby preventing abscess recurrence. In summary, the Lipo/Van@Arg system developed in this study realized controlled delivery and precise release of NO, which had significant clinical implications in the efficient treatment of abscesses.

ICG-Dimeric Her2-Specific Affibody Conjugates for Tumor Imaging and Photothermal Therapy for Her2-Positive Tumors.

Human epidermal growth factor receptor 2 (Her2) is abundantly expressed in various solid tumors. The Her2-specific Affibody (ZHer2:2891) has been clinically tested in patients with Her2-positive breast cancer and is regarded as an ideal drug carrier for tumor diagnosis and targeted treatment. Indocyanine green (ICG) can be used as a photosensitizer for photothermal therapy (PTT), in addition to fluorescent dyes for tumor imaging. In this study, a dimeric Her2-specific Affibody (ZHer2) based on ZHer2:2891 was prepared using the E. coli expression system and then coupled to ICG through an N-hydroxysuccinimide (NHS) ester reactive group to construct a novel bifunctional protein drug (named ICG-ZHer2) for tumor diagnosis and PTT. In vitro, ICG-ZHer2-mediated PTT selectively and efficiently killed Her2-positive BT-474 and SKOV-3 tumor cells rather than Her2-negative HeLa tumor cells. In vivo, ICG-ZHer2 specifically accumulated in Her2-positive SKOV-3 tumor grafts rather than Her2-negative HeLa tumor grafts; high-contrast tumor optical images were obtained. However, Her2-negative HeLa tumor grafts were not detected. More importantly, ICG-ZHer2-mediated PTT exhibited a significantly enhanced antitumor effect in mice bearing SKOV-3 tumor grafts owing to the good photothermal properties of ICG-ZHer2. Of note, ICG-ZHer2 did not exhibit acute toxicity in mice during short-term treatment. Overall, our findings indicate that ICG-ZHer2 is a promising bifunctional drug for Her2-positive tumor diagnosis and PTT.

pH/Hyal-Responsive Surface-Charge Switchable Electrostatic Complexation for Efficient Elimination of MRSA Infection.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a great threat to human health worldwide, making new effective antibacterial strategies urgently desired. In this study, a cationic pH-responsive delivery system (pHSM) was developed based on poly(ß-amino esters)-methoxy poly(ethylene glycol), by which linezolid (LZD) could be encapsulated to form pHSM/LZD. The biocompatibility and stability of pHSM/LZD were further enhanced by adding low-molecular-weight hyaluronic acid (LWT HA) on the surface through electrostatic interaction to form pHSM/LZD@HA, of which the positive surface charges were neutralized by LWT HA under physiological conditions. LWT HA can be degraded by hyaluronidase (Hyal) after arriving at the infection site. In vitro, pHSM/LZD@HA could rapidly change to being positively charged on the surface within 0.5 h under acidic conditions, especially when Hyal was present, thus promoting bacterial binding and biofilm penetration of pHSM/LZD@HA. In addition, the pH/Hyal-dependent accelerated drug release behavior was also observed and it is beneficial for the comprehensive treatment of MRSA infection in vitro and in vivo. Our study provides a novel strategy to develop a pH/Hyal-responsive drug delivery system for the treatment of MRSA infection.