Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation.

Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body ß-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating Gi/o protein or ß-arrestin effectors. Here, we characterize compound 9n as a Gi-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-Gi pathway. Furthermore, four structures of HCAR2-Gi complex bound to orthosteric agonists (niacin or monomethyl fumarate), compound 9n, and niacin together with compound 9n simultaneously reveal a common orthosteric site and a unique allosteric site. Combined with functional studies, we decipher the action framework of biased allosteric modulation of compound 9n on the orthosteric site. Moreover, co-administration of compound 9n with orthosteric agonists could enhance anti-inflammatory effects in the mouse model of colitis. Together, our study provides insight to understand the molecular pharmacology of the BAM and facilitates exploring the therapeutic potential of the BAM with orthosteric drugs.

High genetic diversity of the himalayan marmot relative to plague outbreaks in the Qinghai-Tibet Plateau, China.

Plague, as an ancient zoonotic disease caused by Yersinia pestis, has brought great disasters. The natural plague focus of Marmota himalayana in the Qinghai-Tibet Plateau is the largest, which has been constantly active and the leading source of human plague in China for decades. Understanding the population genetics of M. himalayana and relating that information to the biogeographic distribution of Yersinia pestis and plague outbreaks are greatly beneficial for the knowledge of plague spillover and arecrucial for pandemic prevention. In the present research, we assessed the population genetics of M. himalayana. We carried out a comparative study of plague outbreaks and the population genetics of M. himalayana on the Qinghai-Tibet Plateau. We found that M. himalayana populations are divided into two main clusters located in the south and north of the Qinghai-Tibet Plateau. Fourteen DFR genomovars of Y. pestis were found and exhibited a significant region-specific distribution. Additionally, the increased genetic diversity of plague hosts is positively associated with human plague outbreaks. This insight gained can improve our understanding of biodiversity for pathogen spillover and provide municipally directed targets for One Health surveillance development, which will be an informative next step toward increased monitoring of M. himalayana dynamics.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study.

BACKGROUND: TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes. METHODS: In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18-75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103. RESULTS: A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 µg*h/mL, and AUC0-inf ranged from 159 to 340 µg*h/mL. TG103 had a half-life of 110-116 h, with a median Tmax of 36-48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p < 0.05 for all comparisons with placebo. CONCLUSIONS: In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.

Deep polarization of the ensemble nitrogen-vacancy centers in diamonds induced by an Airy beam with a long focal depth.

Solid-state spin systems with nitrogen-vacancy (NV) centers in diamonds constitute an increasingly popular platform for quantum sensing. However, most existing platforms designed with ensemble NV centers exhibit a sensitivity that is significantly less than the theoretical maximum. This low sensitivity limits the expansion of the experimental results and application areas. In this study, the sensitivity is improved by increasing the pumping depth of the excitation beam to increase the number of particles involved in spin polarization at a given laser intensity. Compared with the proposed Airy beam with a long focal depth (25.46 λ) and the widely utilized Gauss beam pumping ensemble NV centers, the spin resonance factor fSR can be improved by 10.02%. This sensitivity-optimized approach enhances the functionality of sensors with NV centers.

Genotypic and phenotypic characterization of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Guangzhou, China.

BACKGROUND: G6PD deficiency is a common inherited disorder worldwide and has a higher incidence rate in southern China. Many variants of G6PD result from point mutations in the G6PD gene, leading to decreased enzyme activity. This study aimed to analyse the genotypic and phenotypic characteristics of G6PD deficiency in Guangzhou, China. METHODS: In this study, a total of 20,208 unrelated participants were screened from 2020 to 2022. G6PD deficiency was further analysed by quantitative enzymatic assay and G6PD mutation analysis. The unidentified genotype of the participants was further ascertained by direct DNA sequencing. RESULTS: A total of 12 G6PD mutations were identified. Canton (c.1376G>T) and Kaiping (c.1388G>A) were the most common variants, and different mutations led to varying levels of G6PD enzyme activity. Comparing the enzyme activities of the 6 missense mutations between the sexes, we found significant differences (P < 0.05) in the enzyme activities of both male hemizygotes and female heterozygotes. Two previously unreported mutations (c.1438A>T and c.946G>A) were identified. CONCLUSIONS: This study provided detailed genotypes of G6PD deficiency in Guangzhou, which could be valuable for diagnosing and researching G6PD deficiency in this area.

Arbitrary combinations of helical-conical optical beams in free space.

Helical-conical optical beams (HCOBs) have attracted considerable interest due to their peculiar optical features. Their characteristic helical light intensity distribution has exerted unprecedented advantages in many fields, but multiple combinations of HCOBs have not been reported due to the limitations of algorithms and light field modulation techniques. We propose and experimentally demonstrate arbitrary combinations of multiple HCOBs in free space to construct hybrid HCOB arrays. The similarity between the experimental results and the numerical simulation results is 94.22%. The initial orientation of the HCOBs is flexibly tuned by the rotation factor ß, and the optical pen is used to combine the HCOBs. This approach allows multiple parameters in the array to be precisely tuned, including the type, number, and position of HCOBs, adding more design flexibility. The constructed HCOB arrays have a higher degree of modulation freedom and may find applications in fields where dynamic control is in high demand, including optical tweezers, biological cell sorting, and multiparticle manipulation.

The causal relationship between psoriasis and chronic obstructive pulmonary disease: A bidirectional mendelian randomization study.

PURPOSE: Although many studies have investigated the association between psoriasis and chronic obstructive pulmonary disease (COPD), the causal relationship between psoriasis and COPD is still unknown. METHODS: We employed bidirectional Mendelian randomization to investigate the causal relationship between psoriasis and COPD. Genetic instruments for exposure were selected from two distinct genome-wide association study databases. Single nucleotide polymorphisms associated with exposures at the genome-wide significance level (p < 5 × 10^-8 ) and exhibiting low linkage disequilibrium (r^2  < 0.001) were chosen as instrumental variables. Causality was assessed using multiple MR methods, including Inverse-Variance Weighted (IVW), MR-Egger, Weighted Median, Simple Mode, and Weighted Mode. A significance level of p < 0.05 was considered statistically significant. Heterogeneity was examined using Cochran's Q test, and MR-Egger regression was employed to detect pleiotropy. The robustness and reliability of the results were further evaluated through leave-one-out analysis. RESULTS: We found a positive causal association between psoriasis and COPD [IVW: odds ratio (OR): 1.0006; p = 0.0056]. Heterogeneity and pleiotropy have not been discovered, so the results of the study are reliable. In the reverse analysis, no causal association between CPOD and psoriasis was found. CONCLUSION: Our findings revealed that psoriasis was associated with an elevated risk of COPD. However, no causal association between COPD and psoriasis was identified in our study.

Target-allele-specific probe single-base extension (TASP-SBE): a novel MALDI-TOF-MS strategy for multi-variants analysis and its application in simultaneous detection of α-/ß-thalassemia mutations.

Single-nucleotide variants (SNVs) and copy number variations (CNVs) are the most common genomic variations that cause phenotypic diversity and genetic disorders. MALDI-TOF-MS is a rapid and cost-effective technique for multi-variant genotyping, but it is challenging to efficiently detect CNVs and clustered SNVs, especially to simultaneously detect CNVs and SNVs in one reaction. Herein, a novel strategy termed Target-Allele-Specific Probe Single-Base Extension (TASP-SBE) was devised to efficiently detect CNVs and clustered SNVs with MALDI-TOF-MS. By comprehensive use of traditional SBE and TASP-SBE strategies, a MALDI-TOF-MS assay was also developed to simultaneously detect 28 α-/ß-thalassemia mutations in a single reaction system, including 4 α-thalassemia deletions, 3 HBA and 21 HBB SNVs. The results showed that all 28 mutations were sensitively identified, and the CNVs of HBA/HBB genes were also accurately analyzed based on the ratio of peak height (RPH) between the target allele and reference gene. The double-blind evaluation results of 989 thalassemia carrier samples showed a 100% concordance of this assay with other methods. In conclusion, a one-tube MALDI-TOF-MS assay was developed to simultaneously genotype 28 thalassemia mutations. This novel TASP-SBE was also verified a practicable strategy for the detection of CNVs and clustered SNVs, providing a feasible approach for multi-variants analysis with MALDI-TOF-MS technique.

Free-space creation of a perfect vortex beam with fractional topological charge.

Perfect vortex beams can only propagate stably with integer topological charges. Thus, creating perfect fractional vortex beams capable of stable propagation in free space, as perfect integer vortex beams, is crucial. This study proposed perfect vortex beams carrying fractional topological charge of l + 0.5, which are special solutions of the wave equation, and can maintain stable propagation with physical laws same as integer topological charge. Perfect fractional vortex beams were created in free space, which can break the cognition of traditional fractional perfect vortex beams and promote the development of scientific fields such as optical communication, quantum sensing, and optical imaging.

Orientation of the NV centers are determined using the cylindrical vector beam array.

The determination of nitrogen-vacancy centers plays an important role in quantum information sensing. Efficiently and rapidly determining the orientation of multiple nitrogen-vacancy center s in a low-concentration diamond is challenging due to its size. Here, we solve this scientific problem by using an azimuthally polarized beam array as the incident beam. In this paper, the optical pen is used to modulate the position of beam array to excite distinctive fluorescence characterizing multiple and different orientations of nitrogen-vacancy centers. The important result is that in a low concentration diamond layer, the orientation of multiple NV centers can be judged except when they are too close within the diffraction limit. Hence, this efficient and rapid method has a good application prospect in quantum information sensing.

A new inhibitor of human peptide deformylase suppresses cell proliferation and induces cell apoptosis and autophagy in cancers.

Human peptide deformylase (hsPDF) has been found overexpressed in many cancer cells and its inhibitors exhibit antitumor activity. Studies were performed to validate that hsPDF is a good antitumor target. The inhibitory effect of PDF64 on hsPDF enzymatic activity was measured and confirmed by computation analysis. Antiproliferation activity was determined and in-vivo antitumor activity were analyzed in HCT116 and HL60 nude mice xenografts. Mitochondrial membrane potential (MMP), cell apoptosis, and autophagic cell death were analyzed by flow cytometry. ATP level was quantified using an ATP assay kit. Protein expression and kinase phosphorylation were determined by western blotting. A new hsPDF inhibitor PDF64 was identified. It showed evident antiproliferation activity in 10 cancer cells and significantly suppressed tumor growth in HCT116 and HL60 xenografts. It induced an obvious decrease in MMP and caused apparent cell apoptosis and autophagy in HCT116 and Jurkat cells. PDF64 treatment also led to an evident decrease in cellular ATP levels in these cells. Moreover, PDF64 downregulated c-Myc expression and had some effects on extracellular regulated protein kinases (ERK) and protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) pathways. PDF64 exhibited good antitumor effects both in vivo and in vitro . It caused cell apoptosis and autophagic death in HCT116 and Jurkat cells. The effects may be mediated by inhibiting c-Myc expression and ERK or PI3K-Akt-mTOR pathway. Therefore, PDF64 may be a promising reagent for antitumor drug development, which further supports that hsPDF is a good antitumor drug target.

Free-space generation of three-dimensional tunable vector optical cages.

The generation of three-dimensional tunable vector optical cages through full polarization modulation requires complex polarization states. This paper takes the vector Airy optical cage as an example to generate a three-dimensional tunable high-quality optical cage based on the Pancharatnam-Berry phase principle. The proposed method in this paper possesses the capability of arbitrary modulation in various aspects, including the quantity of optical cages and their respective sizes as well as three-dimensional spatial positions. Moreover, the intensity of each optical cage can be modulated independently. This research will improve the capture efficiency of optical tweezers and promote further development in fields of efficient optical trapping, particle manipulation, high-resolution microscopic manipulation, and optical communication.

Cyclothymic Temperament, Physical Neglect, and Earlier Age of Onset Predict Poor Medication Adherence in Patients With Bipolar Disorder.

ABSTRACT: Individual-level risk factors may predict poor medication adherence (PMA) in bipolar disorder (BD). This study aimed to evaluate the association between affective temperament, childhood trauma, age of first onset, and PMA in patients with BD in China. A total of 168 patients completed the eight-item Morisky Medication Adherence Scale; the Short Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire; and the Childhood Trauma Questionnaire-Short Form. Scores were then compared between PMA and non-PMA groups. Binary logistic regression showed that age of first onset was negatively correlated with PMA ( ß = -0.106, p = 0.002), whereas physical neglect and cyclothymic temperament were positively correlated with PMA ( ß = 0.143, p = 0.029; ß = 0.19, p = 0.001, respectively). These findings indicate that cyclothymic temperament, physical neglect, and earlier onset are predictors of PMA in patients with BD and that such patients may require further attention to improve medical compliance.

Immobilization effect of heavy metals in biochar via the copyrolysis of sewage sludge and apple branches.

The excess sludge produced by sewage treatment plants can be recycled into energy through pyrolysis, and the byproduct biochar can be used for soil remediation. However, the heavy metals in sludge are retained in biochar after pyrolysis and may cause secondary pollution during its soil application. Herein, a fast copyrolysis method of activated sludge (AS) and apple branches (AT) was proposed to immobilize heavy metals while improving bio-oil yield. The results showed that the heavy metal release from the copyrolyzed biochar was markedly reduced compared with that from the biochar produced through the pyrolysis of AS alone (78% for Cr and 28% for Pb). The kinetic behavior of ion release from different biochars could be described by a first-order kinetic model. The excellent fixation of heavy metals was attributed to complexation by abundant oxygen-containing surface functional groups (-O-, =O, and -CHO) that were mainly donated by AT. Furthermore, high-temperature pyrolysis was conducive to the fixation of metals, and the release of Pb2+ and Cr3+ from the biochar pyrolyzed at 600 °C was approximately 2/3 and 1/10 of that from the biochar pyrolyzed at 400 °C, respectively. A growth experiment on Staphylococcus aureus and Escherichia coli revealed that the toxicity of the copyrolyzed biochar was greatly reduced. This work can provide a method for heavy metal fixation and simultaneous resource recovery from organic wastes.

Mass Spectrometric Multiplex Detection of MicroRNA and Protein Biomarkers for Liver Cancer.

The occurrence of cancers is often accompanied by the abnormal expression of several sorts of biomarkers (e.g., nucleic acids and proteins). The multiplex assessment of them would substantially aid in the early detection and precise diagnosis, which is often hampered by their different detection schemes, different reaction matrix and reagents, and spectral overlapping. Herein, we propose a simple and sensitive mass spectrometric method for the multiplex detection of nucleic acid and protein, in which liver cancer-related biomarkers miRNA 223 and alpha-fetoprotein (AFP) were selected as model analytes. The self-amplification effect of metal atom-based nanoparticle probes can provide high sensitivity in complex serum samples without any additional amplification procedure. The detection limits for the simultaneous detection of miRNA 223 and AFP were 103 (2.1 pM) and 219 amol (0.15 ng/mL), respectively, with high specificity and selectivity. The proposed method is potentially useful for the rapid screening of cancers.

Biomimetic 3D Recognition with 2D Flexible Nanoarchitectures for Ultrasensitive and Visual Extracellular Vesicle Detection.

Despite increasing recognition of extracellular vesicles being important circulating biomarkers in disease diagnosis and prognosis, current strategies for extracellular vesicle detection remain limited due to the compromised sample purification and extensive labeling procedures in complex body fluids. Here, we developed a 2D magnetic platform that greatly improves capture efficiency and readily realizes visible signal conversion for extracellular vesicle detection. The technology, termed high-affinity recognition and visual extracellular vesicle testing (HARVEST), leverages 2D flexible Fe3O4-MoS2 nanostructures to recognize extracellular vesicles through multidentate affinity binding and feasible magnetic separation, thus enhancing the extracellular vesicle capture performance with both yield and separation time, affording high sensitivity with the detection limit of 20 extracellular vesicle particles/µL. Through integration with lipid labeling chemistry and the fluorescence visualization system, the platform enables rapid and visible detection. The number of extracellular vesicles can be feasibly determined by smart mobile phones, readily adapted for point-of-care diagnosis. When clinically evaluated, the strategy accurately differentiates melanoma samples from the normal cohort with an AUC of 0.98, demonstrating the efficient extracellular vesicle detection strategy with 2D flexible platforms for cancer diagnosis.

Generation of perfect optical vortex arrays by an optical pen.

Recently, perfect optical vortexes (POVs) have attracted substantial attention, because they have an orbital angular momentum (OAM) and the beam diameter is independent of the topological charges. There are numerous innovative results that have been found by modulating the POV optical field. However, methods for controlling the arbitrary parameters of POV are lacking. In this paper, we use the optical pen to overcome this problem. The optical pen is a high-precision optical field modulation method construction based on the relationship between the optical path difference and phase. Based on this method, we have achieved POV arrays with controllable arbitrary parameters in free space, including the spatial position, numbers, topological charges, beam diameter, and amplitude. This work can be applied not only in the fields of optical tweezers, particle manipulation, and super-resolution microscopic imaging, but also will promote the development of optical communication, quantum information coding, and so on.

3.1†W mid-infrared fiber laser at 4.16†µm based on HBr-filled hollow-core silica fibers.

We present the characteristics of a continuous-wave (CW) mid-infrared fiber laser source based on HBr-filled hollow-core fibers (HCFs) made of silica. The laser source delivers a maximum output power of 3.1 W at 4.16 µm, showing a record value for any reported fiber laser beyond 4 µm. Both ends of the HCF are supported and sealed by especially designed gas cells with water cooling and inclined optical windows, withstanding higher pump power accompanied by accumulated heat. The mid-infrared laser exhibits a near-diffraction-limited beam quality with a measured M2 of 1.16. This work paves the way for powerful mid-infrared fiber lasers beyond 4 µm.

Generation of a sub-wavelength sized optical needle with arbitrary longitudinal rotation.

We show that under tight focusing conditions, arbitrarily rotating the longitudinally polarized optical needle in space is possible. Applying the Richards and Wolf vector diffraction methods, the explicit expressions underlying the simultaneous control depth of focus (DoF), intensity suppression of the sidelobes, as well as the orientation of the optical needle can be obtained, and then the strength vectors of the three-dimensional electromagnetic fields can be calculated. Calculations reveal that the sidelobe suppression ratio reaches 5.35% of the principal lobe, the optimal DoF is 5.1λ, and the maximum length is about 18.2λ. In addition, we specify the necessary conditions for rotating the sub-wavelength sized optical needle in the longitudinal field. Such an optical needle with controllable length, purity, and orientation can provide a flexible approach and additional degree of freedom for 3D precise fabrication and some other potential application areas.

Multiplex Nucleic Acid Assay of SARS-CoV-2 via a Lanthanide Nanoparticle-Tagging Strategy.

Early diagnosis, early isolation, and early treatment are efficient solutions to control the COVID-19 pandemic. To achieve the accurate early diagnosis of SARS-CoV-2, a multiplex detection strategy is required for the cross-validation to solve the problem of "false negative" of the existing gold standard assay. Here, we present a multicomponent nucleic acid assay platform for SARS-CoV-2 detection based on lanthanide nanoparticle (LnNP)-tagging strategy. For targeting SARS-CoV-2's RNA fragments ORF1ab gene, RdRp gene, and E gene, three LnNP probes can be used simultaneously to identify three sites in one sample through elemental mass spectrometry detection with limits of detection of 1.2, 1.3, and 1.3 fmol, respectively. With the multisite cross-validation, we envision that this multiplex and sensitive detection platform may provide an effective strategy for SARS-CoV-2 fast screening with a high accuracy.