Poly-l-lysine modified MOF nanoparticles with pH/ROS sensitive CIP release and CUR triggered photodynamic therapy against drug-resistant bacterial infection.

The challenge of drug resistance in bacteria caused by the over use of biotics is increasing during the therapy process, which has attracted great attentions of the clinicians and scientists around the world. Recently, photodynamic therapy (PDT) triggered by photosensitizer (PS) has become a promising treatment method because of its high efficacy, easy operation, and low side effect. Herein, the poly-l-lysine (PLL) modified metal-organic framework (MOF) nanoparticles, ZIF/PLL-CIP/CUR, were synthesized to allow both reactive oxygen species (ROS) responsive drug release and photodynamic effect for synergistic therapy against drug resistant bacterial infections. The PLL was modified on the shell of the zeolite imidazole framework (ZIF) by the ROS-responsive thioketal linker for controllable CIP release. CUR were encapsulated in ZIF as the photosensitizer for blue light mediated photodynamic effect to produce singlet oxygen (1O2) and superoxide anion radical (O2-) for efficient inhibition towards methicillin-resistant Staphylococcus aureus (MRSA). The charge conversion from negative charge (-4.6 mV) to positive charge (2.6 mV) was observed at pH 7.4 and pH 5.5, and 70.9 % CIP was found released at pH 5.5 in the presence of H2O2, which suggests the good biosafety at physiological pH and ROS-responsive drug release of the as-prepared nanoparticle in the bacterial microenvironment. The as-prepared nanoparticles could effectively kill MRSA and disrupt bacterial biofilm by combination of chemo- and photodynamic therapy. In mice model, the as-prepared nanoparticles exhibited excellent biosafety and synergistic effect with 98.81 % healing rate in treatment of MRSA infection, which is considered as a promising candidate in combating drug resistant bacterial infection.

Spatial and single-nucleus transcriptomics decoding the molecular landscape and cellular organization of avian optic tectum.

The avian optic tectum (OT) has been studied for its diverse functions, yet a comprehensive molecular landscape at the cellular level has been lacking. In this study, we applied spatial transcriptome sequencing and single-nucleus RNA sequencing (snRNA-seq) to explore the cellular organization and molecular characteristics of the avian OT from two species: Columba livia and Taeniopygia guttata. We identified precise layer structures and provided comprehensive layer-specific signatures of avian OT. Furthermore, we elucidated diverse functions in different layers, with the stratum griseum periventriculare (SGP) potentially playing a key role in advanced functions of OT, like fear response and associative learning. We characterized detailed neuronal subtypes and identified a population of FOXG1+ excitatory neurons, resembling those found in the mouse neocortex, potentially involved in neocortex-related functions and expansion of avian OT. These findings could contribute to our understanding of the architecture of OT, shedding light on visual perception and multifunctional association.

A novel protein purification scheme based on salt inducible self-assembling peptides.

BACKGROUND: Protein purification remains a critical need for biosciences and biotechnology. It frequently requires multiple rounds of chromatographic steps that are expensive and time-consuming. Our lab previously reported a cleavable self-aggregating tag (cSAT) scheme for streamlined protein expression and purification. The tag consists of a self-assembling peptide (SAP) and a controllable self-cleaving intein. The SAP drives the target protein into an active aggregate, then by intein-mediated cleavage, the target protein is released. Here we report a novel cSAT scheme in which the self-assembling peptide is replaced with a salt inducible self-assembling peptide. This allows a target protein to be expressed first in the soluble form, and the addition of salt then drives the target protein into the aggregated form, followed by cleavage and release. RESULTS: In this study, we used MpA (MKQLEDKIEELLSKAAMKQLEDKIEELLSK) as a second class of self-assembling peptide in the cSAT scheme. This scheme utilizes low salt concentration to keep the fusion protein soluble, while eliminating insoluble cellular matters by centrifugation. Salt then triggers MpA-mediated self-aggregation of the fusion, removing soluble background host cell proteins. Finally, intein-mediated cleavage releases the target protein into solution. As a proof-of-concept, we successfully purified four proteins and peptides (human growth hormone, 22.1 kDa; LCB3, 7.7 kDa; SpyCatcherΔN-ELP-SpyCatcherΔN, 26.2 kDa; and xylanase, 45.3 kDa) with yields ranging from 12 to 87 mg/L. This was comparable to the classical His-tag method both in yield and purity (72-97%), but without the His-tag. By using a further two-step column purification process that included ion-exchange chromatography and size-exclusion chromatography, the purity was increased to over 99%. CONCLUSION: Our results demonstrate that a salt-inducible self-assembling peptide can serve as a controllable aggregating tag, which might be advantageous in applications where soluble expression of the target protein is preferred. This work also demonstrates the potential and advantages of utilizing salt inducible self-assembling peptides for protein separation.

Clinical characteristics and acute complication of COVID-19 patients with diabetes: a multicenter, retrospective study in Southern China.

Aims: This study aims to describe the clinical characteristics, laboratory data and complications of hospitalized COVID-19 patients with type 2 diabetes mellitus (T2DM) since epidemic prevention and control optimization was adjusted in December 2022 in China. Methods: This retrospective multicenter study included 298 patients with confirmed type 2 diabetes mellitus with or without COVID-19. We collected data from the first wave of the pandemic in The Fifth Affiliated Hospital of Guangzhou Medical University, Loudi Central Hospital and The First People's Hospital of Xiangtan from December 1, 2022 to February 1, 2023. We extracted baseline data, clinical symptoms, acute complications, laboratory findings, treatment and outcome data of each patient from electronic medical records. Results: For among 298 hospitalized patients with type 2 diabetes, 136 (45.6%) were COVID-19 uninfected, and 162 (54.4%) were COVID-19 infected. We found that the incidence of cough, fatigue, fever, muscle soreness, sore throat, shortness of breath, hyposmia, hypogeusia and polyphagia (all p<0.01) were significantly higher in the exposure group. They showed higher levels of ketone (p=0.04), creatinine (p<0.01), blood potassium (p=0.01) and more diabetic ketoacidosis (p<0.01). Patients with COVID-19 less use of metformin (p<0.01), thiazolidinediones (p<0.01) and SGLT2 (p<0.01) compared with patients without COVID-19. Conclusion: COVID-19 patients with diabetes showed more severe respiratory and constitutional symptoms and an increased proportion of hyposmia and hypogeusia. Moreover, COVID-19 patients with diabetes have a higher incidence of acute complications, are more prone to worsening renal function, and are more cautious about the use of antidiabetic drugs.

Metachronous double primary malignant tumors with nasopharyngeal carcinoma and diffuse malignant peritoneal mesothelioma accompanied with paraneoplastic syndromes treated with nivolumab: A case report.

RATIONALE: Multiple primary malignant tumors are rare and challenging to diagnose. Diffuse malignant peritoneal mesothelioma (DMPM) originate from the peritoneum, which lacks specific clinical manifestations and is difficult to diagnose, with a short survival about 10 to 13 months for inoperable ones. This is the first report of metachronous double primary malignant tumors in nasopharyngeal carcinoma and DMPM accompanied with paraneoplastic syndromes. PATIENT CONCERNS: A 61-year-old man presented with abdominal discomfort with a history of nasopharyngeal carcinoma 5 years ago. DIAGNOSES: The diagnosis of DMPM was finally confirmed by laparoscopic mesenteric biopsies. Paraneoplastic syndromes including increased platelets were present when diagnosis, followed by increased neutrophils after disease progression. INTERVENTIONS: Due to intolerable for surgery, he was treated with pemetrexed combined with nivolumab, intraperitoneal infusion of nivolumab, radiotherapy, anlotinib and maintenance treatment of nivolumab. OUTCOMES: Progression-free survival in first line is 12 months, overall survival is 23 months. LESSONS: This indicate that comprehensive treatment including immunotherapy may be helpful for inoperable DMPM patients with nasopharyngeal carcinoma accompanied with paraneoplastic syndromes.

Topical Ozone Accelerates Diabetic Wound Healing by Promoting Re-Epithelialization through the Activation of IGF1R-EGFR Signaling.

Ozonated oil increases the healing of chronic diabetic wounds, but the underlying mechanisms remain unclear. We investigated the effect of topical ozonated oil on wound healing in mice with diabetes with diet-induced obesity and further elucidated the role of EGFR and IGF1R signaling in diabetic wound healing. We found that topical ozonated oil accelerated wound healing; increased phosphorylation of IGF1R, EGFR, and VEGFR; and improved vascularization at the wound leading edge in mice with diabetes with diet-induced obesity. Exposure of normal epidermal keratinocytes to ozonated medium (20 µM for 2 hours daily) increased cell proliferation and migration distance by increasing phosphorylation of IGF1R and EGFR and downstream phosphoinositide 3-kinase, protein kinase B, and extracellular signal-regulated kinase. These findings shed light on the mechanism for topical ozone action in chronic wounds and support its potential therapeutic application.

Magnetic ion-imprinted polyacrylonitrile-chitosan electro-spun nanofibrous membrane as recyclable adsorbent with selective heavy metal removal and antibacterial fouling in water treatment.

Water pollution has become one of the most concerned environmental issues on the worldwide scale. Due to the harmfulness of the heavy metal ions and microorganisms in wastewater, novel filtration membranes for water treatment are expected to simultaneously clear these pollutants. Herein, the electro-spun polyacrylonitrile (PAN) based magnetic ion-imprinted membrane (MIIM) were fabricated to achieve both selective removal of Pb(II) ions and excellent antibacterial efficiency. The competitive removal experiments showed that the MIIM displayed efficiently selective removal of Pb(II) (45.4 mg·g-1). Pseudo-second-order mode and Langmuir isotherm equation is well matched with the equilibrium adsorption. The MIIM showed sustained removal performance (~79.0 %) against Pb(II) ions after 7 adsorption-desorption cycles with negligible Fe ions loss of 7.3 %. Moreover, the MIIM exhibited excellent antibacterial properties that >90 % of E. coli and S. aureus were killed by the MIIM. In conclusion, the MIIM provides a novel technological platform for integration of multi-function with selective metal ions removal, excellent cycling reusability, and enhanced antibacterial fouling property, which can be potentially utilized as a promising adsorbent in actual treatment of polluted water.

Efficacy and tolerability of pharmacological treatments for insomnia in adults: A systematic review and network meta-analysis.

Insomnia is one of the most common and burdensome disorders in adults. We compared and ranked insomnia medication on the basis of their efficacy and tolerability. We performed a systematic review and network meta-analysis of placebo-controlled or head-to-head randomized controlled trials for primary insomnia in adults comparing 20 drugs. We searched eight databases and seven trial registers from inception to March 1st, 2022. Primary outcomes included sleep latency (SL), awake time after sleep onset (WASO) and discontinuation for adverse events (AED), and secondary outcomes included total sleep time (TST), sleep efficiency (SE), sleep quality (SQ) and adverse events (ADE). Pooled standardized mean differences or odds ratios with 95% credible intervals were estimated using pairwise and network meta-analysis with random-effects. Differences among trial findings were explored in subgroup and sensitivity analyses. Confidence in evidence was assessed using GRADE. The PROSPERO registered number is CRD42020182144. We identified 22,538 records and included 69 studies (17,319 patients). Orexin receptor antagonists (ORAs) are more efficacious than benzodiazepine-like drugs (Z-drugs) and placebo for WASO and SE, and better than melatonin receptor agonists (MRAs) for SL, WASO and SE. ORAs ranked the best in SL (SUCRA value: 0.84), WASO (0.93), TST (0.86) and SE (0.96). Lemborexant and daridorexant (two ORAs) showed greater efficacy than placebo for SL, WASO, and TST, with good tolerability. Z-drugs were more efficacious than placebo for SL, WASO, TST and SE, but with higher risk to safety. Zaleplon and eszopiclone had better efficacy than placebo for TST and SQ respectively. MRAs may also be efficacious for sleep-onset insomnia with good safety. However, the long-term adverse effects of all medications are unclear. Insomnia medications differ in their efficacy and tolerability. ORAs have superior efficacy and tolerability. These findings should aid clinicians in matching risk/benefits of drugs available in their countries to insomnia symptoms.

Preparation and identification of isoquinoline alkaloids with ATP citrate lyase inhibitory activity from Dactylicapnos scandens.

Three new isoquinoline alkaloids including a morphine derivative (1), two aporphine alkaloids (2-3), together with five known alkaloids (4-8) were obtained from the extract of Dactylicapnos scandens (D.Don) Hutch. (D. scandens). Their structures and absolute configurations were elucidated by extensive spectroscopic data analysis including HRESIMS, NMR and electronic circular dichroism (ECD) and ECD calculation. Compounds 1-8 were evaluated for ATP Citrate Lyase (ACLY) inhibitory activity through an enzymatic assay. Among them, 2 and 3 showed the high ACLY inhibitory activity with an IC50 value of 10.48 ± 1.59 and 10.89 ± 4.89 µM.

The First Study of Mating Mistakes in Stoneflies (Plecoptera) from China, with Remarks on Their Biological Implications.

Currently, information on the biology of Plecoptera from China is scarce, particularly on mating behavior. In this paper, the existence of mating mistakes (erroneous mating attempts) involving 13 Chinese stonefly species (belonging to nine genera and three families) is reported. These erroneous mating behaviors can be included into three different categories: mating attempts between conspecific males (including the formation of erroneous mating balls), mating attempts between different taxa (including displacement attempts during copulation), and mating-related behaviors with non-living objects. From these behaviors, some aspects of stoneflies during mating, such as the physical competition between males, the sensorial mechanisms implied in triggering a mating behavior, the conditions favoring the mating mistakes, and the possible consequences of interspecific mating in the hybrid production, are discussed.

Dynamics of protein condensates in weak-binding regime.

Weak complementary interactions between proteins and nucleic acids are the main driving forces of intracellular liquid-liquid phase separation. The sticker-spacer model has emerged as a unifying principle for understanding the phase behavior of these multivalent molecules. It remains elusive how specific interactions mediated by stickers contribute to the rheological properties of the liquid condensates. Previous studies have revealed that for strong binding strength ɛ_{b}, the bulk diffusivity D depends on the effective bond lifetime τ, viz., D∝τ^{-1}. Consequently, equal concentrations of the complementary stickers induce a slow down in the dynamics of the condensates D∝e^{-1.5ɛ_{b}}. However, for weak-binding strength, it is expected that the resulting condensates are dynamic, loose network liquids rather than kinetically arrested, compact clusters. We develop a mean-field theory using the thermodynamics of the associative polymers and perform molecular-dynamics simulations based on the sticker-spacer model to study the controlling factors in the structure and dynamics of such condensates in the weak-binding regime. Through scaling analysis, we delineate how the free sticker fraction W_{f} and the bulk diffusivity D decrease with increasing binding energy and find that the internal dynamics of such network liquids are controlled by the free sticker fraction D∝W_{f}∝e^{-0.5ɛ_{b}} rather than the effective bond lifetime. Referred to as the free-sticker-dominated diffusivity, the microscopic slowdown due to a gradual loss of the free stickers affects the viscosity of the condensates as well, with the scaling of the zero-shear viscosity η∝e^{0.5ɛ_{b}}. Therefore, the way of controlling the structure, diffusivity, and viscosity of the condensates through the binding energy can be tested experimentally.

Three new species of Sinacroneuria Yang amp; Yang, 1995 (Plecoptera: Perlidae) from Zhejiang Province, southeastern China.

Three new species of Sinacroneuria Yang Yang, 1995, Sinacroneuria parallela Xiang Du, sp. nov., Sinacroneuria complana Xiang Du, sp. nov. and Sinacroneuria longiprojecta Du Huo sp. nov., from Zhejiang Province of southeastern China are described and illustrated. A list and provisional key to Sinacroneuria males of Zhejiang Province are also presented.

A discussion of morphological differences within Claassenia qingzanga Xiang, Huo amp; Du, 2022 (Plecoptera: Perlidae) based on molecular data and a redescription of C. magna Wu, 1948.

In the genus Claassenia Wu, 1934, the sensilla basiconica patch is an important identification characteristic, yet there are few studies that have investigated this trait. Recently, we found that tergum 8 of males of Claassenia qingzanga Xiang, Huo Du, 2021 collected from the Qinghai Province of China have a small, scattered basiconica patch, while the specimens collected from the Tibet Autonomous Region of China lack this characteristic. To verify their genetic relationship, we sequenced the mitochondrial cytochrome C oxidase subunit I gene of C. qingzanga collected from Tibet and Qinghai provinces. Phylogenetic analyses using Maximum Likelihood and Bayesian Inference methods, the two forms of C. qingzanga grouped together with strong nodal support and separate from the other Claassenia species analyzed. Genetic distance among these two forms of C. qingzanga is only about 1%. The molecular analyses confirmed that specimens with morphological differences are indeed the same species. A discussion of morphological differences within C. qingzanga and its genetic relationships are presented based on molecular data. Additionally, Claassenia magna Wu, 1948 is redescribed based on recent specimens.

Sensitivity of Sniffer Dogs for a Diagnosis of Parkinson's Disease: A Diagnostic Accuracy Study.

BACKGROUND: The diagnostic criteria for Parkinson's disease (PD) remain complex, which is especially problematic for nonmovement disorder experts. A test is required to establish a diagnosis of PD with improved accuracy and reproducibility. OBJECTIVE: The study aimed to investigate the sensitivity and specificity of tests using sniffer dogs to diagnose PD. METHODS: A prospective, diagnostic case-control study was conducted in four tertiary medical centers in China to evaluate the accuracy of sniffer dogs to distinguish between 109 clinically established medicated patients with PD, 654 subjects without PD, 37 drug-naïve patients with PD, and 185 non-PD controls. The primary outcomes were sensitivity and specificity of sniffer dog's identification. RESULTS: In the study with patients who were medicated, when two or all three sniffer dogs yielded positive detection results in a sample tested, the index test sensitivity, specificity, and positive and negative likelihood ratios were 91% (95% CI: 84%-96%), 95% (95% CI: 93%-97%), and 19.16 (95% CI: 13.52-27.16) and 0.10 (95% CI: 0.05-0.17), respectively. The corresponding sensitivity, specificity, and positive and negative likelihood ratios in patients who were drug-naïve were 89% (95% CI: 75%-96%), 86% (95% CI: 81%-91%), and 6.6 (95% CI: 4.51-9.66) and 0.13 (95% CI: 0.05-0.32), respectively. CONCLUSIONS: Tests using sniffer dogs may be a useful, noninvasive, fast, and cost-effective method to identify patients with PD in community screening and health prevention checkups as well as in neurological practice. © 2022 International Parkinson and Movement Disorder Society.

Association of rare PPARGC1A variants with Parkinson's disease risk.

BACKGROUND: Recent researches on Parkinson's disease (PD) pathogenesis discovered the correlation between PD and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) dysfunction and reduction of PPARGC1A gene expression. Hence, we detected PPARGC1A rare variants to clarify their effect on PD risk in a large population of PD patients in mainland China. METHODS: We applied whole-exome sequencing (WES) to 1917 patients with early-onset or familial PD and 1652 controls (WES cohort), and whole-genome sequencing (WGS) to 1962 patients with sporadic late-onset PD and 1279 controls (WGS cohort). To identify PPARGC1A rare variants, we used burden analysis to assess the relationship between PPARGC1A rare variants and PD susceptibility. RESULTS: 30 rare missense variants in the cohort WES and 21 missense variants in the cohort WGS have been detected in the study and PPARGC1A missense variants are significantly associated with early-onset and familial PD susceptibility in our study (P = 0.012), which supports evidence that PPARGC1A rare variants are involved in the onset of early-onset and familial PD. CONCLUSIONS: The study suggested that PPARGC1A rare variants may contribute to the risk of early-onset and familial PD.

Zwitterionic meso-silica/polypeptide hybrid nanoparticles for efficient azithromycin delivery and photodynamic therapy for synergistic treatment of drug-resistant bacterial infection.

The treatment of drug-resistant bacterial infections attributed to the overuse of antibiotics still remains a serious challenge globally. Herein, zwitterionic charge switchable meso-silica/polypeptide hybrid nanoparticles (MSPNs) were prepared for the synergistic chemo-photodynamic therapy in the treatment of drug-resistant bacterial infections. Subsequently, azithromycin (AZT) and methylene blue (MB) were loaded in the MSPNs to form the combined chemo-photodynamic therapeutic nanoparticles (MSPNs-AZT/MB) for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Remarkably, the as-prepared MSPNs-AZT/MB exhibited a negative surface charge of -5.2 mV at physiological pH while switching into positive surface charge of 24.7 mv in an acidic environment, leading to enhanced binding with bacterial surface. The lipase-triggered AZT release up to 77.9 % was achieved, and the loaded MB demonstrated efficient singlet oxygen (1O2) generation for photodynamic therapy. The in vitro experimental results displayed an excellent antibacterial effect against MRSA in both planktonic and biofilm phenotypes. Additionally, the as-prepared MSPNs-AZT/MB exhibited synergistic and enhanced antibacterial infection effect up to 94 % comparing to monotherapy in a mice model. Considering the above advantages, the as-prepared combined chemo-photodynamic therapeutic nanoparticles showed promising biocompatibility and clinical potential for the efficient therapy of drug-resistant bacteria.

LncRNA FGD5-AS1 enhances the proliferation and stemness of hepatocellular carcinoma cells through targeting miR-223 and regulating the expression of ECT2 and FAT1.

AIM: Hepatocellular carcinoma (HCC) is common and causes many deaths worldwide. The aim of this study is to explore the mechanism by which long non-coding RNA FGD5-AS1 regulates HCC cell proliferation and stemness. METHODS: Tumor and normal adjacent tissues were harvested from HCC patients. Real-time quantitative reverse transcription-PCR was applied to examine the expression of FGD5-AS1, miR-223, Epithelial cell transforming sequence 2 (ECT2) and FAT1. The protein levels of ECT2, FAT1, proliferating cell nuclear antigen (PCNA), OCT4, CD133 and CD90 were analyzed by western blot. The localization of FGD5-AS1 was examined by Fluorescence in situ hybridization. Cell proliferation was analyzed with CCK-8 and colony formation assays. Spheroid formation was used for analyzing cell stemness. Gene interaction was examined by RNA immunoprecipitation and luciferase activity assays. A subcutaneous xenograft mouse model was established to analyze HCC growth and stemness in vivo. Immunohistochemistry staining was used to analyze the expression PCNA and OCT4 in subcutaneous tumors. RESULTS: FGD5-AS1 was upregulated in HCC and its high expression indicated poor prognosis of patients. High expression of FGD5-AS1 enhanced HCC cell proliferation and stemness. Knockdown of FGD5-AS1 restrained tumor growth and stemness in mice. FGD5-AS1 directly sponged miR-223 and promoted the expression of ECT2 and FAT1 in HCC. Both knockdown of miR-223 and overexpression of ECT2 and FAT1 reversed FGD5-AS1 silencing-mediated suppression of HCC cell proliferation and stemness. CONCLUSION: FGD5-AS1 directly sponged miR-223 and promoted the expression of ECT2 and FAT1 in HCC, thus enhancing HCC cell proliferation and stemness. Our study identifies potential prognostic biomarkers and therapeutic targets for HCC.

A new species of the genus Claassenia (Plecoptera: Perlidae) from China.

A new species, Claassenia qingzanga Xiang, Huo Du, sp. nov. is described from Tibet and Qinghai Province of western China, this is the first record of Claassenia in Qinghai-Tibet Plateau. Males of the new species are brachypterous, the apex of the aedeagus with tiny spines dorsally and with dense protrusion laterally. The new species is compared to all regional Claassenia.