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Objectives: Polymyxins are the last-line therapy for top-priority multidrug-resistant (MDR) gram-negative bacteria. However, polymyxin nephrotoxicity impedes its clinical application. This study aimed to design, synthesize, and identify a novel and promising polymyxin derivative with high efficacy and low toxicity., Methods: To design polymyxin derivatives, we reduced the hydrophobicity of the two hydrophobic domains (fatty acyl chain and D-Phe 6 -L-Leu 7 ) and modified the positive charged L-2,4-diaminobutyric acid (Dab) residues. Twenty-five derivatives were synthesized, and their antibacterial activities in vitro and renal cytotoxicities were determined. The nephrotoxicity and pharmacokinetic parameters of compound 12 were examined in rats. Antibacterial efficacy in vivo was evaluated using a mouse systemic infection model. Surface plasmon resonance analysis, compound 12-rifampicin combination therapy, and scanning electron microscopy were used to study the mechanism of action of compound 12., Results: This research found a new compound, identified as compound 12, which showed similar or increased antibacterial activity against all tested sensitive and carbapenem-resistant gram-negative bacteria. It exhibited reduced renal cytotoxicity and nephrotoxicity, a favorable pharmacokinetic profile, and maintained or improved antibacterial efficacy in vivo. Importantly, its anti-Pseudomonas aeruginosa activity significantly improved. Compound 12, when combined with rifampicin, enhanced the activity of rifampin against gram-negative bacteria. Compound 12 also showed a high affinity for lipopolysaccharide and disrupted cell membrane integrity., Conclusion: Reducing the hydrophobicity of the two domains reduced renal cytotoxicity and nephrotoxicity. Shortening the side chain of Dab 3 by one carbon maintained or increased its antibacterial activity both in vitro and in vivo. Furthermore, only the length of the side chain of Dab 9 could be shortened by one carbon among the Dab 1,5 and Dab 8,9 residues. The bactericidal effects of compound 12 were related to the disruption of cell membrane integrity. Compound 12 may be a promising candidate for combating sensitive and carbapenem-resistant gram-negative bacterial infections, especially Pseudomonas aeruginosa., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Identifying epitopes and their corresponding T-cell receptor (TCR) sequences is crucial in the face of rapidly mutating viruses. Peptide synthesis is often required to confirm the exact epitope sequences, which is time-consuming and expensive. In this study, we introduce a scalable workflow to identify the exact sequences of virus epitopes and reactive TCRs targeting the epitopes from memory T cells. Following the narrowing down of epitopes to specific regions via the tandem minigene (TMG) system, our workflow incorporates the utilization of peptide-major histocompatibility complex-displaying yeasts (pMHC-displaying yeasts) to rapidly screen immunogenic epitopes' precise sequences, obviating the necessity for the chemical synthesis of peptides. Focusing on SARS-CoV-2, we identify the precise sequences of reactive TCRs, targeting conserved epitopes across the Coronaviridae family, from the blood of COVID-19-recovered individuals over 8 months. Notably, we reveal that at least 75% (6/8) of the tested donors harbor T cells targeting a shared epitope, KTFPPTEPK, derived from the N protein. Furthermore, several identified TCRs exhibit cross-reactivity to mutant epitopes, suggesting a potential mechanism for sustained T-cell responses against emerging SARS-CoV-2 variants., (© 2024. The Author(s).)

Background: Fine motor impairment is common in Parkinson's disease (PD), which reduces patients' quality of life. There are few suitable targeted treatments. We conducted a clinical trial to determine whether Baduanjin Qigong exercise would increase fine motor skills in PD patients., Methods: Sixty PD patients (Hoehn-Yahr stage 1-4) with hand fine motor impairment were randomly assigned to the Baduanjin group and the physical activity group. Baduanjin group practiced Baduanjin exercise five times weekly for 40 min (warm-up 5 min, Baduanjin 30 min, cool-down 5 min). The usual physical activity groups maintained their habit of usual physical activities. The participants underwent assessments in the "ON" medication state at baseline and 4-week follow-up time points. The Purdue Pegboard Test (PPT) was used as the primary outcome to assess manual dexterity. The secondary outcomes included the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), and the Parkinson's disease questionnaire (PDQ-39)., Results: The results of PPT revealed the Baduanjin group showed statistically significant improvement in the "non-dominant hand" and "assembly" scores compared to the usual physical activity group (P < 0.05), but with no significant difference in "dominant hand" and "both hands" (P > 0.05). Additionally, the Baduanjin group showed better performance in the PDQ-39 (P < 0.05)., Conclusion: Our study concludes that a 4-week Baduanjin exercise is effective in improving fine motor function and quality of life in patients with mild and moderate PD. The results suggest a promising intervention to be implemented in community or home settings for managing fine motor impairment in PD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Aldehyde dehydrogenase 1, family member A2, is a retinoic acid-synthesizing enzyme encoded by Aldh1a2 in mice and ALDH1A2 in humans. This enzyme is indispensable for kidney development, but its role in kidney physiology and pathophysiology remains to be fully defined. In this review, we mined single-cell and single-nucleus RNA sequencing databases of mouse and human kidneys and found that glomerular parietal epithelial cells (PECs) express a full set of genes encoding proteins needed for cellular vitamin A uptake, intracellular transport, and metabolism into retinoic acid. In particular, Aldh1a2/ALDH1A2 mRNAs are selectively enriched in mouse and human PECs. Aldh1a2 expression in PECs is greatly increased in a mouse model of anti-glomerular basement membrane glomerulonephritis and moderately induced in a mouse model of ischemia-reperfusion acute kidney injury. Aldh1a2 expression in PECs is substantially repressed in a chronic kidney disease mouse model combining diabetes, hypertension, and partial nephrectomy and is moderately repressed in mouse models of focal segmental glomerulosclerosis and diabetic nephropathy. Single-nucleus RNA sequencing data show that ALDH1A2 mRNA expression in PECs is diminished in patients with chronic kidney disease associated with diabetes, hypertension and polycystic kidney disease. In addition to data mining, we also performed Spearman's rank correlation coefficient analyses and identified gene transcripts correlated with Aldh1a2/ALDH1A2 transcripts in mouse PECs and PEC subtypes, and in human PECs of healthy subjects and patients with AKI or CKD. Furthermore, we conducted Gene Ontology pathway analyses and identified the biological pathways enriched among these Aldh1a2/ALDH1A2 -correlated genes. Our data mining and analyses led us to hypothesize that ALDH1A2 - mediated retinoic acid synthesis in PECs plays a yet-undefined role in the kidney and that its dysregulation mediates injury. Conditional, PEC-selective Aldh1a2 knockout, RNA silencing and transgenic mouse models will be useful tools to test this hypothesis. Clinical studies on genetics, epigenetics, expression and functions of ALDH1A2 and other genes needed for retinoic acid biosynthesis and signaling are also warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Fermin, Xu, Kopp and Xu.)

Though RNAi and RNA-splicing machineries are involved in regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, their precise roles in coronavirus disease 2019 (COVID-19) pathogenesis remain unclear. Herein, we show that decreased RNAi component (Dicer and XPO5) and splicing factor (SRSF3 and hnRNPA3) expression correlate with increased COVID-19 severity. SARS-CoV-2 N protein induces the autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, inhibiting miRNA biogenesis and RNA splicing and triggering DNA damage, proteotoxic stress, and pneumonia. Dicer, XPO5, SRSF3, and hnRNPA3 knockdown increases, while their overexpression decreases, N protein-induced pneumonia's severity. Older mice show lower expression of Dicer, XPO5, SRSF3, and hnRNPA3 in their lung tissues and exhibit more severe N protein-induced pneumonia than younger mice. PJ34, a poly(ADP-ribose) polymerase inhibitor, or anastrozole, an aromatase inhibitor, ameliorates N protein- or SARS-CoV-2-induced pneumonia by restoring Dicer, XPO5, SRSF3, and hnRNPA3 expression. These findings will aid in developing improved treatments for SARS-CoV-2-associated pneumonia., (© 2024. The Author(s).)

Background: Paragonimiasis, primarily caused by Paragonimus westermani and P. skrjabini in China, is a common food-borne parasitic zoonosis. However, the national distribution of Paragonimus spp. infection and its associated environmental determinants remain poorly understood. In this paper, we summarize the infection of P. westermani and P. skrjabini and describe key biogeographical characteristics of the endemic areas in China., Methods: Data on Paragonimus infection in humans and animal hosts were extracted from eight electronic databases, including CNKI, CWFD, Chongqing VIP, SinoMed, Medline, Embase, PubMed, and Web of Science. A random-effects meta-analysis model was used to estimate the pooled prevalence. All survey locations were georeferenced and plotted on China map, and scatter plots were used to illustrate the biogeographical characteristics of regions reporting Paragonimus infection., Results: A total of 28,948 cases of human paragonimiasis have been documented, with 2,401 cases reported after 2010. Among the 11,443 cases with reported ages, 88.05% were children or adolescents. The pooled prevalence of P. skrjabini is 0.45% (95% CI: 0.27-0.66%) in snails, 31.10% (95% CI: 24.77-37.80%) in the second intermediate host, and 20.31% (95% CI: 9.69-33.38%) in animal reservoirs. For P. westermani, the pooled prevalence is 0.06% (95% CI: 0.01-0.13%) in snails, 52.07% (95% CI: 43.56-60.52%) in the second intermediate host, and 21.40% (95% CI: 7.82-38.99%) in animal reservoirs. Paragonimus are primarily distributed in regions with low altitude, high temperature, and high precipitation. In northeastern China, only P. westermani infections have been documented, while in more southern areas, infections of both P. westermani and P. skrjabini have been reported., Conclusions: Paragonimiasis remains prevalent in China, particularly among children and adolescents. Variations exist in the intermediate hosts and geographical distribution of P. westermani and P. skrjabini. Additionally, altitude, temperature, and precipitation may influence the distribution of Paragonimus., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The landscape of hepatitis B virus (HBV) integration in the plasma cell-free DNA (cfDNA) of HBV-infected patients with different stages of liver diseases [chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC)] remains unclear. In this study, we developed an improved strategy for detecting HBV DNA integration in plasma cfDNA, based on DNA probe capture and next-generation sequencing. Using this optimized strategy, we successfully detected HBV integration events in chimeric artificial DNA samples and HBV-infected HepG2-NTCP cells at day one post infection, with high sensitivity and accuracy. The characteristics of HBV integration events in the HBV-infected HepG2-NTCP cells and plasma cfDNA from HBV-infected individuals (CHB, LC, and HCC) were further investigated. A total of 112 and 333 integration breakpoints were detected in the HepG2-NTCP cells and 22 out of 25 (88%) clinical HBV-infected samples, respectively. In vivo analysis showed that the normalized number of support unique sequences (nnsus) in HCC was significantly higher than in CHB or LC patients (P values ​< ​0.05). All integration breakpoints are randomly distributed on human chromosomes and are enriched in the HBV genome around nt 1800. The majority of integration breakpoints (61.86%) are located in the gene-coding region. Both non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ) interactions occurred during HBV integration across the three different stages of liver diseases. Our study provides evidence that HBV DNA integration can be detected in the plasma cfDNA of HBV-infected patients, including those with CHB, LC, or HCC, using this optimized strategy., Competing Interests: Conflict of interest The authors declare no potential conflicts of interest., (Copyright © 2024 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

We recently identified a class of small cytosolic double-stranded DNA (scDNA) approximately 20-40 bp in size in human and mouse cells. Here, we present a protocol for scDNA isolation from cultured murine cells. We describe steps for cytosolic compartment separation, DNA isolation in the cytosolic fraction using phenol-chloroform extraction, and ethanol precipitation. We then detail procedures for denaturing purified cytosolic DNA through urea polyacrylamide gel electrophoresis and obtaining scDNA in the cytosolic DNA fraction via gel purification. For complete details on the use and execution of this protocol, please refer to Liu et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne zoonosis caused by the SFTS virus (SFTSV). Understanding the prevalence of SFTSV RNA in humans, vertebrate hosts and ticks is crucial for SFTS control., Methods: A systematic review and meta-analysis were conducted to determine the prevalence of SFTSV RNA in humans, vertebrate hosts and questing ticks. Nine electronic databases were searched for relevant publications, and data on SFTSV RNA prevalence were extracted. Pooled prevalence was estimated using a random effects model. Subgroup analysis and multivariable meta-regression were performed to investigate sources of heterogeneity., Results: The pooled prevalence of SFTSV RNA in humans was 5.59% (95% confidence interval [CI] 2.78-9.15%) in those in close contact (close contacts) with infected individuals (infected cases) and 0.05% (95% CI 0.00-0.65%) in healthy individuals in endemic areas. The SFTSV infection rates in artiodactyls (5.60%; 95% CI 2.95-8.96%) and carnivores (6.34%; 95% CI 3.27-10.23%) were higher than those in rodents (0.45%; 95% CI 0.00-1.50%). Other animals, such as rabbits, hedgehogs and birds, also played significant roles in SFTSV transmission. The genus Haemaphysalis was the primary transmission vector, with members of Ixodes, Dermacentor, and Amblyomma also identified as potential vectors. The highest pooled prevalence was observed in adult ticks (1.03%; 95% CI 0.35-1.96%), followed by nymphs (0.66%; 95% CI 0.11-1.50%) and larvae (0.01%; 95% CI 0.00-0.46%). The pooled prevalence in ticks collected from endemic areas (1.86%; 95% CI 0.86-3.14%) was higher than that in ticks collected in other regions (0.41%; 95% CI 0.12-0.81%)., Conclusions: Latent SFTSV infections are present in healthy individuals residing in endemic areas, and close contacts with SFTS cases are at a significantly higher risk of infection. The type of animal is linked to infection rates in vertebrate hosts, while infection rates in ticks are associated with the developmental stage. Further research is needed to investigate the impact of various environmental factors on SFTSV prevalence in vertebrate hosts and ticks., (© 2024. The Author(s).)

The CGAS (cyclic GMP-AMP synthase)-STING1 (stimulator of interferon response cGAMP interactor 1) pathway is an important innate immune pathway that induces proinflammatory cytokine production following stimulation with dsDNA > 45 bp. We recently identified a class of ~ 20-40 bp small cytosolic dsDNA (scDNA) that blocks CGAS-STING1 activation. In this punctum, we discuss the mechanism underlying the inhibition of CGAS-STING1 activation via scDNA. scDNA binds to CGAS but cannot activate its enzymatic activity. It competes with dsDNA > 45 bp for binding with CGAS to inhibit CGAS-STING1 activation. Moreover, scDNA activates macroautophagy/autophagy and induces the autophagic degradation of STING1 and long dsDNA. Autophagy then increases scDNA levels, driving a feedback loop that accelerates the degradation of STING1 and long cytosolic dsDNA. These findings reveal that mutual communication between scDNA and autophagy inhibits CGAS-STING1 activation following stimulation with dsDNA > 45 bp.

Hereditary hearing loss (HHL), a genetic disorder that impairs auditory function, significantly affects quality of life and incurs substantial economic losses for society. To investigate the underlying causes of HHL and evaluate therapeutic outcomes, appropriate animal models are necessary. Pigs have been extensively used as valuable large animal models in biomedical research. In this review, we highlight the advantages of pig models in terms of ear anatomy, inner ear morphology, and electrophysiological characteristics, as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss. Additionally, we discuss the prospects, challenges, and recommendations regarding the use pig models in HHL research. Overall, this review provides insights and perspectives for future studies on HHL using porcine models.

Liver cancer is ranked as the sixth most prevalent from of malignancy globally and stands as the third primary contributor to cancer-related mortality. Metastasis is the main reason for liver cancer treatment failure and patient deaths. Speckle-type POZ protein (SPOP) serves as a crucial substrate junction protein within the cullin-RING E3 ligase complex, acting as a significant tumor suppressor in liver cancer. Nevertheless, the precise molecular mechanism underlying the role of SPOP in liver cancer metastasis remain elusive. In the current study, we identified cAMP response element binding 5 (CREB5) as a novel SPOP substrate in liver cancer. SPOP facilitates non-degradative K63-polyubiquitination of CREB5 on K432 site, consequently hindering its capacity to activate receptor tyrosine kinase MET. Moreover, liver cancer-associated SPOP mutant S119N disrupts the SPOP-CREB5 interactions and impairs the ubiquitination of CREB5.This disruption ultimately leads to the activation of the MET signaling pathway and enhances metastatic properties of hepatoma cells both in vitro and in vivo. In conclusion, our findings highlight the functional significance of the SPOP-CREB5-MET axis in liver cancer metastasis., Competing Interests: Declaration of competing interest The authors declare that there are no potential conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Hepatitis B virus (HBV) infection is a serious global health problem. After the viruses infect the human body, the host can respond to the virus infection by coordinating various cellular responses, in which mitochondria play an important role. Evidence has shown that mitochondrial proteins are involved in host antiviral responses. In this study, we found that the overexpression of TIM22 and TIM29, the members of the inner membrane translocase TIM22 complex, significantly reduced the level of intracellular HBV DNA and RNA and secreted HBV surface antigens and E antigen. The effects of TIM22 and TIM29 on HBV replication and transcription is attributed to the reduction of core promoter activity mediated by the increased expression of SRSF1 which acts as a suppressor of HBV replication. This study provides new evidence for the critical role of mitochondria in the resistance of HBV infection and new targets for the development of treatment against HBV infection., (© 2024 Wiley Periodicals LLC.)

The achievement of a functional cure for chronic hepatitis B (CHB) remains limited to a minority of patients treated with currently approved drugs. The primary objective in developing new anti-HBV drugs is to enhance the functional cure rates for CHB. A critical prerequisite for the functional cure of CHB is a substantial reduction, or even eradication of covalently closed circular DNA (cccDNA). Within this context, the changes in cccDNA levels during treatment become as a pivotal concern. We have previously analyzed the factors influencing cccDNA dynamics and introduced a preliminary classification of hepatitis B treatment strategies based on these dynamics. In this review, we employ a systems thinking perspective to elucidate the fundamental aspects of the HBV replication cycle and to rationalize the classification of treatment strategies according to their impact on the dynamic equilibrium of cccDNA. Building upon this foundation, we categorize current anti-HBV strategies into two distinct groups and advocate for their combined use to significantly reduce cccDNA levels within a well-defined timeframe., (Copyright © 2023 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

The efficacy and safety of different Chinese patent medicines in the treatment of coronary heart disease complicated with heart failure were evaluated by network Meta-analysis. The randomized controlled trial(RCT) of Chinese patent medicines for coronary heart disease complicated with heart failure was retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, EMbase, and Cochrane Library with the time interval from inception to July 5, 2023. The quality of the included RCT was evaluated by the Cochrane's risk of bias assessment tool, and a network Meta-analysis was performed in Stata 16.0. Finally, a total of 82 RCTs were included, involving 9 298 patients and 11 Chinese patent medicines. Network Meta-analysis yielded the following results based on the surface under the cumulative ranking curve(SUCRA).(1)In terms of improving the clinical response rate, the top three interventions were Qishen Yiqi Dripping Pills + conventional western medicine, Zhenyuan Capsules + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(2) In terms of increasing left ventricular ejection fraction(LVEF), the top three interventions were Shexiang Baoxin Pills + conventional western medicine, Compound Danshen Dripping Pills + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(3) In terms of reducing left ventricular end-diastolic diameter(LVEDD), the top three interventions were Shexiang Tongxin Dripping Pills + conventional western medicine, Tongxinluo Capsules + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(4) In terms of reducing N-terminal pro-brain natriuretic peptide(NT-proBNP), the top three interventions were Shexiang Baoxin Pills + conventional western medicine, Qi-shen Yiqi Dripping Pills + conventional western medicine, and Compound Danshen Dripping Pills + conventional western medicine.(5) In terms of reducing hyper-sensitive C-reactive protein(hs-CRP), the top three interventions were Naoxintong Capsules + conventional western medicine, Shexiang Baoxin Pills + conventional western medicine, and Compound Danshen Dripping Pills + conventional western medicine.(6) In terms of increasing the distance of the six-minute walking trail(6MWT), the top three interventions were Zhen-yuan Capsules + conventional western medicine, Qili Qiangxin Capsules + conventional western medicine, and Qishen Yiqi Dripping Pills + conventional western medicine. The results showed that Chinese patent medicines combined with conventional western medicine can effectively improve the clinical response rate, LVEF, and 6MWT and reduce LVEDD, NT-proBNP, and hs-CRP. However, due to the overall low quality of the articles included and the few articles of some Chinese patent medicines, direct comparison between diffe-rent Chinese patent medicines remains to be carried out and the results need to be further verified.