ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2-BECN1 interaction.

Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative disorders. The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72 (C9orf72) is the most genetic cause of both ALS and FTD. According to the previous studies, GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation, which produces dipeptide repeat (DPR) proteins. Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD, whether these DPRs can affect autophagy remains unclear. In the present study, we find that poly-GR and poly-PR, two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies, strongly inhibit starvation-induced autophagy. Moreover, our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation, therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells. Importantly, our study not only highlights the role of C9orf72 DPR in autophagy dysfunction, but also provides novel insight that pharmacological intervention of autophagy using SW063058, a small molecule compound that can disrupt the interaction between BECN1 and BCL2, may reduce C9orf72 DPR-induced neurotoxicity.

Effectiveness and safety of SR-ENS-600endoscopic surgical system in benign and malignant gynecological diseases: a prospective, multicenter, clinical trial with 63 cases.

Single-port laparoscopy has gained more attention, but inherent technical challenges hinder its wider use. To overcome the disadvantage of traditional single-port surgery, robotic laparoendoscopic single-site surgery system was designed and clinically utilized. This multi-center single-arm trial was aimed to present the clinical outcomes of the SHURUI robotic endoscopic single-site surgery system. 63 women with ovary cysts, myoma, cervical epithelial neoplasm, or endometrial carcinoma were recruited at 6 academic medical centers in different districts of China. The trial was registered on September 5, 2023, with the register number: ChiCTR2300075431, retrospectively registered. Patients underwent robotic LESS surgery with the SHURUI endoscopic surgical system from January 17 to May 26, 2023. Demographic information, perioperative parameters, complications, scar healing, and operator satisfaction scores were recorded. Patients were followed up for 30 ± 4 days. Average operative time and estimated blood loss were 157.03 ± 75.24 min and 63.86 ± 98.33 ml, respectively, for all surgeries. Average anal exhaust time and hospitalization stay were 30.99 ± 14.25 h and 3.63 ± 1.59 days, respectively. Patients' postoperative rehabilitation assessment showed satisfactory results on the day of discharge and 30 ± 4 days after surgery. The surgery achieved good cosmetic benefits and was surgeon friendly. There were no conversions to alternative surgical modalities, complications, or readmissions. The SHURUI endoscopic surgical system showed both the technical feasibility and safety of this surgical modality for gynecologic patients. Further randomized studies comparing this modality with traditional LESS surgery are suggested.

Opsonization Inveigles Macrophages Engulfing Carrier-Free Bilirubin/JPH203 Nanoparticles to Suppress Inflammation for Osteoarthritis Therapy.

Osteoarthritis (OA) is a chronic inflammatory disease characterized by cartilage destruction, synovitis, and osteophyte formation. Disease-modifying treatments for OA are currently lacking. Because inflammation mediated by an imbalance of M1/M2 macrophages in the synovial cavities contributes to OA progression, regulating the M1 to M2 polarization of macrophages can be a potential therapeutic strategy. Basing on the inherent immune mechanism and pathological environment of OA, an immunoglobulin G-conjugated bilirubin/JPH203 self-assembled nanoparticle (IgG/BRJ) is developed, and its therapeutic potential for OA is evaluated. After intra-articular administration, IgG conjugation facilitates the recognition and engulfment of nanoparticles by the M1 macrophages. The internalized nanoparticles disassemble in response to the increased oxidative stress, and the released bilirubin (BR) and JPH203 scavenge reactive oxygen species (ROS), inhibit the nuclear factor kappa-B pathway, and suppress the activated mammalian target of rapamycin pathway, result in the repolarization of macrophages and enhance M2/M1 ratios. Suppression of the inflammatory environment by IgG/BRJ promotes cartilage protection and repair in an OA rat model, thereby improving therapeutic outcomes. This strategy of opsonization involving M1 macrophages to engulf carrier-free BR/JPH203 nanoparticles to suppress inflammation for OA therapy holds great potential for OA intervention and treatment.

BV2 Membrane-Coated PEGylated-Liposomes Delivered hFGF21 to Cortical and Hippocampal Microglia for Alzheimer's Disease Therapy.

Microglia-mediated inflammation is involved in the pathogenesis of Alzheimer's disease (AD), whereas human fibroblast growth factor 21 (hFGF21) has demonstrated the ability to regulate microglia activation in Parkinson's disease, indicating a potential therapeutic role in AD. However, challenges such as aggregation, rapid inactivation, and the blood-brain barrier hinder its effectiveness in treating AD. This study develops targeted delivery of hFGF21 to activated microglia using BV2 cell membrane-coated PEGylated liposomes (hFGF21@BCM-LIP), preserving the bioactivity of hFGF21. In vitro, hFGF21@BCM-LIP specifically targets Aß1-42-induced BV2 cells, with uptake hindered by anti-VCAM-1 antibody, indicating the importance of VCAM-1 and integrin α4/ß1 interaction in targeted delivery to BV2 cells. In vivo, following subcutaneous injection near the lymph nodes of the neck, hFGF21@BCM-LIP diffuses into lymph nodes and distributes along the meningeal lymphatic vasculature and brain parenchyma in amyloid-beta (Aß1-42)-induced mice. Furthermore, the administration of hFGF21@BCM-LIP to activated microglia improves cognitive deficits caused by Aß1-42 and reduces levels of tau, p-Tau, and BACE1. It also decreases interleukin-6  (IL-6) and tumor necrosis factor-α (TNF-α) release while increasing interleukin-10 (IL-10) release both in vivo and in vitro. These results indicate that hFGF21@BCM-LIP can be a promising treatment for AD, by effectively crossing the blood-brain barrier and targeting delivery to brain microglia via the neck-meningeal lymphatic vasculature-brain parenchyma pathways.

Bilirubin/morin self-assembled nanoparticle-engulfed collagen/polyvinyl alcohol hydrogel accelerates chronic diabetic wound healing by modulating inflammation and ameliorating oxidative stress.

Chronic diabetic wounds pose a serious threat to human health and safety because of their refractory nature and high recurrence rates. The formation of refractory wounds is associated with wound microenvironmental factors such as increased expression of proinflammatory factors and oxidative stress. Bilirubin is a potent endogenous antioxidant, and morin is a naturally active substance that possesses anti-inflammatory and antioxidant effects. Both hold the potential for diabetic wound treatment by intervening in pathological processes. In this study, we developed bilirubin/morin-based carrier-free nanoparticles (BMn) to treat chronic diabetic wounds. In vitro studies showed that BMn could effectively scavenge overproduced reactive oxygen species and suppress elevated inflammation, thereby exerting a protective effect. BMn was then loaded into a collagen/polyvinyl alcohol gel (BMn@G) for an in vivo study to maintain a moist environment for the skin and convenient biomedical applications. BMn@G exhibits excellent mechanical properties, water retention capabilities, and in vivo safety. In type I diabetic mice, BMn@G elevated the expression of the anti-inflammatory factor IL-10 and concurrently diminished the expression of the proinflammatory factor TNF-α in the tissues surrounding the wounds. Furthermore, BMn@G efficiently mediated macrophage polarization from the M1-type to the M2-type, thereby fostering anti-inflammatory effects. Additionally, BMn@G facilitated the conversion of type III collagen fiber bundles to type I collagen fiber bundles, resulting in a more mature collagen fiber structure. This study provides a promising therapeutic alternative for diabetic wound healing.

Vitamin intake and periodontal disease: a meta-analysis of observational studies.

OBJECTIVE: A meta-analysis was performed to assess the epidemiological correlation between dietary intake of various types of vitamin intake and the risk of periodontal disease. METHODS: A comprehensive computerized search was conducted in eight databases, namely PubMed, Web of Science, Embase, Cochrane Library, China Biology Medicine Disc, CNKI, VIP, and WanFang Database, and a random effect model was applied to combine pooled odds ratio (ORs) with corresponding 95% confidence intervals (CIs) of the included studies, and the sensitivity analysis was performed to explore the impact of a single study on the comprehensive results. RESULTS: We finally included 45 effect groups from 23 observational studies, with a total number of study participants of 74,488. The results showed that higher levels of vitamin A (OR: 0.788, 95% CI: 0.640-0.971), vitamin B complex (OR: 0.884, 95% CI: 0.824-0.948), vitamin C (OR: 0.875, 95% CI: 0.775-0.988), vitamin D (OR: 0.964, 95% CI: 0.948-0.981), and vitamin E (OR: 0.868, 95% CI: 0.776-0.971) intake all were negatively correlated with periodontal disease. After removing each study, leave-one-out sensitivity analysis indicated no significant change in the overall results of any of the five meta-analyses. CONCLUSIONS: The results from this meta-analysis demonstrated a negative association between high-dose vitamin A, vitamin B complex, vitamin C, vitamin D, and vitamin E consumption and the likelihood of developing periodontal disease, revealing the significant role of vitamins in preventing periodontal disease.

Biomaterial-assisted strategies to improve islet graft revascularization and transplant outcomes.

Islet transplantation holds significant promise as a curative approach for type 1 diabetes (T1D). However, the transition of islet transplantation from the experimental phase to widespread clinical implementation has not occurred yet. One major hurdle in this field is the challenge of insufficient vascularization and subsequent early loss of transplanted islets, especially in non-intraportal transplantation sites. The establishment of a fully functional vascular system following transplantation is crucial for the survival and secretion function of islet grafts. This vascular network not only ensures the delivery of oxygen and nutrients, but also plays a critical role in insulin release and the timely removal of metabolic waste from the grafts. This review summarizes recent advances in effective strategies to improve graft revascularization and enhance islet survival. These advancements include the local release and regulation of angiogenic factors (e.g., vascular endothelial growth factor, VEGF), co-transplantation of vascular fragments, and pre-vascularization of the graft site. These innovative approaches pave the way for the development of effective islet transplantation therapies for individuals with T1D.

Dual elastography to discriminate adjacent stages of fibrosis and inflammation in chronic hepatitis B: A prospective multicenter study.

BACKGROUND AND AIMS: To evaluate the diagnostic performance of dual elastography (dual-elasto) in continuous differentiation of liver fibrosis and inflammation in a large prospective cohort of patients with chronic HBV. APPROACH AND RESULTS: Adults with positive HBsAg for at least 6 months were recruited from 12 medical centers. Participants underwent dual-elasto evaluations. Biopsy was performed 3 days after dual-elasto examination. Four logistic regression models were trained and strung together into series models. Decision trees based on the series models were performed to achieve continuous differentiation of liver fibrosis and inflammation. The influence of inflammation on the fibrosis stage was also evaluated. A total of 560 patients were included in the training set and 240 in the validation set. Areas under the receiver operating characteristic curve of the series model were 0.82, 0.86, 0.93, and 0.96 to predict ≥F1, ≥F2, ≥F3, and F4 in the validation set, which were significantly higher than those of serum markers and shear wave elastography (all p < 0.05), except for the ≥ F1 levels ( p = 0.09). The AUCs of the series model were 0.93, 0.86, 0.95, and 0.84 to predict inflammation stages ≥G1, ≥G2, ≥G3, and G4, respectively. Decision trees realized 5 continuous classifications of fibrosis and inflammation. Inflammation could enhance the mild fibrosis stage classification while showing limited influences on severe fibrosis or cirrhosis diagnosis. CONCLUSIONS: Dual-elasto demonstrated high performance in the continuous discrimination of fibrosis and inflammation in patients with HBV and could be used to diagnose mild fibrosis without the influence of inflammation.

4-Octyl itaconate inhibits poly(I:C)-induced interferon-ß secretion in mouse bone marrow-derived macrophages partially by activating Nrf2.

Viruses have become a major threat to human health. Interferon-ß (IFN-ß) has a key role in the antivirus process, as it can increase the expression of antivirus-associated genes. Itaconate and its derivatives can regulate the immune response, secretion of inflammatory factors, and pyroptosis of macrophages. The effect of itaconate on IFN-ß secretion of double-stranded RNA-induced macrophages are not well known. A derivative of itaconate, 4-octoyl itaconate (4-OI), was used to treat mouse bone marrow-derived macrophages (BMDM) induced with 100 µg/mL poly(I:C). The IFN-ß concentration was detected through ELISA, and IFN-ß mRNA expression was detected through quantitative PCR. High-throughput transcriptome sequencing was used to analyze changes in the BMDM transcriptome after 4-OI treatment. The Nrf2 expression was knocked down with siRNA.4-OI inhibited poly(I:C)-induced IFN-ß secretion and mRNA expression in BMDM. Results of transcriptome sequencing revealed that 4-OI downregulated 1047 genes and upregulated 822 genes. GO and KEGG enrichment of differently expressed genes revealed that many downregulated genes were related to the anti-virus process, whereas many upregulated genes were related to metabolism. The Nrf2 inhibitor ML385 and Nrf2 siRNA could partially reverse the inhibitory effect of 4-OI. In conclusion, 4-octyl itaconate could inhibit the poly(I:C)-induced interferon-ß secretion in BMDM partially by regulating Nrf2.

Advances in the prevention and treatment of Alzheimer's disease based on oral bacteria.

With the global population undergoing demographic shift towards aging, the prevalence of Alzheimer's disease (AD), a prominent neurodegenerative disorder that primarily afflicts individuals aged 65 and above, has increased across various geographical regions. This phenomenon is accompanied by a concomitant decline in immune functionality and oral hygiene capacity among the elderly, precipitating compromised oral functionality and an augmented burden of dental plaque. Accordingly, oral afflictions, including dental caries and periodontal disease, manifest with frequency among the geriatric population worldwide. Recent scientific investigations have unveiled the potential role of oral bacteria in instigating both local and systemic chronic inflammation, thereby delineating a putative nexus between oral health and the genesis and progression of AD. They further proposed the oral microbiome as a potentially modifiable risk factor in AD development, although the precise pathological mechanisms and degree of association have yet to be fully elucidated. This review summarizes current research on the relationship between oral bacteria and AD, describing the epidemiological and pathological mechanisms that may potentially link them. The purpose is to enrich early diagnostic approaches by incorporating emerging biomarkers, offering novel insights for clinicians in the early detection of AD. Additionally, it explores the potential of vaccination strategies and guidance for clinical pharmacotherapy. It proposes the development of maintenance measures specifically targeting oral health in older adults and advocates for guiding elderly patients in adopting healthy lifestyle habits, ultimately aiming to indirectly mitigate the progression of AD while promoting oral health in the elderly.

Chlorpromazine affects autophagy in association with altered Rag GTPase-mTORC1-TFEB signaling.

Autophagy is a critical protein and organelle quality control system, which regulates cellular homeostasis and survival. Growing pieces of evidence suggest that autophagic dysfunction is strongly associated with many human diseases, including neurological diseases and cancer. Among various autophagic regulators, microphthalmia (MiT)/TFE transcription factors, including transcription factor EB (TFEB), have been shown to act as the master regulators of autophagosome and lysosome biogenesis in both physiological and pathological conditions. According to the previous studies, chlorpromazine (CPZ), an FDA-approved antipsychotic drug, affects autophagy in diverse cell lines, but the underlying mechanism remains elusive. In our present study, we find that CPZ treatment induces TFEB nuclear translocation through Rag GTPases, the upstream regulators of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Meanwhile, CPZ treatment also blocks autophagosome-lysosome fusion. Notably, we find a significant accumulation of immature autophagosome vesicles in CPZ-treated cells, which may impede cellular homeostasis due to the dysfunction of the autophagy-lysosome pathway. Interestingly and importantly, our data suggest that the expression of the active form of Rag GTPase heterodimers helps in reducing the accumulation of autophagosomes in CPZ-treated cells, further suggesting a major contribution of the Rag GTPase-mTORC1-TFEB signaling axis in CPZ-induced autophagic impairment.

UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two aging-related neurodegenerative diseases that share common key features, including aggregation of pathogenic proteins, dysfunction of mitochondria, and impairment of autophagy. Mutations in ubiquilin 2 (UBQLN2), a shuttle protein in the ubiquitin-proteasome system (UPS), can cause ALS/FTD, but the mechanism underlying UBQLN2-mediated pathogenesis is still uncertain. Recent studies indicate that mitophagy, a selective form of autophagy which is crucial for mitochondrial quality control, is tightly associated with neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and ALS. In this study, we show that after Parkin-dependent ubiquitination of damaged mitochondria, UBQLN2 is recruited to poly-ubiquitinated mitochondria through the UBA domain. UBQLN2 cooperates with the chaperone HSP70 to promote UPS-driven degradation of outer mitochondrial membrane (OMM) proteins. The resulting rupture of the OMM triggers the autophagosomal recognition of the inner mitochondrial membrane receptor PHB2. UBQLN2 is required for Parkin-mediated mitophagy and neuronal survival upon mitochondrial damage, and the ALS/FTD pathogenic mutations in UBQLN2 impair mitophagy in primary cultured neurons. Taken together, our findings link dysfunctional mitophagy to UBQLN2-mediated neurodegeneration.

Targeted to neuronal organelles for CNS drug development.

Significant evidences indicate that sub-cellular organelle dynamics is critical for both physiological and pathological events and therefore may be attractive drug targets displaying great therapeutic potential. Although the basic biological mechanism underlying the dynamics of intracellular organelles has been extensively studied, relative drug development is still limited. In the present review, we show that due to the development of technical advanced imaging tools, especially live cell imaging methods, intracellular organelle dynamics (including mitochondrial dynamics and membrane contact sites) can be dissected at the molecular level. Based on these identified molecular targets, we review and discuss the potential of drug development to target organelle dynamics, especially mitochondria dynamics and ER-organelle membrane contact dynamics, in the central nervous system for treating human diseases, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

Exon-intron boundary inhibits m6A deposition, enabling m6A distribution hallmark, longer mRNA half-life and flexible protein coding.

Regional bias of N6-methyladenosine (m6A) mRNA modification avoiding splice site region, calls for an open hypothesis whether exon-intron boundary could affect m6A deposition. By deep learning modeling, we find that exon-intron boundary represses a proportion (12% to 34%) of m6A deposition at adjacent exons (~100 nt to splice site). Experiments validate that m6A signal increases once the host gene does not undergo pre-mRNA splicing to produce the same mRNA. Inhibited m6A sites have higher m6A enhancers and lower m6A silencers locally and show high heterogeneity at different exons genome-widely, with only a small proportion (12% to 15%) of exons showing strong inhibition, enabling more stable mRNAs and flexible protein coding. m6A is majorly responsible for why mRNAs with more exons be more stable. Exon junction complex (EJC) only partially contributes to this exon-intron boundary m6A inhibition in some short internal exons, highlighting additional factors yet to be identified.

Photocatalytic Charge-Transfer Complex Enables Hydroarylation of Alkenes for Heterocycle Synthesis.

Here, we report a photocatalytic charge-transfer complex (CTC) strategy for one electron reduction of alkenes using thiolate as a catalytic electron donor. This catalytic CTC system could engage hydroarylation of both activated and unactivated alkenes for the synthesis of various heterocycles. The reactions do not require any photocatalysts or acids and are easy to perform. Mechanistic studies revealed the formation of a CTC between catalytic thiolate and alkene.

Factors influencing axial elongation in myopic children using overnight orthokeratology.

Several factors influence axial length in children with myopia treated using overnight orthokeratology. To identify these factors, this retrospective study collected axial length and corneal aberration data on 78 eyes before and 1-year after orthokeratology. Patients were divided according to axial elongation (cut-off, 0.25 mm/year). Baseline characteristics included age, sex, spherical equivalent refraction, pupil diameter, axial length, and orthokeratology lens type. Corneal shape effects were compared through tangential difference maps. Group differences in higher-order aberrations of a 4 mm zone were compared at baseline and 1-year following therapy. Binary logistic regression analysis was conducted to identify the variables determined for axial elongation. Significant differences between both groups included the initial age of wearing orthokeratology lenses, type of orthokeratology lens, size of central flattening area, corneal total surface C12 (1-year), corneal total surface C8 (1-year), corneal total surface spherical aberration (SA) (1-year root mean square [RMS] values), change in total corneal surface C12, and change in front and total corneal surface SA (RMS values). The age when wearing an orthokeratology lens was the most important factor influencing axial length in children with orthokeratology-treated myopia, followed by lens type and change in the C12 of the total corneal surface.

Formulation strategies to provide oxygen-release to contrast local hypoxia for transplanted islets.

Islet transplantation refers to the transfusion of healthy islet cells into the diabetic recipients and reconstruction of their endogenous insulin secretion to achieve insulin independence. It is a minimally invasive surgery that holds renewed prospect as a therapeutic method for type 1 diabetes mellitus. However, poor oxygenation in the early post-transplantation period is considered as one of the major causes of islet loss and dysfunction. Due to the metabolism chacteristics, islets required a high supply of oxygen for cell survival while a hypoxia environment would lead to severe islet loss and graft failure. Emerging strategies have been proposed, including providing external oxygen and speeding up revascularization. From the perspective of formulation science, it is feasible and practical to protect transplanted islets by oxygen-release before revascularization as opposed to local hypoxia. In this study, we review the potential formulation strategies that could provide oxygen-release by either delivering external oxygen or triggering localized oxygen generation for transplanted islets.

QTL-seq and transcriptomic integrative analyses reveal two positively regulated genes that control the low-temperature germination ability of MTP-maize introgression lines.

KEY MESSAGE: Two candidate genes (ZmbZIP113 and ZmTSAH1) controlling low-temperature germination ability were identified by QTL-seq and integrative transcriptomic analyses. The functional verification results showed that two candidate genes positively regulated the low-temperature germination ability of IB030. Low-temperature conditions cause slow maize (Zea mays L.) seed metabolism, resulting in slow seedling emergence and irregular seedling emergence, which can cause serious yield loss. Thus, improving a maize cultivar's low-temperature germination ability (LTGA) is vital for increasing yield production. Wild relatives of maize, such as Z. perennis and Tripsacum dactyloides, are strongly tolerant of cold stress and can thus be used to improve the LTGA of maize. In a previous study, the genetic bridge MTP was constructed (from maize, T. dactyloides, and Z. perennis) and used to obtain a highly LTGA maize introgression line (IB030) by backcross breeding. In this study, IB030 (Strong-LTGA) and Mo17 (Weak-LTGA) were selected as parents to construct an F2 offspring. Additionally, two major QTLs (qCS1-1 and qCS10-1) were mapped. Then, RNA-seq was performed using seeds of IB030 and the recurrent parent B73 treated at 10 °C for 27 days and 25 °C for 7 days, respectively, and two candidate genes (ZmbZIP113 and ZmTSAH1) controlling LTGA were located using QTL-seq and integrative transcriptomic analyses. The functional verification results showed that the two candidate genes positively regulated LTGA of IB030. Notably, homologous cloning showed that the source of variation in both candidate genes was the stable inheritance of introgressed alleles from Z. perennis. This study was thus able to analyze the LTGA mechanism of IB030 and identify resistance genes for genetic improvement in maize, and it proved that using MTP genetic bridge confers desirable traits or phenotypes of Z. perennis and tripsacum essential to maize breeding systems.

QTL Mapping and a Transcriptome Integrative Analysis Uncover the Candidate Genes That Control the Cold Tolerance of Maize Introgression Lines at the Seedling Stage.

Chilling injury owing to low temperatures severely affects the growth and development of maize (Zea mays.L) seedlings during the early and late spring seasons. The existing maize germplasm is deficient in the resources required to improve maize's ability to tolerate cold injury. Therefore, it is crucial to introduce and identify excellent gene/QTLs that confer cold tolerance to maize for sustainable crop production. Wild relatives of maize, such as Z. perennis and Tripsacum dactyloides, are strongly tolerant to cold and can be used to improve the cold tolerance of maize. In a previous study, a genetic bridge among maize that utilized Z. perennis and T. dactyloides was created and used to obtain a highly cold-tolerant maize introgression line (MIL)-IB030 by backcross breeding. In this study, two candidate genes that control relative electrical conductivity were located on MIL-IB030 by forward genetics combined with a weighted gene co-expression network analysis. The results of the phenotypic, genotypic, gene expression, and functional verification suggest that two candidate genes positively regulate cold tolerance in MIL-IB030 and could be used to improve the cold tolerance of cultivated maize. This study provides a workable route to introduce and mine excellent genes/QTLs to improve the cold tolerance of maize and also lays a theoretical and practical foundation to improve cultivated maize against low-temperature stress.

Recombinant protein drugs-based intra articular drug delivery systems for osteoarthritis therapy.

Osteoarthritis (OA) is the most prevalent chronic degenerative joint disease. It weakens the motor function of patients and imposes a significant economic burden on society. The current medications commonly used in clinical practice do not meet the need for the treatment of OA. Recombinant protein drugs (RPDs) can treat OA by inhibiting inflammatory pathways, regulating catabolism/anabolism, and promoting cartilage repair, thereby showing promise as disease-modifying OA drugs (DMOADs). However, the rapid clearance and short half-life of them in the articular cavity limit their clinical translation. Therefore, the reliable drug delivery systems for extending drug treatment are necessary for the further development. This review introduces RPDs with therapeutic potential for OA, and summarizes their research progress on related drug delivery systems, and make proper discussion on the certain keys for optimal development of this area.