Salivary proteins NlSP5 and NlSP7 are required for optimal feeding and fitness of the brown planthopper, Nilaparvata lugens.

BACKGROUND: Saliva has a crucial role in determining the compatibility between piercing-sucking insects and their hosts. The brown planthopper (BPH) Nilaparvata lugens, a notorious pest of rice in East and Southeast Asia, secretes gelling and watery saliva when feeding on rice sap. Nlsalivap-5 (NlSP5) and Nlsalivap-7 (NlSP7) were identified as potential planthopper-specific gelling saliva components, but their biological functions remain unknown. RESULTS: Here, we showed by transcriptomic analyses that NlSP5 and NlSP7 were biasedly expressed in the salivary glands of BPHs. Using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated genome-editing system, we constructed NlSP5 and NlSP7 homozygous mutants (NlSP5-/- and NlSP7-/-). Electrical penetration graph assay showed that NlSP5-/- and NlSP7-/- mutants exhibited abnormal probing and feeding behaviors. Bioassays revealed that the loss-of-function of NlSP5 and NlSP7 significantly reduced the fitness of BPHs, with extended developmental duration, shortened lifespan, reduced weight, and impaired fecundity and hatching rates. CONCLUSION: These findings deepen our understanding of the BPH-host interaction and may provide potential targets for the management of rice planthoppers. © 2024 Society of Chemical Industry.

The effect of preoperative different dexamethasone regimens on postoperative glycemic control in patients with type 2 diabetes mellitus undergoing total joint arthroplasty: a retrospective cohort study.

BACKGROUND: Concerns have been raised regarding the impact of preoperative intravenous dexamethasone on postoperative glycemic control in diabetic patients undergoing total joint arthroplasty (TJA). This study aimed to determine relationships between preoperative different dexamethasone regimens and postoperative fasting blood glucose (FBG), as well as to identify risk factors for postoperative FBG ≥ 200 mg/dl in diabetic patients undergoing TJA. METHODS: This retrospective study included 1216 diabetic patients undergoing TJA and categorized into group A (dexamethasone = 0 mg), group B (dexamethasone = 5 mg), and group C (dexamethasone = 10 mg). All dexamethasone was administered before skin incision. FBG levels were monitored until postoperative day (POD) 3. Analyses were conducted for periprosthetic joint infection (PJI) and wound complications during 90 days postoperatively. And the risk factors for postoperative FBG ≥ 200 mg/dl were identified. RESULTS: Preoperative dexamethasone administration resulted in a transiently higher FBG on POD 0 and POD 1 (all P < 0.001). However, no differences were observed on POD 2 (P = 0.583) and POD 3 (P = 0.131) among three groups. While preoperative dexamethasone led to an increase in postoperative mean FBG and postoperative maximum FBG (all P < 0.001), no differences were found in wound complications (P = 0.548) and PJI (P = 1.000). Increased HbA1c and preoperative high FBG, but not preoperative dexamethasone, were identified as risk factors for postoperative FBG ≥ 200 mg/dl. Preoperative HbA1c level of ≥ 7.15% was associated with an elevated risk of postoperative FBG ≥ 200 mg/dl. CONCLUSIONS: Although preoperative intravenous administration of 5 mg or 10 mg dexamethasone in diabetic patients showed transient effects on postoperative FBG after TJA, no differences were found in the rates of PJI and wound complications during 90 days postoperatively. Notably, patients with a preoperative HbA1c level of ≥ 7.15% and elevated preoperative FBG may encountered postoperative FBG ≥ 200 mg/dl.

Preoperative serum cortisone levels are associated with cognition in preschool-aged children with tetralogy of Fallot after corrective surgery: new evidence from human populations and mice.

BACKGROUND: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Children with TOF would be confronted with neurological impairment across their lifetime. Our study aimed to identify the risk factors for cerebral morphology changes and cognition in postoperative preschool-aged children with TOF. METHODS: We used mass spectrometry (MS) technology to assess the levels of serum metabolites, Wechsler preschool and primary scale of intelligence-Fourth edition (WPPSI-IV) index scores to evaluate neurodevelopmental levels and multimodal magnetic resonance imaging (MRI) to detect cortical morphological changes. RESULTS: Multiple linear regression showed that preoperative levels of serum cortisone were positively correlated with the gyrification index of the left inferior parietal gyrus in children with TOF and negatively related to their lower visual spaces index and nonverbal index. Meanwhile, preoperative SpO2 was negatively correlated with levels of serum cortisone after adjusting for all covariates. Furthermore, after intervening levels of cortisone in chronic hypoxic model mice, total brain volumes were reduced at both postnatal (P) 11.5 and P30 days. CONCLUSIONS: Our results suggest that preoperative serum cortisone levels could be used as a biomarker of neurodevelopmental impairment in children with TOF. Our study findings emphasized that preoperative levels of cortisone could influence cerebral development and cognition abilities in children with TOF.

Exploring the catalytic diversity of two short-chain dehydrogenases/reductases from Stachybotrys chartarum.

Short-chain dehydrogenase/reductases (SDRs) belong to the NAD(P)(H)-dependent oxidoreductase superfamily, which have various functions of catalyzing oxidation/reduction reactions and have been generally used as powerful biocatalysts in the production of pharmaceuticals. In this study, ScSDR1 and ScSDR2, two new SDRs have been identified and characterized from Stachybotrys chartarum 3.5365. Substrate scope investigation revealed that both of the enzymes possessed the ability to oxidize ß-OH to ketone specifically, and exhibited substrate promiscuity and high stereo-selectivity for efficiently catalyzing the structurally different prochiral ketones to chiral alcohols. These findings not only suggest that ScSDR1 and ScSDR2 might be potent synthetic tools in drug research and development, but also provide good examples for further engineered enzymes with higher efficiency and stereo-selectivity.

Purkinje-cell-specific MeCP2 deficiency leads to motor deficits and autistic-like behavior due to aberrations in PTP1B-TrkB-SK signaling.

Patients with Rett syndrome suffer from a loss-of-function mutation of the Mecp2 gene, which results in various symptoms including autistic traits and motor deficits. Deletion of Mecp2 in the brain mimics part of these symptoms, but the specific function of methyl-CpG-binding protein 2 (MeCP2) in the cerebellum remains to be elucidated. Here, we demonstrate that Mecp2 deletion in Purkinje cells (PCs) reduces their intrinsic excitability through a signaling pathway comprising the small-conductance calcium-activated potassium channel PTP1B and TrkB, the receptor of brain-derived neurotrophic factor. Aberration of this cascade, in turn, leads to autistic-like behaviors as well as reduced vestibulocerebellar motor learning. Interestingly, increasing activity of TrkB in PCs is sufficient to rescue PC dysfunction and abnormal motor and non-motor behaviors caused by Mecp2 deficiency. Our findings highlight how PC dysfunction may contribute to Rett syndrome, providing insight into the underlying mechanism and paving the way for rational therapeutic designs.

Assessment of vasa vasorum on coronary plaques in patients with acute coronary syndromes using intravascular ultrasound and iMap analysis: A retrospective cohort study.

Studies have revealed that vasa vasorum (VV) neovascularization is vital for the progression and vulnerability of coronary atherosclerotic plaques. The correlation between VV, plaque constituents, and the no-reflow phenomenon (NRP) in percutaneous coronary intervention (PCI) remains elusive. We explored plaque constituents in iMap-intravascular ultrasound (iMap-IVUS) and NRP during PCI for VV lesions. We studied 166 coronary lesions in 166 patients with acute coronary syndromes (ACS) (118 lesions with VV) undergoing pre-intervention intravascular ultrasound (IVUS). We evaluated the diversity in plaque morphological status and post-PCI results based on the presence or absence of VV. The lesions with VV group had significantly higher high-sensitivity C-reactive protein (hs-CRP) levels than the lesions without VV group (8.41 ± 4.98 vs 4.19 ± 3.69 mg/L, P < .001). The frequency of after-stent deployment thrombolysis in myocardial infarction (TIMI) flow grades 0, 1, and 2 was remarkably greater in lesions with VV than in those without VV (22.9% vs 10.4%, P < .001). Plaques at the minimum lumen, necrotic core (1.26 ± 0.64 vs 0.92 ± 0.61 mm2, P < .001; 20.95 ± 7.19 vs 13.34% ± 6.54%, P < .001), and fibrous areas (4.23 ± 1.32 vs 3.92 ± 1.01 mm2, P = .006; 61.01 ± 9.41 vs 56.92% ± 11.42%, P = .001) were considerably larger in the lesions with VV than in those without VV. In addition, densely calcified plaques (0.41 ± 0.26 vs 0.81 ± 0.59 mm2, P < .001; 3.63 ± 2.19 vs 7.18% ± 2.01%, P < .001) were considerably smaller in the lesions with VV than in those without VV. Multivariate analyses revealed that VV and plaque volume were independent predictors of NRP after stent deployment (odds ratio [OR]: 5.13, 95% confidence interval [CI]: 1.19-15.32, P = .002; OR: 4.79, 95% CI: 1.08-9.01, P = .005). Lesions with VV exhibited considerable plaque vulnerability in patients with ACS, and they displayed more NRP during PCI. VV and plaque volume were independent predictors of NRP after stent deployment.

cAMP-EPAC-PKCε-RIM1α signaling regulates presynaptic long-term potentiation and motor learning.

The cerebellum is involved in learning of fine motor skills, yet whether presynaptic plasticity contributes to such learning remains elusive. Here, we report that the EPAC-PKCε module has a critical role in a presynaptic form of long-term potentiation in the cerebellum and motor behavior in mice. Presynaptic cAMP-EPAC-PKCε signaling cascade induces a previously unidentified threonine phosphorylation of RIM1α, and thereby initiates the assembly of the Rab3A-RIM1α-Munc13-1 tripartite complex that facilitates docking and release of synaptic vesicles. Granule cell-specific blocking of EPAC-PKCε signaling abolishes presynaptic long-term potentiation at the parallel fiber to Purkinje cell synapses and impairs basic performance and learning of cerebellar motor behavior. These results unveil a functional relevance of presynaptic plasticity that is regulated through a novel signaling cascade, thereby enriching the spectrum of cerebellar learning mechanisms.

A patient-derived mutation of epilepsy-linked LGI1 increases seizure susceptibility through regulating Kv1.1.

BACKGROUND: Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that functional LGI1 is secreted by excitatory neurons, GABAergic interneurons, and astrocytes, and regulates AMPA-type glutamate receptor-mediated synaptic transmission by binding ADAM22 and ADAM23. However, > 40 LGI1 mutations have been reported in familial ADLTE patients, more than half of which are secretion-defective. How these secretion-defective LGI1 mutations lead to epilepsy is unknown. RESULTS: We identified a novel secretion-defective LGI1 mutation from a Chinese ADLTE family, LGI1-W183R. We specifically expressed mutant LGI1W183R in excitatory neurons lacking natural LGI1, and found that this mutation downregulated Kv1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring Kv1.1 in excitatory neurons rescued the defect of spiking capacity, improved epilepsy susceptibility, and prolonged the life-span of mice. CONCLUSIONS: These results describe a role of secretion-defective LGI1 in maintaining neuronal excitability and reveal a new mechanism in the pathology of LGI1 mutation-related epilepsy.

FoxO is required for optimal fitness of the migratory brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae).

The forkhead box O (FoxO) protein is the main transcriptional effector downstream of the insulin/insulin-like signaling pathway and regulates many developmental and physiological processes. Holometabolous insects with loss-of-function mutations in FoxO exhibit phenotypes distinct from those of hemimetabolous insects in which RNA interference was used. Despite the functional importance of FoxO, whether hemimetabolous insects share an evolutionally conserved function of FoxO with holometabolous insects remains to be clarified. We used the clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9) genome editing-system to establish a homozygous FoxO-null mutant (NlFoxO4E ) of the wing-dimorphic brown planthopper (BPH) Nilaparvata lugens, an economically important insect pest of rice fields. The phenotypes of NlFoxO4E mutants included extended nymphal duration, shortened lifespan, reduced reproduction, and decreased stress resistance. In addition, depletion of NlFoxO promoted cell proliferation in wing buds and led to 100% long-winged morphs, in stark contrast to short-winged wild-type BPHs. These findings indicate that NlFoxO is highly functionally conserved with its counterpart in holometabolous insects, and is required for optimal fitness of N. lugens. The insights from FoxO studies may facilitate the identification of potential target genes for BPH control applications.

Perioperative Protocol of Ankle Fracture and Distal Radius Fracture Based on Enhanced Recovery after Surgery Program: A Multicenter Prospective Clinical Controlled study.

Background: The enhanced recovery after surgery (ERAS) program is aimed to shorten patients' recovery process and improve clinical outcomes. This study aimed to compare the outcomes between the ERAS program and the traditional pathway among patients with ankle fracture and distal radius fracture. Methods: This is a multicenter prospective clinical controlled study consisting of 323 consecutive adults with ankle fracture from 12 centers and 323 consecutive adults with distal radial fracture from 13 centers scheduled for open reduction and internal fixation between January 2017 and December 2018. According to the perioperative protocol, patients were divided into two groups: the ERAS group and the traditional group. The primary outcome was the patients' satisfaction of the whole treatment on discharge and at 6 months postoperatively. The secondary outcomes include delapsed time between admission and surgery, length of hospital stay, postoperative complications, functional score, and the MOS item short form health survey-36. Results: Data describing 772 patients with ankle fracture and 658 patients with distal radius fracture were collected, of which 323 patients with ankle fracture and 323 patients with distal radial fracture were included for analysis. The patients in the ERAS group showed higher satisfaction levels on discharge and at 6 months postoperatively than in the traditional group (P < 0.001). In the subgroup analysis, patients with distal radial fracture in the ERAS group were more satisfied with the treatment (P=0.001). Furthermore, patients with ankle fracture had less time in bed (P < 0.001) and shorter hospital stay (P < 0.001) and patients with distal radial fracture received surgery quickly after being admitted into the ward in the ERAS group than in the traditional group (P=0.001). Conclusions: Perioperative protocol based on the ERAS program was associated with high satisfaction levels, less time in bed, and short hospital stay without increased complication rate and decreased functional outcomes.

Three-Dimensional Heterogeneity of Cerebellar Interposed Nucleus-Recipient Zones in the Thalamic Nuclei.

The cerebellum is conceptualized as a processor of complex movements and is also endowed with roles in cognitive and emotional behaviors. Although the axons of deep cerebellar nuclei are known to project to primary thalamic nuclei, macroscopic investigation of the characteristics of these projections, such as the spatial distribution of recipient zones, is lacking. Here, we studied the output of the cerebellar interposed nucleus (IpN) to the ventrolateral (VL) and centrolateral (CL) thalamic nuclei using electrophysiological recording in vivo and trans-synaptic viral tracing. We found that IpN stimulation induced mono-synaptic evoked potentials (EPs) in the VL but not the CL region. Furthermore, both the EPs induced by the IpN and the innervation of IpN projections displayed substantial heterogeneity across the VL region in three-dimensional space. These findings indicate that the recipient zones of IpN inputs vary between and within thalamic nuclei and may differentially control thalamo-cortical networks.

Cerebellar Dysfunction, Cerebro-cerebellar Connectivity and Autism Spectrum Disorders.

The cerebellum has long been conceptualized to control motor learning and motor coordination. However, increasing evidence suggests its roles in cognition and emotion behaviors. In particular, the cerebellum has been recognized as one of key brain regions affected in autism spectrum disorder (ASD). To better understand the contribution of the cerebellum in ASD pathogenesis, we here discuss recent behavioral, genetic, and molecular studies from the human and mouse models. In addition, we raise several questions that need to be investigated in future studies from the point view of cerebellar dysfunction, cerebro-cerebellar connectivity and ASD.

Deletion of Mea6 in Cerebellar Granule Cells Impairs Synaptic Development and Motor Performance.

The cerebellum is conceptualized as a processor of complex movements. Many diseases with gene-targeted mutations, including Fahr's disease associated with the loss-of-function mutation of meningioma expressed antigen 6 (Mea6), exhibit cerebellar malformations, and abnormal motor behaviors. We previously reported that the defects in cerebellar development and motor performance of Nestin-Cre;Mea6 F/F mice are severer than those of Purkinje cell-targeted pCP2-Cre;Mea6 F/F mice, suggesting that Mea6 acts on other types of cerebellar cells. Hence, we investigated the function of Mea6 in cerebellar granule cells. We found that mutant mice with the specific deletion of Mea6 in granule cells displayed abnormal posture, balance, and motor learning, as indicated in footprint, head inclination, balanced beam, and rotarod tests. We further showed that Math1-Cre;Mea6 F/F mice exhibited disrupted migration of granule cell progenitors and damaged parallel fiber-Purkinje cell synapses, which may be related to impaired intracellular transport of vesicular glutamate transporter 1 and brain-derived neurotrophic factor. The present findings extend our previous work and may help to better understand the pathogenesis of Fahr's disease.

MEA6 Deficiency Impairs Cerebellar Development and Motor Performance by Tethering Protein Trafficking.

Meningioma expressed antigen 6 (MEA6), also called cutaneous T cell lymphoma-associated antigen 5 (cTAGE5), was initially found in tumor tissues. MEA6 is located in endoplasmic reticulum (ER) exit sites and regulates the transport of collagen, very low density lipoprotein, and insulin. It is also reported that MEA6 might be related to Fahr's syndrome, which comprises neurological, movement, and neuropsychiatric disorders. Here, we show that MEA6 is critical to cerebellar development and motor performance. Mice with conditional knockout of MEA6 (Nestin-Cre;MEA6F/F) display smaller sizes of body and brain compared to control animals, and survive maximal 28 days after birth. Immunohistochemical and behavioral studies demonstrate that these mutant mice have defects in cerebellar development and motor performance. In contrast, PC deletion of MEA6 (pCP2-Cre;MEA6F/F) causes milder phenotypes in cerebellar morphology and motor behaviors. While pCP2-Cre;MEA6F/F mice have normal lobular formation and gait, they present the extensive self-crossing of PC dendrites and damaged motor learning. Interestingly, the expression of key molecules that participates in cerebellar development, including Slit2 and brain derived neurotrophic factor (BDNF), is significantly increased in ER, suggesting that MEA6 ablation impairs ER function and thus these proteins are arrested in ER. Our study provides insight into the roles of MEA6 in the brain and the pathogenesis of Fahr's syndrome.

Numb-p72, but not Numb-p65, contributes to the trafficking of group I metabotropic glutamate receptors.

The protein Numb localizes to clathrin-coated vesicles and participates in the trafficking of transmembrane receptors. We previous reported that Numb promotes the presence of metabotropic glutamate receptor 1 (mGlu1) on neuronal membrane, and Numb deficiency impairs synaptic expression of mGlu1. However, the actions of different Numb isoforms on mGlu1 trafficking are unknown. Here, we found that Numb-p72 and Numb-p65 are distinctly expressed in HEK293T cells. Interestingly, Numb-p72, but not Numb-p65, binds to mGlu1α and promotes the membrane expression of mGlu1α by antagonizing its internalization. We hypothesize that the incomplete structure of Numb-p65 does not act in the same way as Numb-p72 on mGlu1 trafficking.

Efficacy and Safety of Zhuanggu Joint Capsules in Combination with Celecoxib in Knee Osteoarthritis: A Multi-center, Randomized, Double-blind, Double-dummy, and Parallel Controlled Trial.

BACKGROUND: Knee osteoarthritis (KOA) is a chronic joint disease that manifests as knee pain as well as different degrees of lower limb swelling, stiffness, and movement disorders. The therapeutic goal is to alleviate or eliminate pain, correct deformities, improve or restore joint functions, and improve the quality of life. This study aimed to evaluate the efficacy and safety of Zhuanggu joint capsules combined with celecoxib and the benefit of treatment with Zhuanggu alone for KOA. METHODS: This multi-center, randomized, double-blind, double-dummy, parallel controlled trial, started from December 2011 to May 2014, was carried out in 6 cities, including Beijing, Shanghai, Chongqing, Changchun, Chengdu, and Nanjing. A total of 432 patients with KOA were divided into three groups (144 cases in each group). The groups were treated, respectively, with Zhuanggu joint capsules combined with celecoxib capsule simulants, Zhuanggu joint capsules combined with celecoxib capsules, and celecoxib capsules combined with Zhuanggu joint capsule simulants for 4 weeks consecutively. The improvement of Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and the decreased rates in each dimension of WOMAC were evaluated before and after the treatment. Intergroup and intragroup comparisons of quantitative indices were performed. Statistically significant differences were evaluated with pairwise comparisons using Chi-square test (or Fisher's exact test) and an inspection level of α = 0.0167. RESULTS: Four weeks after treatment, the total efficacies of Zhuanggu group, combination group, and celecoxib group were 65%, 80%, and 64%, respectively, with statistically significant differences among the three groups (P = 0.005). Intergroup pairwise comparisons showed that the total efficacy of the combination group was significantly higher than that of the Zhuanggu (P = 0.005) and celecoxib (P = 0.003) groups. The difference between the latter two groups was not statistically significant (P > 0.0167). Four weeks after discontinuation, the efficacies of the three groups were 78%, 95%, and 65%, respectively, with statistically significant differences (P < 0.0001). Intergroup pairwise comparisons revealed that the efficacy of the combination group was significantly better than that of the Zhuanggu and the celecoxib groups (P < 0.0001). The difference between the latter two groups was not statistically significant (P > 0.0167). The incidences of adverse events in Zhuanggu group, combination group, and celecoxib group were 8.5%, 8.5%, and 11.1%, respectively, with insignificant differences (P > 0.05). CONCLUSIONS: Zhuanggu joint capsules alone or combined with celecoxib showed clinical efficacy in the treatment of KOA. The safety of Zhuanggu joint capsules alone or combined with celecoxib was acceptable. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IPR-15007267; http://www.medresman.org/uc/project/projectedit.aspx?proj=1364.