Deep brain stimulation for pediatric pantothenate kinase-associated neurodegeneration with status dystonicus: A case report and literature review.

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is a type of inherited metabolic disorder caused by mutation in the PANK2 gene. The metabolic disorder mainly affects the basal ganglia region and eventually manifests as dystonia. For patients of dystonia, their dystonic symptom may progress to life-threatening emergency--status dystonicus. OBJECTIVE: We described a case of a child with PKAN who had developed status dystonicus and was successfully treated with deep brain stimulation (DBS). Based on this rare condition, we analysed the clinical features of PKAN with status dystonicus and reviewed the reasonable management process of this condition. CONCLUSION: This case confirmed the rationality of choosing DBS for the treatment of status dystonicus. Meanwhile, we found that children with classic PKAN have a cluster of risk factors for developing status dystonicus. Once children diagnosed with similar neurodegenerative diseases are under status dystonicus, DBS can be active considered because it has showed high control rate of this emergent condition.

Efficacy of deep brain stimulation for Tourette syndrome and its comorbidities: A meta-analysis.

Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and vocal tics, often accompanied by comorbid disorders. Optional treatments for patients with TS include behavioral therapy, pharmacotherapy, and neurostimulation techniques. Deep brain stimulation (DBS) has been considered a therapeutic approach for refractory TS and its comorbid symptoms. However, systematic comparison is necessary to understand the therapeutic effect of DBS among patients with TS with various comorbid symptoms, demographic characteristics, or stimulation targets. Consequently, our research aimed to assess the clinical efficacy of DBS in alleviating the symptoms of TS and its comorbidities. A systematic literature search was conducted across five databases: PubMed, Web of Science, MEDLINE, Embase, and PsycINFO. The primary outcome was the mean change in the global score of the Yale Global Tic Severity Scale (YGTSS), which assesses the severity of tics. The secondary outcomes included mean improvement of comorbid symptoms, such as obsessive-compulsive behaviors (OCB), depression symptoms and anxiety symptoms. In total, 51 studies with 673 participants were included in this meta-analysis. Overall, the DBS led to a significant improvement in tic symptoms (p â€‹< â€‹0.001), as well as the comorbid obsessive-compulsive, depression, and anxiety symptoms with effect sizes of 1.88, 0.88, 1.04, and 0.76 accordingly. In the subgroup analysis, we found that striatum stimulation led to a more significant improvement in OCB in patients with TS compared to that observed with thalamic stimulation (p â€‹= â€‹0.017). The relationship between sex, age, and target with the improvement of tics, depression, and anxiety was not statistically significant (p â€‹= â€‹0.923, 0.438, 0.591 for different male proportions; p â€‹= â€‹0.463, 0.425, 0.105 for different age groups; p â€‹= â€‹0.619, 0.113, 0.053 for different targets). In conclusion, DBS is an efficient treatment option for TS, as well as the comorbid OCB, depression symptoms, and anxiety symptoms. It is important to highlight that stimulating the striatum is more effective in managing obsessive-compulsive symptoms compared to stimulating the thalamus.

Clinical characteristics and surgical outcomes of low-grade epilepsy-associated brain tumors.

Background: Low-grade epilepsy-associated brain tumors (LEATs) are found to be the second most common lesion-related epilepsy. Malignant potential of LEATs is very low and the overall survival is good, so the focus of treatment is focused more on seizure outcome rather than oncological prognosis. Objectives: This study was conducted to evaluate the risk factors of seizure outcomes after resection in patients with LEATs. Design: A retrospective study. Methods: A retrospective analysis of patients with LEATs who underwent resective surgery in our three epilepsy centers between October 2010 and April 2023 with a minimum follow-up of 1 year. Demography, clinical characters, neurophysiology, and molecular neuropathology were assessed for association with postoperative seizure outcomes at 1-, 2-, and 5-year follow-up. Synthetic minority oversampling technique (SMOTE) algorithm model was performed to handle the imbalance of data distribution. Gaussian Naïve Bayes (GNB) algorithms were created as a basis for classifying outcomes according to observation indicators. Results: A total of 111 patients were enrolled in the cohort. The most common pathology was ganglioglioma (n = 37, 33.3%). The percentage of patients with seizure freedom was 91.0% (101/111) at 1-year follow-up, 87.5% (77/88) at 2-year follow-up, and 79.1% (53/67) at 5-year follow-up. Partial resection had a significantly poor seizure outcome compared to total resection and supratotal resection (p < 0.05). The epileptiform discharge on post-resective intraoperative electrocorticography (ECoG) or postoperative scalp electroencephalography (EEG) were negative factors on postoperative seizure freedom at 1-, 2-, or 5-year follow-ups (p < 0.05). The area under the receiver-operating characteristic curve value of the GNB-SMOTE model was 0.95 (95% CI, 0.876-1.000), 0.892 (95% CI, 0.656-0.934), and 0.786 (95% CI, 0.491-0.937) at 1-, 2-, and 5-year follow-up, respectively. Conclusion: The partial resection, post-resective intraoperative ECoG, and postoperative scalp EEG were valuable indicators of poor seizure outcomes. The utilization of post-resective intraoperative ECoG is beneficial to improve seizure outcomes. Based on the data diversity and completeness of three medical centers, a multivariate correlation analysis model was established based on GNB algorithm.

Effects of transcutaneous auricular vagus nerve stimulation and exploration of brain network mechanisms in children with high-functioning autism spectrum disorder: study protocol for a randomized controlled trial.

Background: Autism Spectrum Disorders (ASD) are a collection of neurodevelopmental diseases characterized by poor social interaction and communication, a limited range of interests, and stereotyped behavior. High-functioning autism (HFA) indicates a subgroup of individuals with autism who possess cognitive and/or language skills that are within the average to above-normal range for their age. Transcutaneous auricular vagus nerve stimulation (taVNS) holds promise in children with HFA. However, few studies have used randomized controlled trials to validate the effectiveness of taVNS. Therefore, in this study, we intend to provide a study protocol to examine the therapeutic effects of taVNS in individuals diagnosed with HFA and to investigate the process of brain network remodeling in individuals with ASD using functional imaging techniques to observe alterations in large-scale neural networks. Methods and design: We planned to employ a randomized, double-blind experimental design, including 40 children receiving sham stimulation and 40 children receiving real stimulation. We will assess clinical scales and perform functional imaging examinations before and after the stimulation. Additionally, we will include age- and gender-matched healthy children as controls and conduct functional imaging examinations. We plan first to observe the therapeutic effects of taVNS. Furthermore, we will observe the impact of taVNS stimulation on the brain network. Discussion: taVNS was a low-risk, easy-to-administer, low-cost, and portable option to modulate the vagus system. taVNS may improve the social performance of HFA. Changes in the network properties of the large-scale brain network may be related to the efficacy of taVNS. Clinical trial registration: http://www.chictr.org.cn, identifier ChiCTR2300074035.

Ictal hypersalivation as a prominent symptom in a girl with insulo-opercular epilepsy.

Introduction: Hypersalivation has been associated with Rolandic epilepsy and other childhood epilepsy syndromes. However, pure salivatory seizures are a rare type of focal seizure in which ictal hypersalivation is the dominant feature throughout the seizures. Case presentation: We present a case of pure salivatory seizures originating from the right post-central operculum cortex, confirmed by the favorable surgical outcome. We attempt to analyze the symptom from behavioral and neural network perspectives and propose a possible mechanism to generate ictal hypersalivation and pure salivatory seizures. Conclusion: Based on previous reports in the literature and our case, we emphasize the importance of the operculum in patients with ictal hypersalivation, particularly in patients with pure salivatory seizures.

Metabolic Engineering of Pichia pastoris for High-Level Production of Lycopene.

Lycopene is widely used in cosmetics, food, and nutritional supplements. Microbial production of lycopene has been intensively studied. However, few metabolic engineering studies on Pichia pastoris have been aimed at achieving high-yield lycopene production. In this study, the CRISPR/Cpf1-based gene repression system was developed and the gene editing system was optimized, which were applied to improve lycopene production successfully. In addition, the sterol regulatory element-binding protein SREBP (Sre) was used for the regulation of lipid metabolic pathways to promote lycopene overproduction in P. pastoris for the first time. The final engineered strain produced lycopene at 7.24 g/L and 75.48 mg/g DCW in fed-batch fermentation, representing the highest lycopene yield in P. pastoris reported to date. These findings provide effective strategies for extended metabolic engineering assisted by the CRISPR/Cpf1 system and new insights into metabolic engineering through transcriptional regulation of related metabolic pathways to enhance carotenoid production in P. pastoris.

Discovery of a selective NLRP3-targeting compound with therapeutic activity in MSU-induced peritonitis and DSS-induced acute intestinal inflammation.

The aberrant activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is known to contribute to the pathogenesis of various human inflammation-related diseases. However, to date, no small-molecule NLRP3 inhibitor has been used in clinical settings. In this study, we have identified SB-222200 as a novel direct NLRP3 inhibitor through the use of drug affinity responsive target stability assay, cellular thermal shift assay, and surface plasmon resonance analysis. SB-222200 effectively inhibits the activation of the NLRP3 inflammasome in macrophages, while having no impact on the activation of NLRC4 or AIM2 inflammasome. Furthermore, SB-222200 directly binds to the NLRP3 protein, inhibiting NLRP3 inflammasome assembly by blocking the NEK7 - NLRP3 interaction and NLRP3 oligomerization. Importantly, treatment with SB-222200 demonstrates alleviation of NLRP3-dependent inflammatory diseases in mouse models, such as monosodium urate crystal-induced peritonitis and dextran sulfate sodium-induced acute intestinal inflammation. Therefore, SB-222200 holds promise as a lead compound for the development of NLRP3 inhibitors to combat NLRP3-driven disease and serves as a versatile tool for pharmacologically investigating NLRP3 biology.

Conduction treatment of temporal lobe epilepsy in rats: the dose-effect relationship between current resistance and therapeutic effect.

Objective: To investigate the effect of current resistance on therapeutic outcomes, and the mechanism of current conduction treatment in a rat model of temporal lobe epilepsy (TLE). Methods: Rats were randomly divided into four groups: normal control, epileptic group, low-resistance conduction (LRC) and high-resistance conduction (HRC) group. The content of glutamate (Glu) and gamma-amino butyric acid (GABA) in the hippocampus was determined using a neurotransmitter analyzer. mRNA and protein expression of interleukin 1ß (IL-1ß) /IL-1 receptor 1(IL-1R1) and high mobility group protein B1 (HMGB-1)/toll-like receptor-4 (TLR-4) in hippocampal neurons were tested. Video electroencephalogram monitoring was used to record seizures and EEG discharges. Cognitive function in the rats was tested using the Morris water maze. Results: Glu/GABA ratio in the epileptic control and HRC groups was significant differences from LRC group. The levels of HMGB1/TLR4 and IL-1ß/IL-1R1 in the LRC group and normal control group were significantly lower than those in epileptic control group (p < 0.01) and the HRC group. The mRNA levels of HMGB1/TLR4 and IL-1ß/IL-1R1 in the LRC group and normal control group were significantly lower than those in epileptic control group. The frequency of total and propagated seizures was lower in the LRC group than in the epileptic control and HRC groups (p < 0.01). The numbers of platform crossings in the LRC group and normal control group were significantly higher than those in the epileptic control and HRC groups in the space exploration experiment. Conclusion: Current resistance affected seizure control and cognitive protection in rats with TLE treated by current conduction. The lower current resistance, the better seizure control and cognitive protection in rats with TLE treated by current conduction. Glu/GABA, IL-1ß/IL-1R1, and HMGB1/TLR-4 may participate in the anti-seizure mechanism of current conduction treatment.

Multi-scale goal distance representations in human hippocampus during virtual spatial navigation.

Goal-directed navigation relies on both coarse and fine-grained coding of spatial distance between the current position of a navigating subject and a goal destination. However, the neural signatures underlying goal distance coding remain poorly understood. Using intracranial EEG recordings from the hippocampus of drug-resistant epilepsy patients who performed a virtual spatial navigation task, we found that the right hippocampal theta power was significantly modulated by goal distance and decreased with goal proximity. This modulation varied along the hippocampal longitudinal axis such that theta power in the posterior hippocampus decreased more strongly with goal proximity. Similarly, neural timescale, reflecting the duration across which information can be maintained, increased gradually from the posterior to anterior hippocampus. Taken together, this study provides empirical evidence for multi-scale spatial representations of goal distance in the human hippocampus and links the hippocampal processing of spatial information to its intrinsic temporal dynamics.

Influence of resective extent of epileptogenic tuber on seizure outcome in patients with tuberous sclerosis complex-related epilepsy: A systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis to identify whether tuberectomy and tuberectomy plus are associated with different postoperative seizure outcomes in patients with tuberous sclerosis complex (TSC) -related epilepsy. METHODS: Electronic databases (PubMed, Embase, Cochrane, Proquest, Web of Science, Scopus, Biosis Previews) were searched without date restriction. Retrospective cohort studies of participants with TSC-associated epilepsy undergoing resective surgery that reported demographics, presurgical evaluation, extent of resection and postoperative seizure outcomes were included. Title, abstract and the full text were checked independently and in duplicate by two reviewers. Disagreements were resolved through discussion. One author extracted data which was verified by a second author using identified common standard in advance, including using a risk of bias tool we agreed on to evaluate study quality. RESULTS: Five studies, with a total of 327 participants, were included. One hundred and sixty patients received tuberectomy, and 93 of them (58.1%) achieved postoperative seizure freedom, while the other 167 patients underwent tuberectomy plus, and 128 of them (76.6%) achieved seizure freedom after adequate follow-ups (RR=0.72, 95% CI [0.60, 0.87], P<0.05). Subgroup analysis found that 40 of 63 (63.5%) patients after tuberectomy and 66 of 78 (84.6%) patients after tuberectomy plus of a single tuber achieved seizure freedom (RR = 0.71, 95% CI [0.56,0.91], P<0.05). In the multituber subrgroup, 16 of 42 (38.1%) and 21 of 31 (67.7%) patients achieved seizure freedom, after tuberectomy and tuberectomy plus, respectively (RR = 0.57, 95% CI [0.32,1.03], P = 0.06). CONCLUSIONS: Tuberectomy plus is a more effective treatment than tuberectomy for patients with TSC-related intractable epilepsy.

Factors that Influence Subdural Hemorrhage Secondary to Intracranial Arachnoid Cysts in Children.

OBJECTIVE: This study aimed to investigate factors that influence subdural haemorrhage (SDH) secondary to intracranial arachnoid cysts (IACs) in children. METHODS: Data of children with unruptured IACs (IAC group) and those with SDH secondary to IACs (IAC-SDH group) were analyzed. Nine factors, sex, age, birth type (vaginal or caesarean), symptoms, side (left, right, or midline), location (temporal or nontemporal), image type (I, II, or III), volume, and maximal diameter, were selected. IACs were classified as types I, II, and III according to their morphological changes observed on computed tomography images. RESULTS: There were 117 boys (74.5%) and 40 girls (25.5%); 144 (91.7%) patients comprised the IAC group and 13 (8.3%) comprised the IAC-SDH group. There were 85 (53.8%) IACs on the left side, 53 (33.5%) on the right side, 20 (12.7%) in the midline region, and 91 (58.0%) in the temporal region. The univariate analysis showed significant differences in age, birth type, symptoms, cyst location, cyst volume, and cyst maximal diameter (P < 0.05) between the 2 groups. Logistic regression using the synthetic minority oversampling technique model showed that image type III and birth type were independent factors that influenced SDH secondary to IACs (ß0 = 4.143; ß for image type = -3.979; ß for birth type = -2.542) and that the representative area under the receiver-operating characteristic curve value was 0.948 (95% confidence interval, 0.898-0.997). CONCLUSIONS: IACs are more common in boys than in girls. They can be divided into 3 groups according to their morphological changes on computed tomography images. Image type III and caesarean delivery were independent factors that influenced SDH secondary to IACs.

The regulatory function of lncRNA and constructed network in epilepsy.

BACKGROUND: Epilepsy is a neurological disease characterized by neural network dysfunction. Although most reports indicate that the pathological process of epilepsy is related to inflammation, synaptic plasticity, cell apoptosis, and ion channel dysfunction, the underlying molecular mechanisms of epilepsy are not fully understood. METHODS: This review summarizes the latest literature on the roles and characteristics of long noncoding RNAs (lncRNAs) in the pathogenesis of epilepsy. RESULTS: lncRNAs are a class of long transcripts without protein-coding functions that perform important regulatory functions in various biological processes. lncRNAs are involved in the regulation of the pathological process of epilepsy and are abnormally expressed in both patients and animal models. This review provides an overview of research progress in epilepsy, the multifunctional features of lncRNAs, the lncRNA expression pattern related to epileptogenesis and status epilepticus, and the potential mechanisms for the two interactions contributing to epileptogenesis and progression. CONCLUSION: lncRNAs can serve as new diagnostic markers and therapeutic targets for epilepsy in the future.

Overproduction of Patchoulol in Metabolically Engineered Komagataella phaffii.

Patchoulol, a plant-derived sesquiterpene compound, is widely used in perfumes, cosmetics, and pharmaceuticals. Microbial production provides a promising alternative approach for the efficient and sustainable production of patchoulol. However, there are no systematic engineering studies on Komagataella phaffii aimed at achieving high-yield patchoulol production. Herein, by fusion overexpression of FPP synthase and patchoulol synthase (ERG20LPTS), increasing the precursor supply, adjusting the copy number of ERG20LPTS and PTS, and combined with adding auxiliary carbon source and methanol concentration optimization, we constructed a high-yield patchoulol-producing strain P6H53, which produced 149.64 mg/L patchoulol in shake-flask fermentation with methanol as the substrate. In fed-batch fermentation, strain P6H53 achieved the highest production (2.47 g/L, 21.48 mg/g DCW, and 283.25 mg/L/d) to date in a 5 L fermenter. This study will lay a good foundation for the development of K. phaffii as a promising chassis microbial cell for the synthesis of patchoulol and other sesquiterpenes with methanol as the carbon source.

Wearable and flexible electrochemical sensors for sweat analysis: a review.

Flexible wearable sweat sensors allow continuous, real-time, noninvasive detection of sweat analytes, provide insight into human physiology at the molecular level, and have received significant attention for their promising applications in personalized health monitoring. Electrochemical sensors are the best choice for wearable sweat sensors due to their high performance, low cost, miniaturization, and wide applicability. Recent developments in soft microfluidics, multiplexed biosensing, energy harvesting devices, and materials have advanced the compatibility of wearable electrochemical sweat-sensing platforms. In this review, we summarize the potential of sweat for medical detection and methods for sweat stimulation and collection. This paper provides an overview of the components of wearable sweat sensors and recent developments in materials and power supply technologies and highlights some typical sensing platforms for different types of analytes. Finally, the paper ends with a discussion of the challenges and a view of the prospective development of this exciting field.

Rapid prototyping enzyme homologs to improve titer of nicotinamide mononucleotide using a strategy combining cell-free protein synthesis with split GFP.

Engineering biological systems to test new pathway variants containing different enzyme homologs is laborious and time-consuming. To tackle this challenge, a strategy was developed for rapidly prototyping enzyme homologs by combining cell-free protein synthesis (CFPS) with split green fluorescent protein (GFP). This strategy featured two main advantages: (1) dozens of enzyme homologs were parallelly produced by CFPS within hours, and (2) the expression level and activity of each homolog was determined simultaneously by using the split GFP assay. As a model, this strategy was applied to optimize a 3-step pathway for nicotinamide mononucleotide (NMN) synthesis. Ten enzyme homologs from different organisms were selected for each step. Here, the most productive homolog of each step was identified within 24 h rather than weeks or months. Finally, the titer of NMN was increased to 1213 mg/L by improving physiochemical conditions, tuning enzyme ratios and cofactor concentrations, and decreasing the feedback inhibition, which was a more than 12-fold improvement over the initial setup. This strategy would provide a promising way to accelerate design-build-test cycles for metabolic engineering to improve the production of desired products.

Enhanced Expression of Alcohol Dehydrogenase I in Pichia pastoris Reduces the Content of Acetaldehyde in Wines.

Acetaldehyde is an important carbonyl compound commonly detected in wines. A high concentration of acetaldehyde can affect the flavor of wines and result in adverse effects on human health. Alcohol dehydrogenase I (ADH1) in Saccharomyces cerevisiae catalyzes the reduction reaction of acetaldehyde into ethanol in the presence of cofactors, showing the potential to reduce the content of acetaldehyde in wines. In this study, ADH1 was successfully expressed in Pichia pastoris GS115 based on codon optimization. Then, the expression level of ADH1 was enhanced by replacing its promoter with optimized promoters and increasing the copy number of the expression cassette, with ADH1 being purified using nickel column affinity chromatography. The enzymatic activity of purified ADH1 reached 605.44 ± 44.30 U/mg. The results of the effect of ADH1 on the content of acetaldehyde in wine revealed that the acetaldehyde content of wine samples was reduced from 168.05 ± 0.55 to 113.17 ± 6.08 mg/L with the addition of 5 mM NADH and the catalysis of ADH1, and from 135.53 ± 4.08 to 52.89 ± 2.20 mg/L through cofactor regeneration. Our study provides a novel approach to reducing the content of acetaldehyde in wines through enzymatic catalysis.

Artemisinin-derived artemisitene blocks ROS-mediated NLRP3 inflammasome and alleviates ulcerative colitis.

Artemisinins are well-known antimalarial drugs with clinical safety. In addition to antimalarial effects, their anti-inflammatory and immunoregulatory properties have recently attracted much attention in the treatment of inflammatory diseases. However, these artemisinins only have sub-millimolar anti-inflammatory activity in vitro, which may pose a high risk of toxicity in vivo with high doses of artemisinins. Here, we identified another derivative, artemisitene, which can increase the activity of inhibiting the NLRP3 pathway by more than 200-fold through introducing a covalent binding group while retaining the peroxide bridge structure. Mechanistically, artemisitene inhibits the production of ROS (especially mtROS) and prevents the assembly and activation of NLRP3 inflammasome, thereby inhibiting IL-1ß production. In addition, it can also block IL-1ß secretion mediated by NLRC4 and AIM2 inflammasome and IL-6 production. Furthermore, treatment with artemisitene significantly attenuated inflammatory response in DSS-induced ulcerative colitis. Our work provides a potential artemisinin derivative, which is worthy of further structural optimization based on pharmacokinetic properties as a drug candidate for inflammatory disorders.

Bortezomib inhibits NLRP3 inflammasome activation and NF-κB pathway to reduce psoriatic inflammation.

The abnormal activation of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the pathogenesis of psoriasis. Accordingly, the inhibition of NLRP3 inflammasome may be an effective strategy for psoriasis treatment. However, the NLRP3 inflammasome inhibitors are not available in the clinic. Repurposing FDA-approved drugs is a highly attractive way for identifying new drugs. Here, proteasome inhibitor bortezomib, a marketed drug for treating multiple myeloma, was found to specifically inhibit NLRP3 inflammasome activation at nanomolar concentrations. Mechanistically, bortezomib did not inhibit reactive oxygen species generation, ion efflux, NLRP3 oligomerization, and NLRP3-ASC interactions. Bortezomib reduced ASC oligomerization and ASC speck formation. In addition, bortezomib inhibited the activity of the core subunit ß5i in the immunoproteasome and reduced ß5i binding to NLRP3. Bortezomib reduced the production of interleukin-1ß and attenuated the severity of skin lesions in the imiquimod-induced psoriatic mouse model. Thus, bortezomib is a potential therapeutic drug for psoriasis. Our study also revealed that ß5i may be an indirect target for regulating NLRP3 inflammasome activation and treating psoriasis and other NLRP3 inflammasome-related diseases.