An inactivating mutation in the vacuolar arginine exporter gene Vae results in culture degeneration in the fungus Metarhizium robertsii.

Culture degeneration usually results in great commercial losses in the economically important filamentous fungi, but the genetic causes of the degeneration remain elusive. In the fungus Metarhizium robertsii, we found that deletion of the vacuolar arginine exporter gene Vae caused culture degeneration. Compared to the WT strain, the mutant showed increased apoptosis, reactive oxygen species (ROS) level and mitochondrial membrane potential collapse, reduced conidial yield and abnormal lipid droplet formation. The extent of the degeneration in the mutant gradually increased over the successive subculturing, which eventually became irreversible; compared to the third subculture of the mutant, the seventh subculture showed a lower conidial yield and pathogenicity to insects, stronger apoptosis, higher ROS level and a smaller number of conidial lipid droplets. Incorporation of the genomic clone of Vae could not restore the WT phenotypes in the seventh subculture, but could in the third one. Loss-of-function in Vae resulted in vacuolar arginine accumulation and reduction in the cytosolic arginine. This downregulated the expression of the regulator CAG9 of G protein signalling pathway, which accounted for most of the phenotypic changes associated with the degeneration of the mutant. We identified a deleterious mutation that causes culture degeneration in a filamentous fugus.

Clinical analysis of Gabriele-de Vries caused by YY1 mutations and literature review.

BACKGROUND: Gabriele-de Vries syndrome is a rare autosomal dominant genetic disease characterized by global development delay/intellectual disability, delayed language development, feeding difficulties, and distinctive facial dysmorphism. It is caused by pathogenic variants in YY1. METHODS: The current report describes a female patient with motor delay and a facial dysmorphism phenotype. We identified pathogenic mutations in the patient by whole-exome sequencing and confirmed them by Sanger sequencing. RESULTS: A novel heterozygous frameshift mutation NM_003403.5:c.458_476del (p. V153fs*97) in the YY1 gene was detected in the proband. Finally, we provide a case-based review of the clinical features associated with Gabriele-de Vries syndrome. A total of 28 patients with genetic abnormalities and clinical phenotypes have been reported in the literature thus far. CONCLUSIONS: The mutation site is reported for the first time, and its discovery would expand the mutation spectrum of the YY1 gene. The main clinical manifestations of Gabriele-de Vries syndrome are developmental delay/intellectual disability, craniofacial dysplasia, intrauterine growth delay, low birth weight, feeding difficulties, and rare congenital malformations. Genetic tests are crucial techniques for its diagnosis because of its nonspecific clinical manifestations.

Exosomal miR-1228-5p down-regulates DUSP22 to promotes cell proliferation and migration in small cell lung cancer.

BACKGROUND: Exosomes play a crucial role in promoting tumor progression, dissemination, and resistance to treatment. These extracellular vesicles hold promise as valuable indicators for cancer detection. Our investigation focuses on exploring the significance and clinical relevance of exosomal miRNAs in small cell lung cancer (SCLC). METHODS: Serum exosomes were isolated from both SCLC patients and healthy controls, and subjected to exosomal miRNA sequencing analysis. Mimics and inhibitors were employed to investigate the function of exosomal miR-1128-5p in cell migration and proliferation, both in vitro and in vivo. Western blot and luciferase assay were utilized to identify the interaction between miR-1228-5p and dual specificity phosphatase 22 (DUSP22). RESULTS: Exosomal miRNA sequencing analysis revealed enrichment of specific miRNAs in SCLC compared to healthy controls. Circulating miR-1228-5p was upregulated in SCLC patients, associated with advanced stages, suggesting its potential oncogenic role. In vitro, miR-1228-5p expression was significantly higher in SCLC cells than in normal cells. SCLC cell-derived exosomes contained elevated levels of miR-1228-5p, facilitating its entry into co-cultured cells. Notably, migration and proliferation induced by SCLC exosomes were mainly mediated by miR-1228-5p. In vivo experiments confirmed these findings. Western blot analysis demonstrated miR-1228-5p's regulation of DUSP22 expression, and luciferase reporter assay validated DUSP22 as a direct target gene. Overexpressing DUSP22 counteracted miR-1228-5p's promotion of SCLC cell proliferation and migration. CONCLUSIONS: Collectively, our results suggest that exosomes play a role in facilitating cancer growth and metastasis by delivering miR-1228-5p. Moreover, circulating exosomal miR-1228-5p may serve as a potential marker for SCLC diagnosis and prognosis.

Restoration of coherent reach-grasp-pull movement via sequential intraneural peripheral nerve stimulation in rats.

Objective.Peripheral nerve stimulation (PNS) has been demonstrated as an effective way to selectively activate muscles and to produce fine hand movements. However, sequential multi-joint upper limb movements, which are critical for paralysis rehabilitation, has not been tested with PNS. Here, we aimed to restore multiple upper limb joint movements through an intraneural interface with a single electrode, achieving coherent reach-grasp-pull movement tasks through sequential stimulation.Approach.A transverse intrafascicular multichannel electrode was implanted under the axilla of the rat's upper limb, traversing the musculocutaneous, radial, median, and ulnar nerves. Intramuscular electrodes were implanted into the biceps brachii (BB), triceps brachii (TB), flexor carpi radialis (FCR), and extensor carpi radialis (ECR) muscles to record electromyographic (EMG) activity and video recordings were used to capture the kinematics of elbow, wrist, and digit joints. Charge-balanced biphasic pulses were applied to different channels to recruit distinct upper limb muscles, with concurrent recording of EMG signals and joint kinematics to assess the efficacy of the stimulation. Finally, a sequential stimulation protocol was employed by generating coordinated pulses in different channels.Main results.BB, TB, FCR and ECR muscles were selectively activated and various upper limb movements, including elbow flexion, elbow extension, wrist flexion, wrist extension, digit flexion, and digit extension, were reliably generated. The modulation effects of stimulation parameters, including pulse width, amplitude, and frequency, on induced joint movements were investigated and reach-grasp-pull movement was elicited by sequential stimulation.Significance.Our results demonstrated the feasibility of sequential intraneural stimulation for functional multi-joint movement restoration, providing a new approach for clinical rehabilitation in paralyzed patients.

Miniaturized Implantable Fluorescence Probes Integrated with Metal-Organic Frameworks for Deep Brain Dopamine Sensing.

Continuously monitoring neurotransmitter dynamics can offer profound insights into neural mechanisms and the etiology of neurological diseases. Here, we present a miniaturized implantable fluorescence probe integrated with metal-organic frameworks (MOFs) for deep brain dopamine sensing. The probe is assembled from physically thinned light-emitting diodes (LEDs) and phototransistors, along with functional surface coatings, resulting in a total thickness of 120 µm. A fluorescent MOF that specifically binds dopamine is introduced, enabling a highly sensitive dopamine measurement with a detection limit of 79.9 nM. A compact wireless circuit weighing only 0.85 g is also developed and interfaced with the probe, which was later applied to continuously monitor real-time dopamine levels during deep brain stimulation in rats, providing critical information on neurotransmitter dynamics. Cytotoxicity tests and immunofluorescence analysis further suggest a favorable biocompatibility of the probe for implantable applications. This work presents fundamental principles and techniques for integrating fluorescent MOFs and flexible electronics for brain-computer interfaces and may provide more customized platforms for applications in neuroscience, disease tracing, and smart diagnostics.

Clinical analysis of Noonan syndrome caused by RRAS2 mutations and literature review.

Noonan syndrome is a common developmental disorder characterized by distinctive facial dysmorphism, short stature, congenital heart defects, pectus deformity, and developmental delay. It is related to the abnormal activation of genes involved in the RAS-MAPK signaling pathway, more than a dozen of which can be affected. However, mutations of the RRAS2 gene are rare, with only 6 different RRAS2 variants in 13 patients reported to date. In this case report, whole-exome sequencing revealed a novel heterozygous variant in the RRAS2 gene NM_012250: c.212G > A, p.(Gly71Glu). Phenotypically, our patient had typical Noonan syndrome-related clinical manifestations consistent with published reports, such as short stature, facial dysmorphism, short neck, patent foramen ovale, moderate global developmental delay, and hearing impairment. In addition, our patient also had a distal middle finger deformity and hair defect, which have not been reported in previous cases. We analyzed the clinical characteristics of all patients with Noonan syndrome caused by RRAS2 variants and reviewed the literature. This discovery expands the genetic and phenotypic spectrum of Noonan syndrome.

Force Decoding of Caudal Forelimb Area and Rostral Forelimb Area in Chronic Stroke Rats.

Brain machine interfaces (BMIs) used for movement restoration primarily rely on studies of motor decoding. It has been proved that local field potentials (LFPs) from primary motor cortex and premotor cortex of normal rodents could be used for decoding motor signals. However, few studies have explored the decoding performance of these brain areas under motor cortex damage. In this work, we focus on force decoding performance of LFPs spectrum from both ipsilesional caudal forelimb area (CFA) and rostral forelimb area (RFA) of rodents with ischemia over CFA. After three months of ischemia induced by photothrombosis over CFA, the power of high-frequency bands (>120 Hz) from both CFA and RFA can decode force signals by Kalman filters. The fair performance of CFA indicates motor reorganization over penumbra. Further exploration of RFA decoding ability proves that at least four electrodes of RFA should be used on decoding and electrodes far from CFA of stroke rats could achieve almost as good results as those close to CFA of normal rats, which indicates the motor remapping. Experimental results show the long-term stability of PM LFPs decoding performance of stroke rats as the trained Kalman model could be used to accurately decode force some days later which provides a possibility for online decoding system. In conclusion, our work shows that even under CFA ischemia, high-frequency power of LFPs from RFA is still able to accurately decode force signals and has long stability, which provides the possibility of BMIs for motor function reconstruction of chronic stroke patients.

Bioresorbable Electrode Array for Electrophysiological and Pressure Signal Recording in the Brain.

Medical implantation of an electrocorticography (ECoG) recording system for brain monitoring is an effective clinical tool for seizure focus location and brain disease diagnosis. Planar and flexible ECoG electrodes can minimize the risks of infection and serious inflammatory response, and their good shape adaptability allows the device to fit complex cortex shape and structure to record brain signals with high spatial and temporal resolution. However, these ECoG electrodes require an additional surgery to remove the implant, which imposes potential medical risks. Here, a novel flexible and bioresorbable ECoG device integrated with an intracortical pressure sensor for monitoring swelling of the cortex during operation is reported. The ECoG device is fabricated with poly(l-lactide) and polycaprolactone composite and transient metal molybdenum. In vivo tests on rats show that the ECoG system can record the dynamic changes in brain signals for the different epilepsy stages with high resolution, while the malleable pressure sensor shows a linear relationship between the pressure and resistance in in vitro tests. In vitro degradation experiments show that the ECoG system can work stably for about five days before loss of efficacy, and the whole ECoG system degrades completely in a phosphate buffer solution in about 100 days.

Intrinsic optical imaging study on cortical responses to electrical stimulation in ventral posterior medial nucleus of thalamus.

Intracortical electrical micro-stimulation has been applied widely for the attempts on reconstruction of sensory functions. More recently, thalamic electrical stimulation has been proposed as a promising target for somatosensory stimulation. However, the cortical activations and mechanisms evoked by VPM stimulation remained unclear. In this report, the cortical neural responses to electrical stimulations were recorded by optical imaging of intrinsic signals. The impact of stimulation parameters was characterized to illustrate how the VPM stimulation alter cortical activities. Significant increases were found in cortical responses with increased stimulation amplitude or pulse width. However, frequency modulation exhibited significant inhibition with higher frequency stimulation. Our results suggest that optical imaging of intrinsic signals is sensitive and reliable to deep brain stimulations. These results may not only help to understand the modulation effects through thalamocortical pathway, but also show the possibility to use VPM stimulation to evoke frequency-tuned tactile sensations in rats.

Effect of testosterone on the proliferation and collagen synthesis of cardiac fibroblasts induced by angiotensin II in neonatal rat.

The objective is to explore the effect of testosterone on the proliferation and collagen synthesis of neonatal rat cardiac fibroblasts (CF) induced by Angiotensin II (Ang II) and the underlying mechanisms. Derived from neonatal rats, the CFs were divided into 4 groups: the control group, Ang II group, testosterone group, and testosterone + Ang II group in vitro. Cell cycle distribution, collagen counts, and phosphorylated extracellular signal-regulated kinase (ERK1/2) (p - ERK1/2) expression were assessed by flow cytometry, VG staining, and immunocytochemistry, respectively. The Ang II group had a much higher proportion of cells in the S-phase, higher collagen contents, and a higher p - ERK1/2 expression level than either the control or testosterone group. However, these factors were significantly reduced in the testosterone + Ang II group as compared to the Ang II group. In terms of cells in the S-phase and the collagen contents, there was not a significant difference between the testosterone group and the control. However, the protein expression of p-ERK1/2 was significantly increased in the testosterone group as compared to the control. Testosterone inhibits the proliferation and collagen synthesis of CF induced by Ang II. The underlying mechanism may involve the ERK1/2 signaling pathway.

Portable wireless electrocorticography system with a flexible microelectrodes array for epilepsy treatment.

In this paper, we present a portable wireless electrocorticography (ECoG) system. It uses a high resolution 32-channel flexible ECoG electrodes array to collect electrical signals of brain activities and to stimulate the lesions. Electronic circuits are designed for signal acquisition, processing and transmission using Bluetooth Low Energy 4 (LTE4) for wireless communication with cell phone. In-vivo experiments on a rat show that the flexible ECoG system can accurately record electrical signals of brain activities and transmit them to cell phone with a maximal sampling rate of 30 ksampling/s per channel. It demonstrates that the epilepsy lesions can be detected, located and treated through the ECoG system. The wireless ECoG system has low energy consumption and high brain spatial resolution, thus has great prospects for future application.