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Amyotrophic lateral sclerosis (ALS) is a fatal and intricate neurodegenerative disease that impacts upper and lower motor neurons within the central nervous system, leading to their progressive destruction. Despite extensive research, the pathogenesis of this multifaceted disease remains elusive. The United States Food and Drug Administration (FDA) has granted approval for seven medications designed to address ALS and mitigate its associated symptoms. These FDA-sanctioned treatments are Qalsody, Relyvrio, Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta. In this review, the effects of these seven drugs on ALS based on their mechanism of action, dosing, and clinical presentations are comprehensively summarized. Each medication offers a distinct approach to manage ALS, aiming to alleviate the burdensome symptoms and slow the disease's progression, thereby improving the quality of life for individuals affected by this neurological condition. However, despite these advancements in pharmaceutical interventions, finding a definitive cure for ALS remains a significant challenge. Continuous investigation into ALS pathophysiology and therapeutic avenues remains imperative, necessitating further research collaborations and innovative approaches to unravel the complex mechanisms underlying this debilitating condition.

In recent years, the development of biodegradable hydrogels as an alternative over the traditional wound dressing has become increasingly significant. These specific hydrogels are able to offer suitable microenvironments to further aid the process of tissue or organ regeneration. However, application of biodegradable hydrogels in clinical medicine remains uncommon due to most biodegradable hydrogels struggle with achieving satisfactory adhesiveness property, high mechanical support and cell compatibility simultaneously. In order to overcome these constraints and enhance the applicability of biodegradable hydrogels, methods have been employed in this study.By reacting gellan gum with methacrylic anhydride and incorporating a biodegradable protein, keratin, we endowed the hydrogels with high pliability via photo-polymerization chain extension, thereby obtaining a biodegradable hydrogel with exceptional properties. Through a series of in vitro tests, GGMA/keratin hydrogels exhibited great cell compatibility via providing an appropriate environment for cell proliferation. Furthermore, this hydrogel not only exhibits extraordinary adhesive ability on visceral tissues but also extends to scenarios involving skin or organ damage, offering valuable assistance in wound healing. Our design provides a suitable platform for cell proliferation and tissue regeneration, which shows prospects for future medical research and clinical applications.

Health management and physical rehabilitation often involve personalized plans. Exercise intensity measurements help tailor these plans to the specific needs, abilities, and medical conditions of the individual. Accelerometers can be utilized for estimating exercise intensity, although their accuracy may be somewhat limited. This study’s focus was to determine whether accelerometers with the assistance of specialized algorithms could replace conventional heart rate monitoring approaches for exercise intensity estimations. Seventeen participants were enrolled and performed a discontinuous exercise test on a treadmill with seven different exercise regimens –three walking and four running routines. Acceleration measurements were acquired using two tri-axial accelerometers worn at the hip and wrist. Pulse measurements were simultaneously collected to calculate the heart rate reserve. The measurements acquired from hip-worn and wrist-worn accelerometers were processed using integral, peak, and mean amplitude deviation algorithms and correlated with the different walking and running speeds. Strong correlations between resultant accelerations and walking speeds ( $r =$ ׅn913, $P \lt $ ׅ001) were observed in the data collected by the combination of a hip-worn accelerometer and the mean amplitude deviation algorithm. Strong correlations for running speeds ( $r =$ ׅ786, $P \lt $ ׅ001) were also observed in the data collected by the combination of a wrist-worn accelerometer and the integral algorithm. The heart rate reserve increased with incremental speeds (walking: $r =$ ׅ850, $P \lt $ ׅ001; running: $r =$ ׅ764, $P \lt $ ׅ001). The appropriate combination of accelerometer placement and estimation algorithm provides excellent exercise intensity estimations without the limitations presented by heart rate index referencing.

This literature review explores the pivotal roles of the Uncoordinated-13 (UNC13) protein family, encompassing UNC13A, UNC13B, UNC13C, and UNC13D, in the pathogenesis of various human diseases. These proteins, which are evolutionarily conserved and crucial for synaptic vesicle priming and exocytosis, have been implicated in a range of disorders, spanning from neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) to immune-related conditions such as familial hemophagocytic lymphohistiocytosis (FHL). The involvement of UNC13A in neurotransmitter release and synaptic plasticity is linked to ALS and FTD, with genetic variations affecting disease progression. UNC13B, which is closely related to UNC13A, plays a role in autism spectrum disorders (ASD), epilepsy, and schizophrenia. UNC13C is implicated in oral squamous cell carcinoma (OSCC) and hepatocellular carcinoma (HCC), and has a neuroprotective role in Alzheimer's disease (AD). UNC13D has an essential role in immune cell function, making it a key player in FHL. This review highlights the distinct molecular functions of each UNC13 family member and their implications in disease contexts, shedding light on potential therapeutic strategies and avenues for future research. Understanding these proteins' roles offers new insights into the management and treatment of neurological and immunological disorders.

Abstract Reactive oxygen species (ROS) have been recognized as prevalent contributors to the development of inner retinal injuries including optic neuropathies such as glaucoma, non‐arteritic anterior ischemic optic neuropathy, traumatic optic neuropathy, and Leber hereditary optic neuropathy, among others. This underscores the pivotal significance of oxidative stress in the damage inflicted upon retinal tissue. To combat ROS‐related challenges, this study focuses on creating an injectable and tissue‐adhesive hydrogel with tailored antioxidant properties for retinal applications. GelCA, a gelatin‐modified hydrogel with photo‐crosslinkable and injectable properties, is developed. To enhance its antioxidant capabilities, curcumin‐loaded polydopamine nanoparticles (Cur@PDA NPs) are incorporated into the GelCA matrix, resulting in a multifunctional nanocomposite hydrogel referred to as Cur@PDA@GelCA. This hydrogel exhibits excellent biocompatibility in both in vitro and in vivo assessments, along with enhanced tissue adhesion facilitated by NPs in an in vivo model. Importantly, Cur@PDA@GelCA demonstrates the potential to mitigate oxidative stress when administered via intravitreal injection in retinal injury models such as the optic nerve crush model. These findings underscore its promise in advancing retinal tissue engineering and providing an innovative strategy for acute neuroprotection in the context of inner retinal injuries.

This review explored the role of mitochondria in retinal ganglion cells (RGCs), which are essential for visual processing. Mitochondrial dysfunction is a key factor in the pathogenesis of various vision-related disorders, including glaucoma, hereditary optic neuropathy, and age-related macular degeneration. This review highlighted the critical role of mitochondria in RGCs, which provide metabolic support, regulate cellular health, and respond to cellular stress while also producing reactive oxygen species (ROS) that can damage cellular components. Maintaining mitochondrial function is essential for meeting RGCs’ high metabolic demands and ensuring redox homeostasis, which is crucial for their proper function and visual health. Oxidative stress, exacerbated by factors like elevated intraocular pressure and environmental factors, contributes to diseases such as glaucoma and age-related vision loss by triggering cellular damage pathways. Strategies targeting mitochondrial function or bolstering antioxidant defenses include mitochondrial-based therapies, gene therapies, and mitochondrial transplantation. These advances can offer potential strategies for addressing mitochondrial dysfunction in the retina, with implications that extend beyond ocular diseases.

Abstract Nature offers many examples of materials which exhibit exceptional properties due to hierarchical assembly of their constituents. In well-studied multi-cellular systems, such as the morpho butterfly, a visible indication of having ordered submicron features is given by the display of structural color. Detailed investigations of nature’s designs have yielded mechanistic insights and led to the development of biomimetic materials at laboratory scales. However, the manufacturing of hierarchical assemblies at industrial scales remains difficult. Biomanufacturing aims to leverage the autonomy of biological systems to produce materials at lower cost and with fewer carbon emissions. Earlier reports documented that some bacteria, particularly those with gliding motility, self-assemble into biofilms with polycrystalline structures and exhibit glittery, iridescent colors. The current study demonstrates the potential of using one of these bacteria, Cellulophaga lytica, as a platform for the large scale biomanufacturing of ordered materials. Specific approaches for controlling C. lytica biofilm optical, spatial and temporal properties are reported. Complementary microscopy-based studies reveal that biofilm color variations are attributed to changes in morphology induced by cellular responses to the local environment. Incorporation of C. lytica biofilms into materials is also demonstrated, thereby facilitating their handling and downstream processing, as would be needed during manufacturing processes. Finally, the utility of C. lytica as a self-printing, photonic ink is established by this study. In summary, autonomous surface assembly of C. lytica under ambient conditions and across multiple length scales circumvent challenges that currently hinder production of ordered materials in industrial settings.

Introduction: HCHS/SOL is a representative study of Hispanic/Latinos living in the US. HCHS/SOL participants have a high prevalence of diabetes (1) and diabetic associated cognitive decline (2). Previous studies of predominantly non-Hispanic White populations indicate that silent brain infarcts are associated with incident dementia (3). Given that diabetes is prevalent in HCHS/SOL and associated with cognitive decline, we examined whether diabetes may also lead to infarction on MRI. Methods: SOL-INCA-MRI consists of 2668 individuals of Hispanic/Latino Heritage from 4 centers across the US. Demographics of the cohort are summarized in the Table. The presence or absence of infarction on MRI was determined from review of high resolution T1, T2 and FLAIR imaging as well as gradient echo imaging by a neuroradiologist and a stroke neurologist with a high level of agreement (ICC >0.90). Desperate readings were adjudicated by a neurologist with experience in vascular brain injury. Diabetes based on American Diabetes Association definition of normal, prediabetic and diabetic. This definition used measures serum glucose levels adjusted for fasting time and, if available, post-OGTT glucose levels, A1C percentages, and scanned/transcribed anti- diabetic medication use. General linear model was used to test the associated between the presence or absence of MRI and diabetes adjusting for age, gender, heritage, and center. Results: Subjects were 62.3 + 9.2 years of age at MRI range [35-86], 67% were female and the prevalence of MRI infarction was 7% (Table). Pre-diabetes was present in 45% and diabetes in 22%. Stroke prevalence increased with age ranging from

Sensory afferent inputs play an important role in neuromuscular functions. Subsensory level noise electrical stimulation enhances the sensitivity of peripheral sensory system and improves lower extremity motor function. The current study aimed to investigate the immediate effects of noise electrical stimulation on proprioceptive senses and grip force control, and whether there are associated neural activities in the central nervous system. Fourteen healthy adults participated in 2 experiments on 2 different days. In day 1, participants performed grip force and joint proprioceptive tasks with and without (sham) noise electrical stimulation. In day 2, participants performed grip force steady hold task before and after 30-min noise electrical stimulation. Noise stimulation was applied with surface electrodes secured along the course of the median nerve and proximal to the coronoid fossa EEG power spectrum density of bilateral sensorimotor cortex and coherence between EEG and finger flexor EMG were calculated and compared. Wilcoxon Signed-Rank Tests were used to compare the differences of proprioception, force control, EEG power spectrum density and EEG-EMG coherence between noise electrical stimulation and sham conditions. The significance level (alpha) was set at 0.05. Our study found that noise stimulation with optimal intensity could improve both force and joint proprioceptive senses. Furthermore, individuals with higher gamma coherence showed better force proprioceptive sense improvement with 30-min noise electrical stimulation. These observations indicate the potential clinical benefits of noise stimulation on individuals with impaired proprioceptive senses and the characteristics of individuals who might benefit from noise stimulation.

Abstract Novel stimulation protocols for neuromodulation with magnetic fields are explored in clinical and laboratory settings. Recent evidence suggests that the activation state of the nervous system plays a significant role in the outcome of magnetic stimulation, but the underlying cellular and molecular mechanisms of state-dependency have not been completely investigated. We recently reported that high frequency magnetic stimulation could inhibit neural activity when the neuron was in a low active state. In this paper, we investigate state-dependent neural modulation by applying a magnetic field to single neurons, using the novel micro-coil technology. High frequency magnetic stimulation suppressed single neuron activity in a state-dependent manner. It inhibited neurons in slow-firing states, but spared neurons from fast-firing states, when the same magnetic stimuli were applied. Using a multi-compartment NEURON model, we found that dynamics of voltage-dependent sodium and potassium channels were significantly altered by the magnetic stimulation in the slow-firing neurons, but not in the fast-firing neurons. Variability in neural activity should be monitored and explored to optimize the outcome of magnetic stimulation in basic laboratory research and clinical practice. If selective stimulation can be programmed to match the appropriate neural state, prosthetic implants and brain-machine interfaces can be designed based on these concepts to achieve optimal results.

Platinum‐based chemotherapy has been the cornerstone treatment for small cell lung cancer (SCLC) for decades, but no major progress has been made in the past 20 years with regard to overcoming chemoresistance. As the cell cycle checkpoint kinase 1 (Chk1) plays a key role in DNA damage response to chemotherapeutic drugs, we explored the mechanisms of acquired drug resistance to the Chk1 inhibitor prexasertib in SCLC. We established prexasertib resistance in two SCLC cell lines and found that DNA copy number, messengerRNA (mRNA) and protein levels of the cell cycle regulator Wee1 significantly correlate with the level of acquired resistance. Wee1 small interfering RNA (siRNA) or Wee1 inhibitor reversed prexasertib resistance, whereas Wee1 transfection induced prexasertib resistance in parental cells. Reverse phase protein microarray identified up‐regulated proteins in the resistant cell lines that are involved in apoptosis, cell proliferation and cell cycle. Down‐regulation of CDK1 and CDC25C kinases promoted acquired resistance in parental cells, whereas down‐regulation of p38MAPK reversed the resistance. High Wee1 expression was significantly correlated with better prognosis of resected SCLC patients. Our results indicate that Wee1 overexpression plays an important role in acquired resistance to Chk1 inhibition. We also show that bypass activation of the p38MAPK signaling pathway may contribute to acquired resistance to Chk1 inhibition. The combination of Chk1 and Wee1 inhibitors may provide a new therapeutic strategy for the treatment of SCLC.

The calcium-independent phospholipase iPLA2β has been identified as a transcriptional target of the tumor suppressor TP53 (or p53). Unlike GPX4 (glutathione peroxidase 4), iPLA2β is not required for normal homeostasis but critical for ferroptosis during stress responses. Our results implicate iPLA2β as an essential regulator in a noncanonical ferroptosis pathway.

BackgroundOsimertinib is an effective first-line therapy option for EGFR-mutant NSCLC, but virtually all patients develop resistance. CRIPTO, through Src activation, has been implicated in resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Dasatinib, a Src inhibitor, has shown preclinical synergy with EGFR-TKI therapy.MethodThis is a single-arm phase I/II trial of osimertinib and dasatinib in TKI-naïve advanced EGFR-mutant NSCLC (NCT02954523). A 3 + 3 design was used in the phase I to establish the recommended phase II dose (RP2D). Osimertinib 80 mg QD was combined with dasatinib 70 mg BID (DL2), 50 mg BID (DL1), 70 mg QD (DL-1), and 50 mg QD (DL-2).ResultsTen patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches/body pain, neutropenia, rash, one each). Common treatment-related adverse events included pleural effusion (n=10), diarrhea (n=8), rash (n=7), transaminitis (n=7), thrombocytopenia (n=7), and neutropenia (n=7). While the MTD was not determined by protocol-defined DLT criteria, DL-2 was chosen as the RP2D, considering overall tolerability. Nine (90%) patients had a PR, including 1 unconfirmed PR. Median PFS was 19.4 months and median OS 36.1 months. The trial was closed to accrual prematurely due to slow accrual after the approval of osimertinib as first-line therapy.ConclusionsThe combination of dasatinib and osimertinib demonstrated anticancer activity. The treatment was limited by chronic toxicities mainly attributed to dasatinib. To improve the safety and tolerability of Src and EGFR co-inhibition, Src inhibitors with a more favorable safety profile should be utilized in future studies.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02954523

Background: Rathke’s cleft cysts (RCC) arise from the pars intermedia because of incomplete regression of the embryologic Rathke pouch. A subset of RCC becomes symptomatic causing headaches, visual and endocrinological disturbances such that surgical intervention is indicated. Several points in surgical management remain controversial including operative strategy (simple fenestration (SF) vs complete cyst wall resection (CWR)) as well as reconstructive techniques. Methods: A retrospective analysis was conducted of pathologically confirmed RCC operated on by endoscopic endonasal approach from 2006 to 2019. Pre-operative symptoms, imaging characteristics, operative strategy, symptom response, complications and recurrences were recorded. Results: Thirty-nine patients were identified. Thirty-three underwent SF and six underwent CWR. Worsening pituitary function was significantly increased with CWR (50%) compared to SF (3%) (p = 0.008). All patients underwent “closed” reconstruction with a post-operative CSF leak rate of 5% (3% SF vs 16% CWR, p = 0.287). Six (15%) recurrences necessitating surgery were reported. Recurrence rates stratified by surgical technique (18% SF vs 0% CWR, p = 0.564) were not found to be significantly different. Conclusions: The current series illustrates variability in the surgical management of RCCs. SF with closed reconstruction is a reasonable operative strategy for most symptomatic RCCs cases while CWR can be reserved for selected cases.

Placental-specific protein 1 (PLAC1) is an X-linked trophoblast gene that is re-expressed in several malignancies, including breast cancer, and is therefore a potential biomarker to follow disease onset and progression. Sera from 117 preoperative/pretreatment breast cancer patients and 51 control subjects, including those with fibrocystic disease, were analyzed for the presence of PLAC1 protein as well as its expression by IHC in tumor biopsies in a subset of subjects. Serum PLAC1 levels exceeded the mean plus one standard deviation (mean+SD) of the level in control subjects in 67% of subjects with ductal carcinoma in situ (DCIS), 67% with HER2+ tumors, 73% with triple-negative cancer and 73% with ER+/PR+ tumors. Greater sensitivity was achieved using the mean+2 SD of control PLAC1 serum values, where the false positive rate was 3% and was exceeded by 38%, 40%, 60% and 43% of subjects with DCIS, HER2+, TNBC and ER+/PR+/HER2- tumors. PLAC1 was detected in 97% of tumor biopsies, but did not correlate quantitatively with serum levels. There was no significant correlation of serum PLAC1 levels with race, age at diagnosis, body mass index (BMI) or the presence of metastatic disease. It remains to be determined whether PLAC1 serum levels can serve as a diagnostic biomarker for the presence or recurrence of disease post-surgery and/or therapy.

Huntington's disease is caused by an expanded CAG repeat in the gene encoding huntingtin (HTT), resulting in loss of striatal and cortical neurons. Given that the gene product is widely expressed, it remains unclear why neurons are selectively targeted. Here we show the relationship between synaptic and extrasynaptic activity, inclusion formation of mutant huntingtin protein (mtHtt) and neuronal survival. Synaptic N-methyl-D-aspartate-type glutamate receptor (NMDAR) activity induces mtHtt inclusions via a T complex-1 (TCP-1) ring complex (TRiC)-dependent mechanism, rendering neurons more resistant to mtHtt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increases the vulnerability of mtHtt-containing neurons to cell death by impairing the neuroprotective cyclic AMP response element-binding protein (CREB)-peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) cascade and increasing the level of the small guanine nucleotide-binding protein Rhes, which is known to sumoylate and disaggregate mtHtt. Treatment of transgenic mice expressing a yeast artificial chromosome containing 128 CAG repeats (YAC128) with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine, which blocks both extrasynaptic and synaptic NMDAR activity, decreases neuronal inclusions and worsens these outcomes. Our findings offer a rational therapeutic approach for protecting susceptible neurons in Huntington's disease.