Three-stage hybrid spiking neural networks fine-tuning for speech enhancement.

Introduction: In the past decade, artificial neural networks (ANNs) have revolutionized many AI-related fields, including Speech Enhancement (SE). However, achieving high performance with ANNs often requires substantial power and memory resources. Recently, spiking neural networks (SNNs) have emerged as a promising low-power alternative to ANNs, leveraging their inherent sparsity to enable efficient computation while maintaining performance.

Opaganib Promotes Weight Loss and Suppresses High-Fat Diet-Induced Obesity and Glucose Intolerance.

Introduction: Sphingolipid metabolism has been implicated in many diseases including cancer, pathologic inflammation, viral infection, neurologic pathologies and metabolic pathologies, including obesity and diabetes. We have previously shown that opaganib (aka ABC294640) inhibits three key enzymes in the sphingolipid metabolism pathway: sphingosine kinase-2, dihydroceramide desaturase and glucosylceramide synthase. We and others have demonstrated anticancer, anti-inflammatory and antiviral activities of opaganib in multiple experimental models.

Dynamic proportional loss of functional connectivity revealed change of left superior frontal gyrus in subjective cognitive decline: an explanatory study based on Chinese and Western cohorts.

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear.

Opaganib Downregulates N-Myc Expression and Suppresses In Vitro and In Vivo Growth of Neuroblastoma Cells.

Neuroblastoma (NB), the most common cancer in infants and the most common solid tumor outside the brain in children, grows aggressively and responds poorly to current therapies. We have identified a new drug (opaganib, also known as ABC294640) that modulates sphingolipid metabolism by inhibiting the synthesis of sphingosine 1-phosphate (S1P) by sphingosine kinase-2 and elevating dihydroceramides by inhibition of dihydroceramide desaturase. The present studies sought to determine the potential therapeutic activity of opaganib in cell culture and xenograft models of NB.

The Sphingolipid-Modulating Drug Opaganib Protects against Radiation-Induced Lung Inflammation and Fibrosis: Potential Uses as a Medical Countermeasure and in Cancer Radiotherapy.

Fibrosis is a chronic pathology resulting from excessive deposition of extracellular matrix components that leads to the loss of tissue function. Pulmonary fibrosis can follow a variety of diverse insults including ischemia, respiratory infection, or exposure to ionizing radiation. Consequently, treatments that attenuate the development of debilitating fibrosis are in desperate need across a range of conditions.

Opaganib (ABC294640) Induces Immunogenic Tumor Cell Death and Enhances Checkpoint Antibody Therapy.

Antibody-based cancer drugs that target the checkpoint proteins CTLA-4, PD-1 and PD-L1 provide marked improvement in some patients with deadly diseases such as lung cancer and melanoma. However, most patients are either unresponsive or relapse following an initial response, underscoring the need for further improvement in immunotherapy. Certain drugs induce immunogenic cell death (ICD) in tumor cells in which the dying cells promote immunologic responses in the host that may enhance the in vivo activity of checkpoint antibodies.

Spiking neural networks fine-tuning for brain image segmentation.

Introduction: The field of machine learning has undergone a significant transformation with the progress of deep artificial neural networks (ANNs) and the growing accessibility of annotated data. ANNs usually require substantial power and memory usage to achieve optimal performance. Spiking neural networks (SNNs) have recently emerged as a low-power alternative to ANNs due to their sparsity nature.

Opioid cutting agents for use as internal standards in ion mobility spectrometry (IMS).

Opioids have become a serious public health concern over the last decade. These compounds are commonly found mixed, or cut, with safer compounds to make the opioids appear unadulterated while also enhancing the psychoactive effect on the user. Commercial benchtop and handheld IMS devices are capable of detection but published reduced ion mobility (K) values, used to identify the target analytes with IMS instrumentation, have shown variability.

The Sphingosine Kinase 2 Inhibitor Opaganib Protects Against Acute Kidney Injury in Mice.

Introduction: Acute kidney injury (AKI) is a common multifactorial adverse effect of surgery, circulatory obstruction, sepsis or drug/toxin exposure that often results in morbidity and mortality. Sphingolipid metabolism is a critical regulator of cell survival and pathologic inflammation processes involved in AKI. Opaganib (also known as ABC294640) is a first-in-class experimental drug targeting sphingolipid metabolism that reduces the production and activity of inflammatory cytokines and, therefore, may be effective to prevent and treat AKI.

Opaganib Protects against Radiation Toxicity: Implications for Homeland Security and Antitumor Radiotherapy.

Exposure to ionizing radiation (IR) is a lingering threat from accidental or terroristic nuclear events, but is also widely used in cancer therapy. In both cases, host inflammatory responses to IR damage normal tissue causing morbidity and possibly mortality to the victim/patient. Opaganib, a first-in-class inhibitor of sphingolipid metabolism, has broad anti-inflammatory and anticancer activity.

Recent Progress in the Development of Opaganib for the Treatment of Covid-19.

The Covid-19 pandemic driven by the SARS-CoV-2 virus continues to exert extensive humanitarian and economic stress across the world. Although antivirals active against mild disease have been identified recently, new drugs to treat moderate and severe Covid-19 patients are needed. Sphingolipids regulate key pathologic processes, including viral proliferation and pathologic host inflammation.

Characteristics of VCP mutation-associated cardiomyopathy.

VCP associated inclusion body myopathy, Paget's disease of bone, and Frontotemporal Dementia (IBMPFD, VCP disease, or multisystem proteinopathy type 1 (MSP1)) is an autosomal dominant disease caused by missense mutations in the VCP gene, which plays a crucial role in ubiquitin-proteasome dependent degradation of cytosolic proteins. Those diagnosed with the disorder often suffer from cardiovascular complications in the advanced stages. We conducted an observational cross-section study to investigate echocardiographic features of asymptomatic carriers and those affected by the disease to determine the differences and potential early features of the VCP-associated cardiomyopathy.

Development of a protocol to assess within-subject, regional white matter hyperintensity changes in aging and dementia.

Background: White matter hyperintensities (WMH), associated with both dementia risk and progression, can individually progress, remain stable, or even regress influencing cognitive decline related to specific cerebrovascular-risks. This study details the development and validation of a registration protocol to assess regional, within-subject, longitudinal WMH changes (ΔWMH) that is currently lacking in the field.

New Method: 3D-FLAIR images (baseline and one-year-visit) were used for protocol development and validation.

Memory-Related Frontal Brainwaves Predict Transition to Mild Cognitive Impairment in Healthy Older Individuals Five Years Before Diagnosis.

Background: Early prognosis of high-risk older adults for amnestic mild cognitive impairment (aMCI), using noninvasive and sensitive neuromarkers, is key for early prevention of Alzheimer's disease. We have developed individualized measures in electrophysiological brain signals during working memory that distinguish patients with aMCI from age-matched cognitively intact older individuals.

Objective: Here we test longitudinally the prognosis of the baseline neuromarkers for aMCI risk.

Support loading effects on the performance of an extraction chromatographic resin: Toward improved separation of trivalent lanthanides.

Changes in the level of impregnation of an Amberchrom CG-71m support with bis(2-ethylhexyl)phosphoric acid (HDEHP) are shown to alter the column efficiency, peak tailing, and metal ion uptake capacity associated with the resulting extraction chromatographic resins. Optimum efficiency and minimum peak tailing are observed at intermediate levels (ca. 20% (w/w)) of support loading.

Analysis of selective target engagement by small-molecule sphingosine kinase inhibitors using the Cellular Thermal Shift Assay (CETSA).

The recently renewed interest in scientific rigor and reproducibility is of critical importance for both scientists developing new targeted small-molecule inhibitors and those employing these molecule in cellular studies, alike. While off-target effects are commonly considered as limitations for any given small-molecule inhibitor, the ability of a given compound to distinguish between enzyme isoforms is often neglected when employing compounds in cellular studies. To call attention to this issue, we have compared the results of an assay for "direct target engagement", the Cellular Thermal Shift Assay (CETSA), to the published isoform selectivity of 12 commercially available sphingosine kinase 1 and 2 (SphK 1 and SphK2) inhibitors.

Brain structure changes over time in normal and mildly impaired aged persons.

Structural brain changes in aging are known to occur even in the absence of dementia, but the magnitudes and regions involved vary between studies. To further characterize these changes, we analyzed paired MRI images acquired with identical protocols and scanner over a median 5.8-year interval.

Diffuse optical assessment of cerebral-autoregulation in older adults stratified by cerebrovascular risk.

Diagnosis of cerebrovascular disease (CVD) at early stages is essential for preventing sequential complications. CVD is often associated with abnormal cerebral microvasculature, which may impact cerebral-autoregulation (CA). A novel hybrid near-infrared diffuse optical instrument and a finger plethysmograph were used to simultaneously detect low-frequency oscillations (LFOs) of cerebral blood flow (CBF), oxy-hemoglobin concentration ([HbO ]), deoxy-hemoglobin concentration ([Hb]) and mean arterial pressure (MAP) in older adults before, during and after 70° head-up-tilting (HUT).

Post-acquisition processing confounds in brain volumetric quantification of white matter hyperintensities.

Background: Disparate research sites using identical or near-identical magnetic resonance imaging (MRI) acquisition techniques often produce results that demonstrate significant variability regarding volumetric quantification of white matter hyperintensities (WMH) in the aging population. The sources of such variability have not previously been fully explored.

New Method: 3D FLAIR sequences from a group of randomly selected aged subjects were analyzed to identify sources-of-variability in post-acquisition processing that can be problematic when comparing WMH volumetric data across disparate sites.

White Matter Hyperintensity Regression: Comparison of Brain Atrophy and Cognitive Profiles with Progression and Stable Groups.

Subcortical white matter hyperintensities (WMHs) in the aging population frequently represent vascular injury that may lead to cognitive impairment. WMH progression is well described, but the factors underlying WMH regression remain poorly understood. A sample of 351 participants from the Alzheimer's Disease Neuroimaging Initiative 2 (ADNI2) was explored who had WMH volumetric quantification, structural brain measures, and cognitive measures (memory and executive function) at baseline and after approximately 2 years.

Distinct patterns of default mode and executive control network circuitry contribute to present and future executive function in older adults.

Executive function (EF) performance in older adults has been linked with functional and structural profiles within the executive control network (ECN) and default mode network (DMN), white matter hyperintensities (WMH) burden and levels of Alzheimer's disease (AD) pathology. Here, we simultaneously explored the unique contributions of these factors to baseline and longitudinal EF performance in older adults. Thirty-two cognitively normal (CN) older adults underwent neuropsychological testing at baseline and annually for three years.

Distinct White Matter Changes Associated with Cerebrospinal Fluid Amyloid-β1-42 and Hypertension.

Background: Alzheimer's disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults.

Objective: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations.

Methods: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer's Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans.

Targeting Sphingosine Kinases for the Treatment of Cancer.

Sphingosine kinases (SK1 and SK2) are key, druggable targets within the sphingolipid metabolism pathway that promote tumor growth and pathologic inflammation. A variety of isozyme-selective and dual inhibitors of SK1 and SK2 have been described in the literature, and at least one compound has reached clinical testing in cancer patients. In this chapter, we will review the rationale for targeting SKs and summarize the preclinical and emerging clinical data for ABC294640 as the first-in-class selective inhibitor of SK2.

Age and Alzheimer's pathology disrupt default mode network functioning via alterations in white matter microstructure but not hyperintensities.

The default mode network (DMN) comprises defined brain regions contributing to internally-directed thought processes. Reductions in task-induced deactivation in the DMN have been associated with increasing age and poorer executive task performance, but factors underlying these functional changes remain unclear. We investigated contributions of white matter (WM) microstructure, WM hyperintensities (WMH) and Alzheimer's pathology to age-related alterations in DMN function.