PI5P4K inhibitors: promising opportunities and challenges.

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4K), also known as type II PIPKs or PIPKIIs, convert the lipid second messenger PI5P to PI(4,5)P. The PI5P4K family consists of three isozymes in mammals-PI5P4Kα, β, and γ-which notably utilize both GTP and ATP as phosphodonors. Unlike the other two isozymes, which can utilize both ATP and GTP, PI5P4Kβ exhibits a marked preference for GTP over ATP, acting as an intracellular GTP sensor that alters its kinase activity in response to physiological changes in GTP concentration.

Barriers to Medication Adherence in People Living With Epilepsy.

Background And Objectives: Epilepsy affects approximately 1.2% of the US population, resulting in 3.4 million Americans with active epilepsy.

A high dose KRP203 induces cytoplasmic vacuoles associated with altered phosphoinositide segregation and endosome expansion.

In animal cells, vacuoles are absent, but can be induced by diseases and drugs. While phosphoinositides are critical for membrane trafficking, their role in the formation of these vacuoles remains unclear. The immunosuppressive KRP203/Mocravimod, which antagonizes sphingosine-1-phosphate receptors, has been identified as having novel multimodal activity against phosphoinositide kinases.

Trends Over Time in Stroke Incidence by Race in the Greater Cincinnati Northern Kentucky Stroke Study.

Background And Objectives: Understanding the current status of and temporal trends of stroke epidemiology by age, race, and stroke subtype is critical to evaluate past prevention efforts and to plan future interventions to eliminate existing inequities. We investigated trends in stroke incidence and case fatality over a 22-year time period.

Methods: In this population-based stroke surveillance study, all cases of stroke in acute care hospitals within a 5-county population of southern Ohio/northern Kentucky in adults aged ≥20 years were ascertained during a full year every 5 years from 1993 to 2015.

Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells.

Increased phosphoinositide signaling is commonly associated with cancers. While "one-drug one-target" has been a major drug discovery strategy for cancer therapy, a "one-drug multi-targets" approach for phosphoinositide enzymes has the potential to offer a new therapeutic approach. In this study, we sought a new way to target phosphoinositides metabolism.

Beyond Warburg: LDHA activates RAC for tumour growth.

The physiological role of aerobic glycolysis (also known as the Warburg effect), which is observed in many tumours, is still not fully understood. The finding that lactate dehydrogenase A (LDHA) activates RAC1 in breast cancer sheds new light on this persistently enigmatic aspect of cancer metabolism.

Epigenetic upregulation of Schlafen11 renders WNT- and SHH-activated medulloblastomas sensitive to cisplatin.

Background: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas.

Substance Use and Performance of Toxicology Screens in the Greater Cincinnati Northern Kentucky Stroke Study.

Background: Though stroke risk factors such as substance use may vary with age, less is known about trends in substance use over time or about performance of toxicology screens in young adults with stroke.

Methods: Using the Greater Cincinnati Northern Kentucky Stroke Study, a population-based study in a 5-county region comprising 1.3 million people, we reported the frequency of documented substance use (cocaine/marijuana/opiates/other) obtained from electronic medical record review, overall and by race/gender subgroups among physician-adjudicated stroke events (ischemic and hemorrhagic) in adults 20 to 54 years of age.

Eighteen-hour inhibitory effect of s-ketamine on potassium- and ischemia-induced spreading depolarizations in the gyrencephalic swine brain.

Spreading depolarizations (SDs) are characterized by near-complete breakdown of the transmembrane ion gradients, cytotoxic edema, and glutamate release. SDs are associated with poor neurological outcomes in cerebrovascular diseases and brain trauma. Ketamine, a N-methyl-d-aspartate receptor antagonist, has shown to inhibit SDs in animal models and in humans.

The GTP responsiveness of PI5P4Kβ evolved from a compromised trade-off between activity and specificity.

Unlike most kinases, phosphatidylinositol 5-phosphate 4-kinase β (PI5P4Kβ) utilizes GTP as a physiological phosphate donor and regulates cell growth under stress (i.e., GTP-dependent stress resilience).

Recognizing Atypical Dopa-Responsive Dystonia and Its Mimics.

Purpose Of Review: Dopa-responsive dystonia (DRD) encompasses a group of phenotypically and genetically heterogeneous neurochemical disorders. Classic GTP cyclohydrolase 1 ()-associated DRD consists of early-onset lower limb asymmetrical dystonia, with sleep benefit, diurnal variation, and excellent and sustained response to low l-dopa doses.

Recent Findings: Unlike the classic phenotype, -associated DRD may include features inconsistent with the original phenotype.

A randomized controlled trial of self-management for people with epilepsy and a history of negative health events (SMART) targeting rural and underserved people with epilepsy: a methodologic report.

Background: Many people living with epilepsy (PLWE) reside in rural communities, and epilepsy self-management may help address some of the gaps in epilepsy care for these communities. A prior randomized control trial of a remotely delivered, Web-based group format 12-week self-management program (SMART) conducted in Northeast Ohio, a primarily urban and suburban community, demonstrated improved outcomes in negative health events such as depression symptoms and quality of life. However, there is a paucity of research addressing the needs of PLWE in rural settings.

'Hand mechanogram' in epilepsia partialis continua.

Epilepsia partialis continua manifests as low-frequency, rhythmic involuntary movements of a focal body part. We report a young man, HIV-positive and with syphilis, who developed right-hand epilepsia partialis continua associated with a small left-sided cortico-subcortical frontal lesion. A pen and paper test provided 'mechanographic' data on frequency, amplitude and rhythmicity of the hand movements, helping distinguish it from other causes of low-frequency repetitive hand movements.

Biphasic (Subtherapeutic) Levodopa-Induced Respiratory Dysfunction in Parkinson Disease.

Objective: To evaluate 3 cases illustrating a rarely recognized phenotype of Parkinson disease (PD), namely, biphasic levodopa-induced respiratory dysfunction manifesting as dyspnea.

Methods: To appreciate the nature of the fluctuations of respiratory function in response to levodopa, we measured changes in respiratory muscle control before and after the best therapeutic response to levodopa in 3 PD patients with fluctuating dyspnea.

Results: Episodes of breathlessness were accompanied by shallow tachypnea and reduced respiratory muscle control, as measured by maximal expiratory pressure, peak cough flow, and forced expiratory volume in 1 second.

Divergent Mechanisms Activating RAS and Small GTPases Through Post-translational Modification.

RAS is a founding member of the RAS superfamily of GTPases. These small 21 kDa proteins function as molecular switches to initialize signaling cascades involved in various cellular processes, including gene expression, cell growth, and differentiation. RAS is activated by GTP loading and deactivated upon GTP hydrolysis to GDP.

SI-MOIRAI: a new method to identify and quantify the metabolic fate of nucleotides.

Since the discovery of nucleotides over 100 years ago, extensive studies have revealed the importance of nucleotides for homeostasis, health and disease. However, there remains no established method to investigate quantitatively and accurately intact nucleotide incorporation into RNA and DNA. Herein, we report a new method, Stable-Isotope Measure Of Influxed Ribonucleic Acid Index (SI-MOIRAI), for the identification and quantification of the metabolic fate of ribonucleotides and their precursors.

TGF-β-dependent reprogramming of amino acid metabolism induces epithelial-mesenchymal transition in non-small cell lung cancers.

Epithelial-mesenchymal transition (EMT)-a fundamental process in embryogenesis and wound healing-promotes tumor metastasis and resistance to chemotherapy. While studies have identified signaling components and transcriptional factors responsible in the TGF-β-dependent EMT, whether and how intracellular metabolism is integrated with EMT remains to be fully elucidated. Here, we showed that TGF-β induces reprogramming of intracellular amino acid metabolism, which is necessary to promote EMT in non-small cell lung cancer cells.

β-Blocker-Induced Tremor.

Background: Although the β-blocker propranolol is considered one of the most effective tremor treatments and other β-blockers are often prescribed to patients with tremor, those with partial β-agonist activity on β-adrenoreceptors can theoretically induce or exacerbate tremor. Here we report 2 patients with tremor induced or worsened by such β-blockers.

Cases: Case 1 is a 38-year-old man with worsening of tremor in both upper extremities after the introduction of pindolol as an adjunct treatment for severe depression.

Medialization Laryngoplasty: A Review for Speech-Language Pathologists.

Purpose The purpose of this study is to familiarize speech-language-pathologists with the current state of the science regarding medialization laryngoplasty in the treatment of voice disorders, with emphasis on current evidence-based practice, voice outcomes, and future directions for research. Method A literature review was performed in PubMed and Embase using the keywords and or . Articles published between 2010 and 2020 were reviewed for data about clinical applications, technical approach, voice-related outcomes, and basic science or clinical innovations with the potential to improve patient care.