Bortezomib-induced neurotoxicity in human neurons is the consequence of nicotinamide adenine dinucleotide depletion.

The proteosome inhibitor bortezomib has revolutionized the treatment of multiple hematologic malignancies, but in many cases, its efficacy is limited by a dose-dependent peripheral neuropathy. We show that human induced pluripotent stem cell (hiPSC)-derived motor neurons and sensory neurons provide a model system for the study of bortezomib-induced peripheral neuropathy, with promising implications for furthering the mechanistic understanding of and developing treatments for preventing axonal damage. Human neurons in tissue culture displayed distal-to-proximal neurite degeneration when exposed to bortezomib. This process coincided with disruptions in mitochondrial function and energy homeostasis, similar to those described in rodent models of bortezomib-induced neuropathy. Moreover, although the degenerative process was unaffected by inhibition of caspases, it was completely blocked by exogenous nicotinamide adenine dinucleotide (NAD+), a mediator of the SARM1-dependent axon degeneration pathway. We demonstrate that bortezomib-induced neurotoxicity in relevant human neurons proceeds through mitochondrial dysfunction and NAD+ depletion-mediated axon degeneration, raising the possibility that targeting these changes might provide effective therapeutics for the prevention of bortezomib-induced neuropathy and that modeling chemotherapy-induced neuropathy in human neurons has utility.

The global spread of misinformation on spiders.

In the internet era, the digital architecture that keeps us connected and informed may also amplify the spread of misinformation. This problem is gaining global attention, as evidence accumulates that misinformation may interfere with democratic processes and undermine collective responses to environmental and health crises1,2. In an increasingly polluted information ecosystem, understanding the factors underlying the generation and spread of misinformation is becoming a pressing scientific and societal challenge3. Here, we studied the global spread of (mis-)information on spiders using a high-resolution global database of online newspaper articles on spider-human interactions, covering stories of spider-human encounters and biting events published from 2010-20204. We found that 47% of articles contained errors and 43% were sensationalist. Moreover, we show that the flow of spider-related news occurs within a highly interconnected global network and provide evidence that sensationalism is a key factor underlying the spread of misinformation.

A Pharmacist-Driven Glycemic Control Protocol to Reduce the Rate of Severe Hypoglycemia in High-Risk Patients.

Purpose: Hospital pharmacists contribute to patient safety and quality initiatives by overseeing the prescribing of antidiabetic medications. A pharmacist-driven glycemic control protocol was developed to reduce the rate of severe hypoglycemia events (SHE) in high-risk hospitalized patients. Methods: We retrospectively analyzed the rates of SHE (defined as blood glucose ≤40 mg/dL), before and after instituting a pharmacist-driven glycemic control protocol over a 4-year period. A hospital glucose management team that included a lead Certified Diabetes Educator Pharmacist (CDEP), 5 pharmacists trained in diabetes, a lead hospitalist, critical care and hospital providers established a process to first identify patients at risk for severe hypoglycemia and then implement our protocol. Criteria from the American Diabetes Association and the American Association of Clinical Endocrinologists was utilized to identify and treat patients at risk for SHE. We analyzed and compared the rate of SHE and physician acceptance rates before and after protocol initiation. Results: From January 2015 to March 2019, 18 297 patients met criteria for this study; 139 patients experienced a SHE and approximately 80% were considered high risk diabetes patients. Physician acceptance rates for the new protocol ranged from 77% to 81% from the year of initiation (2016) through 2018. The absolute risk reduction of SHE was 9 events per 1000 hospitalized diabetic patients and the relative risk reduction was 74% SHE from the start to the end of the protocol implementation. Linear regression analysis demonstrated that SHE decreased by 1.5 events per 1000 hospitalized diabetic patients (95% confidence interval, -1.54 to -1.48, P < .001) during the 2 years following the introduction of the protocol. This represents a 15% relative reduction of SHE per year. Conclusion: The pharmacist-driven glycemic control protocol was well accepted by our hospitalists and led to a significant reduction in SHE in high-risk diabetes patient groups at our hospital. It was cost effective and strengthened our physician-pharmacist relationship while improving diabetes care.

An expert-curated global database of online newspaper articles on spiders and spider bites.

Mass media plays an important role in the construction and circulation of risk perception associated with animals. Widely feared groups such as spiders frequently end up in the spotlight of traditional and social media. We compiled an expert-curated global database on the online newspaper coverage of human-spider encounters over the past ten years (2010-2020). This database includes information about the location of each human-spider encounter reported in the news article and a quantitative characterisation of the content-location, presence of photographs of spiders and bites, number and type of errors, consultation of experts, and a subjective assessment of sensationalism. In total, we collected 5348 unique news articles from 81 countries in 40 languages. The database refers to 211 identified and unidentified spider species and 2644 unique human-spider encounters (1121 bites and 147 as deadly bites). To facilitate data reuse, we explain the main caveats that need to be made when analysing this database and discuss research ideas and questions that can be explored with it.

ß spectrin-dependent and domain specific mechanisms for Na+ channel clustering.

Previously, we showed that a hierarchy of spectrin cytoskeletal proteins maintains nodal Na+ channels (Liu et al., 2020). Here, using mice lacking ß1, ß4, or ß1/ß4 spectrins, we show this hierarchy does not function at axon initial segments (AIS). Although ß1 spectrin, together with AnkyrinR (AnkR), compensates for loss of nodal ß4 spectrin, it cannot compensate at AIS. We show AnkR lacks the domain necessary for AIS localization. Whereas loss of ß4 spectrin causes motor impairment and disrupts AIS, loss of ß1 spectrin has no discernable effect on central nervous system structure or function. However, mice lacking both neuronal ß1 and ß4 spectrin show exacerbated nervous system dysfunction compared to mice lacking ß1 or ß4 spectrin alone, including profound disruption of AIS Na+ channel clustering, progressive loss of nodal Na+ channels, and seizures. These results further define the important role of AIS and nodal spectrins for nervous system function.

NuMA1 promotes axon initial segment assembly through inhibition of endocytosis.

Axon initial segments (AISs) initiate action potentials and regulate the trafficking of vesicles between somatodendritic and axonal compartments. However, the mechanisms controlling AIS assembly remain poorly defined. We performed differential proteomics and found nuclear mitotic apparatus protein 1 (NuMA1) is downregulated in AIS-deficient neonatal mouse brains and neurons. NuMA1 is transiently located at the AIS during development where it interacts with the scaffolding protein 4.1B and the dynein regulator lissencephaly 1 (Lis1). Silencing NuMA1 or protein 4.1B by shRNA disrupts AIS assembly, but not maintenance. Silencing Lis1 or overexpressing NuMA1 during AIS assembly increased the density of AIS proteins, including ankyrinG and neurofascin-186 (NF186). NuMA1 inhibits the endocytosis of AIS NF186 by impeding Lis1's interaction with doublecortin, a potent facilitator of NF186 endocytosis. Our results indicate the transient expression and AIS localization of NuMA1 stabilizes the developing AIS by inhibiting endocytosis and removal of AIS proteins.

The adhesion-GPCR BAI1 shapes dendritic arbors via Bcr-mediated RhoA activation causing late growth arrest.

Dendritic arbor architecture profoundly impacts neuronal connectivity and function, and aberrant dendritic morphology characterizes neuropsychiatric disorders. Here, we identify the adhesion-GPCR BAI1 as an important regulator of dendritic arborization. BAI1 loss from mouse or rat hippocampal neurons causes dendritic hypertrophy, whereas BAI1 overexpression precipitates dendrite retraction. These defects specifically manifest as dendrites transition from growth to stability. BAI1-mediated growth arrest is independent of its Rac1-dependent synaptogenic function. Instead, BAI1 couples to the small GTPase RhoA, driving late RhoA activation in dendrites coincident with growth arrest. BAI1 loss lowers RhoA activation and uncouples it from dendrite dynamics, causing overgrowth. None of BAI1's known downstream effectors mediates BAI1-dependent growth arrest. Rather, BAI1 associates with the Rho-GTPase regulatory protein Bcr late in development and stimulates its cryptic RhoA-GEF activity, which functions together with its Rac1-GAP activity to terminate arborization. Our results reveal a late-acting signaling pathway mediating a key transition in dendrite development.

Diltiazem Promotes Regenerative Axon Growth.

Axotomy results in permanent loss of function after brain and spinal cord injuries due to the minimal regenerative propensity of the adult central nervous system (CNS). To identify pharmacological enhancers of axon regeneration, 960 compounds were screened for cortical neuron axonal regrowth using an in vitro cortical scrape assay. Diltiazem, verapamil, and bromopride were discovered to facilitate axon regeneration in rat cortical cultures, in the presence of chondroitin sulfate proteoglycans (CSPGs). Diltiazem, an L-type calcium channel blocker (L-CCB), also promotes axon outgrowth in adult primary mouse dorsal root ganglion (DRG) and induced human sensory (iSensory) neurons.

Evaluation and management of adult acquired buried penis.

Adult acquired buried penis represents the clinical manifestation of a wide spectrum of pathology due to a variety of etiologies. It can be related to obesity, a laxity in connective tissue, lichen sclerosis (LS), complications from penile/scrotal enlargement surgery, scrotal lymphedema, or hidradenitis suppurativa (HS). Buried penis can be associated with poor cosmesis and hygiene, voiding dysfunction, and sexual dysfunction. Evaluation and management of buried penis largely depends on etiology and degree of affected tissue. It is an increasingly common problem seen by reconstructive urologists and here we present several frequently seen scenarios of buried penis and management options.

Axonal G3BP1 stress granule protein limits axonal mRNA translation and nerve regeneration.

Critical functions of intra-axonally synthesized proteins are thought to depend on regulated recruitment of mRNA from storage depots in axons. Here we show that axotomy of mammalian neurons induces translation of stored axonal mRNAs via regulation of the stress granule protein G3BP1, to support regeneration of peripheral nerves. G3BP1 aggregates within peripheral nerve axons in stress granule-like structures that decrease during regeneration, with a commensurate increase in phosphorylated G3BP1. Colocalization of G3BP1 with axonal mRNAs is also correlated with the growth state of the neuron. Disrupting G3BP functions by overexpressing a dominant-negative protein activates intra-axonal mRNA translation, increases axon growth in cultured neurons, disassembles axonal stress granule-like structures, and accelerates rat nerve regeneration in vivo.

αII Spectrin Forms a Periodic Cytoskeleton at the Axon Initial Segment and Is Required for Nervous System Function.

Spectrins form a submembranous cytoskeleton proposed to confer strength and flexibility to neurons and to participate in ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Neuronal spectrin cytoskeletons consist of diverse ß subunits and αII spectrin. Although αII spectrin is found in neurons in both axonal and somatodendritic domains, using proteomics, biochemistry, and superresolution microscopy, we show that αII and ßIV spectrin interact and form a periodic AIS cytoskeleton. To determine the role of spectrins in the nervous system, we generated Sptan1f/f mice for deletion of CNS αII spectrin. We analyzed αII spectrin-deficient mice of both sexes and found that loss of αII spectrin causes profound reductions in all ß spectrins. αII spectrin-deficient mice die before 1 month of age and have disrupted AIS and many other neurological impairments including seizures, disrupted cortical lamination, and widespread neurodegeneration. These results demonstrate the importance of the spectrin cytoskeleton both at the AIS and throughout the nervous system.SIGNIFICANCE STATEMENT Spectrin cytoskeletons play diverse roles in neurons, including assembly of excitable domains such as the axon initial segment (AIS) and nodes of Ranvier. However, the molecular composition and structure of these cytoskeletons remain poorly understood. Here, we show that αII spectrin partners with ßIV spectrin to form a periodic cytoskeleton at the AIS. Using a new αII spectrin conditional knock-out mouse, we show that αII spectrin is required for AIS assembly, neuronal excitability, cortical lamination, and to protect against neurodegeneration. These results demonstrate the broad importance of spectrin cytoskeletons for nervous system function and development and have important implications for nervous system injuries and diseases because disruption of the spectrin cytoskeleton is a common molecular pathology.

Bladder Recurrence of Clear Cell Sarcoma of the Kidney Seven Years After Initial Presentation.

Clear cell sarcoma of the kidney (CCSK) is the second most common pediatric renal malignancy after Wilms tumor. CCSK has the potential to metastasize to distant sites and was historically known as the bone metastasizing renal tumor. We report an exceedingly rare case of a bladder recurrence of CCSK. Our patient presented with gross hematuria 7 years after initial complete response. He was found to have a large sessile bladder tumor and underwent a partial cystectomy with right pelvic lymph node dissection. Final pathology was metastatic CCSK.

Loss of Frataxin activates the iron/sphingolipid/PDK1/Mef2 pathway in mammals.

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by mutations in Frataxin (FXN). Loss of FXN causes impaired mitochondrial function and iron homeostasis. An elevated production of reactive oxygen species (ROS) was previously proposed to contribute to the pathogenesis of FRDA. We recently showed that loss of frataxin homolog (fh), a Drosophila homolog of FXN, causes a ROS independent neurodegeneration in flies (Chen et al., 2016). In fh mutants, iron accumulation in the nervous system enhances the synthesis of sphingolipids, which in turn activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2) to trigger neurodegeneration of adult photoreceptors. Here, we show that loss of Fxn in the nervous system in mice also activates an iron/sphingolipid/PDK1/Mef2 pathway, indicating that the mechanism is evolutionarily conserved. Furthermore, sphingolipid levels and PDK1 activity are also increased in hearts of FRDA patients, suggesting that a similar pathway is affected in FRDA.

Leading by Success: Impact of a Clinical and Translational Research Infrastructure Program to Address Health Inequities.

Building research infrastructure capacity to address clinical and translational gaps has been a focus of funding agencies and foundations. Clinical and Translational Sciences Awards, Research Centers in Minority Institutions Infrastructure for Clinical and Translational Research (RCTR), and the Institutional Development Award Infrastructure for Clinical and Translational Research funded by the US government to fund clinical translational research programs have existed for over a decade to address racial and ethnic health disparities across the USA. While the impact on the nation's health cannot be made in a short period, assessment of a program's impact could be a litmus test to gauge its effectiveness at the institution and communities. We report the success of a Pilot Project Program in the University of Hawaii RCTR Award in advancing careers of emerging investigators and community collaborators. Our findings demonstrated that the investment has a far-reaching impact on engagement with community-based research collaborators, career advancement of health disparity investigators, and favorable impacts on health policy.

Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration.

Mutations in Frataxin (FXN) cause Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting that the mechanisms are evolutionarily conserved. Our results indicate that an iron/sphingolipid/Pdk1/Mef2 pathway may play a role in FRDA.

Testicular Leydig Cell Tumor with Metachronous Lesions: Outcomes after Metastasis Resection and Cryoablation.

Leydig cell tumors represent 3% of testicular masses and usually occur in prepubertal boys and men between 30 and 60 years of age. Leydig cell tumors are benign in children but can be malignant in 10% of adults. This case report describes a 41-year-old patient who was diagnosed with a Leydig cell tumor that originated in his right testicle that subsequently metastasized to his liver, lungs, and retroperitoneum. We discuss the patient's presentation and review the radiographic findings, surgical treatment, surgical pathology, chemotherapeutic treatment, and published literature on this rare pathology.

Axon initial segment-associated microglia.

Microglia are the brain's resident immune cells and function as the main defense against pathogens or injury. However, in the absence of disease, microglia have other functions in the normal brain. For example, previous studies showed that microglia contribute to circuit refinement and synaptic plasticity in the developing and adult brain, respectively. Thus, microglia actively participate in regulating neuronal excitability and function. Here, we report that in the cortex, but not other brain regions, a subset of microglia extend a single process that specifically associates and overlaps with the axon initial segment (AIS), the site where action potentials are generated. Similar associations were not observed with dendrites or distal axons. Microglia-AIS interactions appear early in development, persist throughout adulthood, and are conserved across species including mice, rats, and primates. However, these interactions are lost after microglial activation following brain injury, suggesting that such interactions may be part of healthy brain function. Loss of microglial CX3CR1 receptors, or the specialized extracellular matrix surrounding the AIS, did not disrupt the interaction. However, loss of AIS proteins by the neuron-specific deletion of the master AIS scaffold AnkyrinG disrupted microglia-AIS interactions. These results reveal a unique population of microglia that specifically interact with the AIS in the adult cortex.

A hierarchy of ankyrin-spectrin complexes clusters sodium channels at nodes of Ranvier.

The scaffolding protein ankyrin-G is required for Na(+) channel clustering at axon initial segments. It is also considered essential for Na(+) channel clustering at nodes of Ranvier to facilitate fast and efficient action potential propagation. However, notwithstanding these widely accepted roles, we show here that ankyrin-G is dispensable for nodal Na(+) channel clustering in vivo. Unexpectedly, in the absence of ankyrin-G, erythrocyte ankyrin (ankyrin-R) and its binding partner ßI spectrin substitute for and rescue nodal Na(+) channel clustering. In addition, channel clustering is also rescued after loss of nodal ßIV spectrin by ßI spectrin and ankyrin-R. In mice lacking both ankyrin-G and ankyrin-R, Na(+) channels fail to cluster at nodes. Thus, ankyrin R-ßI spectrin protein complexes function as secondary reserve Na(+) channel clustering machinery, and two independent ankyrin-spectrin protein complexes exist in myelinated axons to cluster Na(+) channels at nodes of Ranvier.

Smoking and risk of low- and high-grade prostate cancer: results from the REDUCE study.

PURPOSE: Although the relationship between smoking and prostate cancer risk is inconsistent, some studies show that smoking is associated with prostate cancer mortality. Whether this reflects delayed diagnosis or direct smoking-related effects is unknown. REDUCE, which followed biopsy-negative men with protocol-dictated prostate-specific antigen (PSA)-independent biopsies at 2 and 4 years, provides an opportunity to evaluate smoking and prostate cancer diagnosis with minimal confounding from screening biases. EXPERIMENTAL DESIGN: Logistic regression was conducted to test the association between smoking and cancer on the first on-study biopsy (no cancer, low-grade Gleason 4-6, high-grade Gleason 7-10) in REDUCE. RESULTS: Of 6,240 men with complete data and ≥1 on-study biopsy, 2,937 (45.8%) never smoked, 929 (14.5%) were current smokers, and 2,554 (39.8%) were former smokers. Among men with negative first on-study biopsies, smokers were 36% less likely to receive a second on-study biopsy (P < 0.001). At first on-study biopsy, 941 (14.7%) men had cancer. Both current and former smoking were not significantly associated with either total or low-grade prostate cancer (all P > 0.36). Current (OR = 1.44, P = 0.028) but not former smokers (OR = 1.21, P = 0.12) were at increased risk of high-grade disease. On secondary analysis, there was an interaction between smoking and body mass index (BMI; Pinteraction = 0.017): current smokers with BMI ≤ 25 kg/m(2) had an increased risk of low-grade (OR = 1.54, P = 0.043) and high-grade disease (OR = 2.45, P = 0.002), with null associations for BMI ≥ 25 kg/m(2). CONCLUSION: Among men with elevated PSA and negative pre-study biopsy in REDUCE, in which biopsies were largely PSA independent, smoking was unrelated to overall prostate cancer diagnosis but was associated with increased risk of high-grade prostate cancer.