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Autosomal dominant mutations of the RNA/DNA binding protein FUS are linked to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how FUS mutations cause neurodegeneration. Using transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C mice), we found that mutant FUS proteins formed a stable complex with WT FUS proteins and interfered with the normal interactions between FUS and histone deacetylase 1 (HDAC1). Consequently, FUS-R521C mice exhibited evidence of DNA damage as well as profound dendritic and synaptic phenotypes in brain and spinal cord. To provide insights into these defects, we screened neural genes for nucleotide oxidation and identified brain-derived neurotrophic factor (Bdnf) as a target of FUS-R521C-associated DNA damage and RNA splicing defects in mice. Compared with WT FUS, mutant FUS-R521C proteins formed a more stable complex with Bdnf RNA in electrophoretic mobility shift assays. Stabilization of the FUS/Bdnf RNA complex contributed to Bdnf splicing defects and impaired BDNF signaling through receptor TrkB. Exogenous BDNF only partially restored dendrite phenotype in FUS-R521C neurons, suggesting that BDNF-independent mechanisms may contribute to the defects in these neurons. Indeed, RNA-seq analyses of FUS-R521C spinal cords revealed additional transcription and splicing defects in genes that regulate dendritic growth and synaptic functions. Together, our results provide insight into how gain-of-function FUS mutations affect critical neuronal functions.

PurposeComplementary and alternative medicine (CAM) use is common amongst cancer patients. However, there is growing concern about its safety and efficacy. Online crowdfunding campaigns represent a unique avenue to understand the cancer patient’s perspective for using CAM or declining conventional cancer therapy (CCT).MethodsFive hundred GoFundMe campaigns from 2012 to 2019 detailing financial need for cancer treatment were randomly selected and reviewed for endorsement of CAM use, reasons for using CAM, and reasons for declining CCT. Descriptive statistics were used to compare patient and campaign characteristics between 250 CAM users and 250 non-CAM users.ResultsCompared to non-CAM users, CAM users were more likely to be female (70% vs. 54%, p < 0.01), to report more stage IV cancer (54% vs. 12%, p < 0.01), and to have a history of delayed, missed, or misdiagnosis (10% vs. 4%, p < 0.01). Reasons for using CAM include endorsing curative/therapeutic effects 212 (85%), pain/stress reduction 137 (55%), and dissatisfaction with current or past medical treatment options 105 (42%). 87 (35%) CAM users that declined CCT reported that they wanted to try to fight off cancer using CAM first 57 (61%), that CCT was too “toxic” to the body 39 (42%), and cancer was already too advanced, so that CCT would be futile or too aggressive 25 (27%).ConclusionCancer patients on GoFundMe using CAM highly value quality of life, comfort, and autonomy. Physicians should educate themselves on CAM to set realistic expectations and provide comprehensive counseling of the risks and benefits of CAM usage to patients who choose to use CAM to either augment or completely replace CCT.

Despite widespread recognition and known harms, serious surgical errors, known as surgical never events, endure. The California Department of Public Health (CDPH) has developed an oversight system to capture never events and a platform for process improvement that has not yet been critically appraised. To examine surgical never events occurring in hospitals in California and summarize recommendations to prevent future events. This cross-sectional study identified 386 CDPH hospital administrative penalty reports, of which 142 were ascribable to never events occurring during surgery. These never events were identified and summarized from January 1, 2007, to December 31, 2017. A directed qualitative approach was used to analyze CDPH-mandated corrective steps to reduce future errors in this multicenter study of all accredited hospitals in California. Inclusion of surgical never event records was based on definitions established by the US Department of Health and Human Services National Quality Forum. Data analysis was performed from January 1, 2019, to November 30, 2020. Never events include death or disability of an American Society of Anesthesiologists class I patient, wrong site or wrong surgery, retained foreign objects, burns, equipment failure leading to intraoperative injury, nonapproved experimental procedures, insufficient surgeon presence or privileges, or fall from the operating room table. Incident rates, consequences, and improvement plans to prevent additional never events were outcomes of interest. A total of 142 never events were reported to the CDPH (1 per 200 000 operations). Annual surgical volume for hospitals with events was 9203 vs 3251 cases for hospitals without events (P < .001). A total of 94 of 142 events (66.2%) were retained foreign objects ranging from Kocher clamps to drain sponges. Wrong site or patient surgery accounted for 22 events (15.5%), surgical burns for 11 (7.7%), and other for 15 (10.6%). Other included insufficient surgeon presence, equipment failure, or falls in the operating room. Improvement plans included 18 unique categories of recommendations from regulators, many focusing on proper use of checklists. Regulators mandated a mean (SD) of 13 (7) corrective actions in the improvement plans. Policy adherence monitoring (119 [90.2%]), revision of existing policy (84 [63.6%]), and education regarding policy (83 [62.9%]) were common action items, whereas disciplinary action toward staff was rare (11 [8.3%]). Surgical never events are a rare issue in California. Numerous strategies have evolved to reduce errors, many involving the thorough and proper use of intraoperative checklists.

Neurons in the developing rodent cortex are generated from radial glial cells that function as neural stem cells. These epithelial cells line the cerebral ventricles and generate intermediate progenitor cells that migrate into the subventricular zone (SVZ) and proliferate to increase neuronal number. The developing human SVZ has a massively expanded outer region (OSVZ) thought to contribute to cortical size and complexity. However, OSVZ progenitor cell types and their contribution to neurogenesis are not well understood. Here we show that large numbers of radial glia-like cells and intermediate progenitor cells populate the human OSVZ. We find that OSVZ radial glia-like cells have a long basal process but, surprisingly, are non-epithelial as they lack contact with the ventricular surface. Using real-time imaging and clonal analysis, we demonstrate that these cells can undergo proliferative divisions and self-renewing asymmetric divisions to generate neuronal progenitor cells that can proliferate further. We also show that inhibition of Notch signalling in OSVZ progenitor cells induces their neuronal differentiation. The establishment of non-ventricular radial glia-like cells may have been a critical evolutionary advance underlying increased cortical size and complexity in the human brain. Evolving the human brain The human cerebral cortex is large and complex compared to other mammals, and these features underlie our cognitive abilities. What developmental process accounts for the large increase in the number of nerve cells produced? The subventricular zone (SVZ) in the mammalian brain produces neural progenitor cells that migrate to populate the upper layers of the brain. This region is massively expanded in humans, producing an outer SVZ (OSVZ) that may contribute to overall cortical size and complexity. Live-cell imaging of developing human tissue shows that the OSVZ has characteristics very similar to the SVZ, with large numbers of progenitor cells multiplying in a notch signalling-dependent manner. The establishment of a non-ventricular progenitor cell population may have been a significant evolutionary step towards the development of the human brain. In the mammalian brain, the subventricular zone (SVZ) produces neural progenitor cells that migrate into the cortex to populate the upper layers. In humans this region is massively expanded, producing an outer SVZ (OSVZ). Here, live-cell imaging of developing human tissue was used to show that the OSVZ has similar characteristics to the SVZ, with progenitor cells proliferating in a way that depends on the Notch protein. The findings have implications for our understanding of how the complex human brain evolved.

GABAergic cortical interneurons have important roles in the computations of neural circuits, but their developmental origin in primates is controversial. Here the authors characterize neural stem cell and progenitor cell organization in the developing human ganglionic eminences and reveal that, just as in rodents, they give rise to a majority of cortical GABAergic neurons. GABAergic cortical interneurons underlie the complexity of neural circuits and are particularly numerous and diverse in humans. In rodents, cortical interneurons originate in the subpallial ganglionic eminences, but their developmental origins in humans are controversial. We characterized the developing human ganglionic eminences and found that the subventricular zone (SVZ) expanded massively during the early second trimester, becoming densely populated with neural stem cells and intermediate progenitor cells. In contrast with the cortex, most stem cells in the ganglionic eminence SVZ did not maintain radial fibers or orientation. The medial ganglionic eminence exhibited unique patterns of progenitor cell organization and clustering, and markers revealed that the caudal ganglionic eminence generated a greater proportion of cortical interneurons in humans than in rodents. On the basis of labeling of newborn neurons in slice culture and mapping of proliferating interneuron progenitors, we conclude that the vast majority of human cortical interneurons are produced in the ganglionic eminences, including an enormous contribution from non-epithelial SVZ stem cells.

The human neocortex is increased in size and complexity as compared with most other species. Neocortical expansion has recently been attributed to protracted neurogenesis by outer radial glial cells in the outer subventricular zone, a region present in humans but not in rodents. The mechanisms of human outer radial glial cell generation are unknown, but are proposed to involve division of ventricular radial glial cells; neural stem cells present in all developing mammals. Here we show that human ventricular radial glial cells produce outer radial glial cells and seed formation of the outer subventricular zone via horizontal divisions, which occur more frequently in humans than in rodents. We further find that outer radial glial cell mitotic behaviour is cell intrinsic, and that the basal fibre, inherited by outer radial glial cells after ventricular radial glial division, determines cleavage angle. Our results suggest that altered regulation of mitotic spindle orientation increased outer radial glial cell number, and ultimately neuronal number, during human brain evolution. Human neocortex expansion is partly due to neuronal production by outer radial glial cells. In the developing human cortex, LaMonica et al . find that horizontal divisions of ventricular radial glial cells produce outer radial glial cells displaying cell-intrinsic regulation of mitosis and spindle orientation.

Genome modifications are central components of the continuous arms race between viruses and their hosts. The archaeosine base (G + ), which was thought to be found only in archaeal tRNAs, was recently detected in genomic DNA of Enterobacteria phage 9g and was proposed to protect phage DNA from a wide variety of restriction enzymes. In this study, we identify three additional 2′-deoxy-7-deazaguanine modifications, which are all intermediates of the same pathway, in viruses: 2′-deoxy-7-amido-7-deazaguanine (dADG), 2′-deoxy-7-cyano-7-deazaguanine (dPreQ 0 ) and 2′-deoxy-7- aminomethyl-7-deazaguanine (dPreQ 1 ). We identify 180 phages or archaeal viruses that encode at least one of the enzymes of this pathway with an overrepresentation (60%) of viruses potentially infecting pathogenic microbial hosts. Genetic studies with the Escherichia phage CAjan show that DpdA is essential to insert the 7-deazaguanine base in phage genomic DNA and that 2′-deoxy-7-deazaguanine modifications protect phage DNA from host restriction enzymes. Viral genomic DNA is often modified to evade the host bacterial restriction system. Here the authors identified 2′-deoxy-7-deazaguanine modifications on phage DNA by comparative genomics and experimental validation, showing their role in genome protection.

Improving speed and image quality of Magnetic Resonance Imaging (MRI) using deep learning reconstruction is an active area of research. The fastMRI dataset contains large volumes of raw MRI data, which has enabled significant advances in this field. While the impact of the fastMRI dataset is unquestioned, the dataset currently lacks clinical expert pathology annotations, critical to addressing clinically relevant reconstruction frameworks and exploring important questions regarding rendering of specific pathology using such novel approaches. This work introduces fastMRI+, which consists of 16154 subspecialist expert bounding box annotations and 13 study-level labels for 22 different pathology categories on the fastMRI knee dataset, and 7570 subspecialist expert bounding box annotations and 643 study-level labels for 30 different pathology categories for the fastMRI brain dataset. The fastMRI+ dataset is open access and aims to support further research and advancement of medical imaging in MRI reconstruction and beyond. Measurement(s) Pathotology annotations in knee and brain MRI images Technology Type(s) Expert delineation

CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50–650 mg/m 2 ) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m 2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977. G-quadruplex stabilizers, including CX-5461, exhibit synthetic lethality with loss of BRCA1/2 in preclinical models. Here the authors report the results of a phase I study of CX-5461 in patients with solid tumors enriched for DNA-repair deficiencies.