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tis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. INTERPRETATION The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. FUNDING Eli Lilly and Company. Aberrant metabolism is a key factor in many neurological disorders. The ability to measure such metabolic impairment could lead to improved detection of disease progression, and development and monitoring of new therapeutic approaches. Hyperpolarized 13C magnetic resonance spectroscopy (MRS) is a developing imaging technique that enables non-invasive measurement of enzymatic activity in real time in living organisms. Primarily applied in the fields of cancer and cardiac disease so far, this metabolic imaging method has recently been used to investigate neurological disorders. In this review, we summarize the preclinical research developments in this emerging field, and discuss future prospects for this exciting technology, which has the potential to change the clinical paradigm for patients with neurological disorders. Published by Elsevier Ltd.Autism spectrum disorder (ASD) is a largely heritable, multistage prenatal disorder that impacts a child's ability to perceive and react to social information. Most ASD risk genes are expressed prenatally in many ASD-relevant brain regions and fall into two categories broadly expressed regulatory genes that are expressed in the brain and other organs, and brain-specific genes. In trimesters one to three (Epoch-1), one set of broadly expressed (the majority) and brain-specific risk genes disrupts cell proliferation, neurogenesis, migration, and cell fate, while in trimester three and early postnatally (Epoch-2) another set (the majority being brain specific) disrupts neurite outgrowth, synaptogenesis, and the 'wiring' of the cortex. A proposed model is that upstream, highly interconnected regulatory ASD gene mutations disrupt transcriptional programs or signaling pathways resulting in dysregulation of downstream processes such as proliferation, neurogenesis, synaptogenesis, and neural activity. Dysregulation of signaling pathways is correlated with ASD social symptom severity. Since the majority of ASD risk genes are broadly expressed, many ASD individuals may benefit by being treated as having a broader medical disorder. An important future direction is the noninvasive study of ASD cell biology. The peripheral somatosensory system bestows mammals with a diverse repertoire of sensory modalities gentle touch, mechanical pain, itch, thermosensation, and proprioception. The cells and molecules that transduce many of these stimuli have already been characterized. But how somatosensory neurons transduce acutely painful mechanical forces is largely unknown and remains one of the 'final frontiers' of sensory neurobiology. In an effort to fill this gap in knowledge, recent studies have identified subpopulations of mechanical pain neurons and uncovered novel modulators of mechanical pain. These studies have greatly advanced our understanding of how noxious mechanical stimuli are detected in mammals. Here, we discuss recent progress in noxious mechanosensation and highlight new behavioral methods to assess mechanical pain. Sex as a biological variable (SABV) is critical for understanding the broad range of physiological, neurobiological, and behavioral consequences of early life adversity(ELA). The study of the interaction of SABV and ELA ties into several current debates, including the importance of taking into account SABV in research, differing strategies employed by males and females in response to adversity, and the possible evolutionary and developmental mechanisms of altered development in response to adversity. This review highlights the importance of studying both sexes, of understanding sex differences (and similarities) in response to ELA, and provides a context for the debate surrounding whether the response to ELA may be an adaptive process. To compare findings across species, neuroscience relies on cross-species homologies, particularly in terms of brain areas. For cingulate cortex, a structure implicated in behavioural adaptation and control, a homologous definition across mammals is available - but currently not employed by most rodent researchers. The standard partitioning of rodent cingulate cortex is inconsistent with that in any other model species, including humans. Reviewing the existing literature, we show that the homologous definition better aligns results of rodent studies with those of other species, and reveals a clearer structural and functional organisation within rodent cingulate cortex itself. Based on these insights, we call for widespread adoption of the homologous nomenclature, and reinterpretation of previous studies originally based on the nonhomologous partitioning of rodent cingulate cortex. Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease but currently has no effective treatment. Growing evidence suggests that proteome homeostasis underlies ALS pathogenesis. Protein production, trafficking, and degradation all shape the proteome. We present a hypothesis that proposes all genetic lesions associated with ALS (including in mRNA-binding proteins) cause widespread imbalance to an already metastable proteome. The impact of such dysfunction is felt across the entire proteome and is not restricted to a small subset of proteins. Proteome imbalance may cause functional defects, such as excitability alterations, and eventually cell death. While this idea is a unifying principle for all of ALS, we propose that stratification will appear that might dictate the efficacy of therapeutics based on the proteostasis network. People organize and convey their thoughts according to narratives. However, neuroscientists are often reluctant to incorporate narrative stimuli into their experiments. We argue that narratives deserve wider adoption in human neuroscience because they tap into the brain's native machinery for representing the world and provide rich variability for testing hypotheses. Implanted neural probes are among the most important techniques in both fundamental and clinical neuroscience. Despite great successes and promise, neural electrodes are technically limited by their scalability. A recent study by Obaid et al. demonstrated an innovative way to greatly scale up the channel count and density of neural electrode arrays. Developmental and epileptic encephalopathy (DEE) associated with de novo variants in the gene encoding dynamin-1 (DNM1) is a severe debilitating disease with no pharmacological remedy. Like most genetic DEEs, the majority of DNM1 patients suffer from therapy-resistant seizures and comorbidities such as intellectual disability, developmental delay, and hypotonia. We tested RNAi gene therapy in the Dnm1 fitful mouse model of DEE using a Dnm1-targeted therapeutic microRNA delivered by a self-complementary adeno-associated virus vector. Untreated or control-injected fitful mice have growth delay, severe ataxia, and lethal tonic-clonic seizures by 3 weeks of age. These major impairments are mitigated following a single treatment in newborn mice, along with key underlying cellular features including gliosis, cell death, and aberrant neuronal metabolic activity typically associated with recurrent seizures. Our results underscore the potential for RNAi gene therapy to treat DNM1 disease and other genetic DEEs where treatment would require inhibition of the pathogenic gene product. Retinal pigment epithelial (RPE) cell replacement therapy has provided promising outcomes in the treatment of retinal degenerative diseases (RDDs), but the resulting limited visual improvement has raised questions about graft survival and differentiation. Through combined treatment with vitamin C and valproic acid (together, VV), we activated human fetal RPE (fRPE) cells to become highly proliferative fetal RPE stem-like cells (fRPESCs). In this study, we report that SOX2 (SRY-box 2) activation contributed to mesenchymal-epithelial transition and elevated the retinal progenitor and mesenchymal stromal markers expressions of fRPESCs. These fRPESCs could differentiate into RPE cells, rod photoreceptors, and mesenchymal lineage progenies under defined conditions. Finally, fRPESCs were transplanted into the subretinal space of an RDD mouse model, and a photoreceptor rescue benefit was demonstrated. The RPE and rod photoreceptor differentiation of transplanted fRPESCs may account for the neural retinal recovery. This study establishes fRPESCs as a highly proliferative, multi-lineage differentiation potential (including RPE, rod photoreceptor, and mesenchymal lineage differentiation), mesenchymal-to-epithelial-transitioned retinal stem-like cell source for cell-based therapy of RDDs. Adenine base editor (ABE) is a new generation of genome-editing technology through fusion of Cas9 nickase with an evolved E. coli TadA (TadA∗) and holds great promise as novel genome-editing therapeutics for treating genetic disorders. ABEs can directly convert A-T to G-C in specific genomic DNA targets without introducing double-strand breaks (DSBs). We recently showed that computer program-assisted analysis of Sanger sequencing traces can be used as a low-cost and rapid alternative of deep sequencing to assess base-editing outcomes. Here we developed a rapid fluorescence-based reporter assay (Base Editing ON [BEON]) to quantify ABE efficiency. The assay relies on the restoration of the downstream green fluorescent protein (GFP) in ABE-mediated editing of a stop codon located within the guide RNA (gRNA). selleck chemicals llc We showed that this assay can be used to screen for effective ABE variants, characterize the protospacer adjacent motif (PAM) requirement of a novel NNG-targeting ABE based on ScCas9, and enrich for edited cells. Finally, we demonstrated that the reporter assay allowed us to assess the feasibility of ABE editing to correct point mutations associated with dysferlinopathy. Taken together, the BEON assay would facilitate and simplify the studies with ABEs. Severed CNS axons fail to regenerate in adult mammals and there are no effective regenerative strategies to treat patients with CNS injuries. Several genes, including phosphatase and tensin homolog (PTEN) and Krüppel-like factors, regulate intrinsic growth capacity of mature neurons. The Lin28 gene is essential for cell development and pluripotency in worms and mammals. In this study, we evaluated the role of Lin28a in regulating regenerative capacity of diverse populations of CNS neurons in adult mammals. Using a neuron-specific Thy1 promoter, we generated transgenic mice that overexpress Lin28a protein in multiple populations of projection neurons, including corticospinal tracts and retinal ganglion cells. We demonstrate that upregulation of Lin28a in transgenic mice induces significant long distance regeneration of both corticospinal axons and the optic nerve in adult mice. Importantly, overexpression of Lin28a by post-injury treatment with adeno-associated virus type 2 (AAV2) vector stimulates dramatic regeneration of descending spinal tracts and optic nerve axons after lesions.