Neurons of the mammalian central nervous system fail to regenerate. Substantial progress has been made toward identifying the cellular and molecular mechanisms that underlie regenerative failure and how altering those pathways can promote cell survival and/or axon regeneration. Here, we summarize those findings while comparing the regenerative process in the central versus the peripheral nervous system. We also highlight studies that advance our understanding of the mechanisms underlying neural degeneration in response to injury, as many of these mechanisms represent primary targets for restoring functional neural circuits.

Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1.

Author information: (1)Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: alexis.combes@ucsf.edu. (2)Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA. (3)ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA. (4)UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA. (5)Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (6)Aix Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France. (7)UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA. (8)Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. (9)UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Obstetrics, Gynecology, and Reproductive Sciences, Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (10)UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (11)UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (12)Department of Medicine, Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA. (13)Department of Otolaryngology, University of California, San Francisco, San Francisco, CA 94143, USA. (14)Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA. (15)ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA. (16)ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine Division of Rheumatology, University of California, San Francisco, San Francisco, CA 94143, USA. (17)ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; Lung Biology Center, Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA. (18)Sorbonne Université, INSERM, CNRS, Centre d'Immunologie et des Maladies Infectieuses-CIMI, Paris, France. (19)UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA. (20)ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. (21)Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: matthew.krummel@ucsf.edu.

Brain-derived neurotrophic factor (BDNF) is a neuropeptide that plays numerous important roles in synaptic development and plasticity. While its importance in fundamental physiology is well established, studies of BDNF often produce conflicting and unclear results, and the scope of existing research makes the prospect of setting future directions daunting. In this review, we examine the importance of spatial and temporal factors on BDNF activity, particularly in processes such as synaptogenesis, Hebbian plasticity, homeostatic plasticity, and the treatment of psychiatric disorders. Understanding the fundamental physiology of when, where, and how BDNF acts and new approaches to control BDNF signaling in time and space can contribute to improved therapeutics and patient outcomes.

Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized "pattern-block" correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.

Recent progress in fluorescence imaging allows neuroscientists to observe the dynamics of thousands of individual neurons, identified genetically or by their connectivity, across multiple brain areas and for extended durations in awake behaving mammals. We discuss advances in fluorescent indicators of neural activity, viral and genetic methods to express these indicators, chronic animal preparations for long-term imaging studies, and microscopes to monitor and manipulate the activity of large neural ensembles. Ca2+ imaging studies of neural activity can track brain area interactions and distributed information processing at cellular resolution. Across smaller spatial scales, high-speed voltage imaging reveals the distinctive spiking patterns and coding properties of targeted neuron types. Collectively, these innovations will propel studies of brain function and dovetail with ongoing neuroscience initiatives to identify new neuron types and develop widely applicable, non-human primate models. The optical toolkit's growing sophistication also suggests that "brain observatory" facilities would be useful open resources for future brain-imaging studies.

Contrary to multicellular organisms that display segmentation during development, communities of unicellular organisms are believed to be devoid of such sophisticated patterning. Unexpectedly, we find that the gene expression underlying the nitrogen stress response of a developing Bacillus subtilis biofilm becomes organized into a ring-like pattern. Mathematical modeling and genetic probing of the underlying circuit indicate that this patterning is generated by a clock and wavefront mechanism, similar to that driving vertebrate somitogenesis. We experimentally validated this hypothesis by showing that predicted nutrient conditions can even lead to multiple concentric rings, resembling segments. We additionally confirmed that this patterning mechanism is driven by cell-autonomous oscillations. Importantly, we show that the clock and wavefront process also spatially patterns sporulation within the biofilm. Together, these findings reveal a biofilm segmentation clock that organizes cellular differentiation in space and time, thereby challenging the paradigm that such patterning mechanisms are exclusive to plant and animal development.

Comment in Nat Rev Genet. 2022 Mar;23(3):136.

Comment in Nat Rev Drug Discov. 2022 Feb;21(2):96. Cell Host Microbe. 2022 Feb 9;30(2):148-150.

The NIH BRAIN Initiative is entering a new phase. Three large new projects-a comprehensive human brain cell atlas, a whole mammalian brain microconnectivity map, and tools for precision access to brain cell types-promise to transform neuroscience research and the treatment of human brain disorders.

Update of bioRxiv. 2021 Oct 24;:

Small molecule chaperones have been exploited as therapeutics for the hundreds of diseases caused by protein misfolding. The most successful examples are the CFTR correctors, which transformed cystic fibrosis therapy. These molecules revert folding defects of the ΔF508 mutant and are widely used to treat patients. To investigate the molecular mechanism of their action, we determined cryo-electron microscopy structures of CFTR in complex with the FDA-approved correctors lumacaftor or tezacaftor. Both drugs insert into a hydrophobic pocket in the first transmembrane domain (TMD1), linking together four helices that are thermodynamically unstable. Mutating residues at the binding site rendered ΔF508-CFTR insensitive to lumacaftor and tezacaftor, underscoring the functional significance of the structural discovery. These results support a mechanism in which the correctors stabilize TMD1 at an early stage of biogenesis, prevent its premature degradation, and thereby allosterically rescuing many disease-causing mutations.

Comment in Nature. 2022 Oct;610(7931):265-266.

Comment in J Assist Reprod Genet. 2022 Apr;39(4):779-780.

Comment in Nature. 2022 Mar;603(7899):37-38.

Comment in Trends Mol Med. 2022 Mar;28(3):171-172. Nat Rev Drug Discov. 2022 Mar;21(3):177. Commun Biol. 2022 Apr 27;5(1):392. Signal Transduct Target Ther. 2022 Aug 12;7(1):279.

Comment in Nat Rev Mol Cell Biol. 2022 Mar;23(3):167. Nat Rev Gastroenterol Hepatol. 2022 Apr;19(4):216. Signal Transduct Target Ther. 2022 Apr 22;7(1):127.

Comment in Immunity. 2022 Feb 8;55(2):198-200. Nat Rev Gastroenterol Hepatol. 2022 May;19(5):281-282.

Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune cells. Surprisingly, myoepithelial disruption was more advanced in DCIS patients that did not develop IBC, suggesting this process could be protective against recurrence. Taken together, this HTAN Breast PreCancer Atlas study offers insight into drivers of IBC relapse and emphasizes the importance of the TME in regulating these processes.

Comment on Science. 2021 Dec 17;374(6574):1509-1513.

Comment in Cell. 2022 Jan 20;185(2):227-229.

Locomotion is a complex behavior required for animal survival. Vertebrate locomotion depends on spinal interneurons termed the central pattern generator (CPG), which generates activity responsible for the alternation of flexor and extensor muscles and the left and right side of the body. It is unknown whether multiple or a single neuronal type is responsible for the control of mammalian locomotion. Here, we show that ventral spinocerebellar tract neurons (VSCTs) drive generation and maintenance of locomotor behavior in neonatal and adult mice. Using mouse genetics, physiological, anatomical, and behavioral assays, we demonstrate that VSCTs exhibit rhythmogenic properties and neuronal circuit connectivity consistent with their essential role in the locomotor CPG. Importantly, optogenetic activation and chemogenetic silencing reveals that VSCTs are necessary and sufficient for locomotion. These findings identify VSCTs as critical components for mammalian locomotion and provide a paradigm shift in our understanding of neural control of complex behaviors.

Comment in Cell. 2022 Jan 20;185(2):230-231.

Charleese Williams is the winner of the 2021 Rising Black Scientists Award for an undergraduate scholar. For this award, we asked emerging Black scientists to tell us about the experiences that sparked their interest in the life sciences, their vision and goals, and how they want to contribute to a more inclusive scientific community. This is her story.

Comment in Nat Methods. 2022 Mar;19(3):271.

Elle Lett is the winner of the 2021 Rising Black Scientists Award for a post-graduate scholar. For this award, we asked emerging Black scientists to tell us about the experiences that sparked their interest in the life sciences, their vision and goals, and how they want to contribute to a more inclusive scientific community. This is her story.

Comment on Cell. 2022 Jan 20;185(2):361-378.e25.

Comment on Cell. 2022 Jan 20;185(2):266-282.e15.