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1. Neuropeptide Y signaling regulates recurrent excitation in the auditory midbrain

   https://doi.org/10.1523/JNEUROSCI.0900-23.2023  

   Silveira, Marina A. ; Drotos, Audrey C. ; Pirrone, Trinity M. ; Versalle, Trevor S. ; Bock, Amanda ; Roberts, Michael T. ( September 2023 , The Journal of Neuroscience)

   Neuropeptides play key roles in shaping the organization and function of neuronal circuits. In the inferior colliculus (IC), which is in the auditory midbrain, Neuropeptide Y (NPY) is expressed by a class of GABAergic neurons that project locally and outside the IC. Most neurons in the IC have local axon collaterals, however the organization and function of local circuits in the IC remain unknown. We previously found that excitatory neurons in the IC can express the NPY Y₁receptor (Y₁R⁺) and application of the Y₁R agonist, [Leu³¹, Pro³⁴]-NPY (LP-NPY), decreases the excitability of Y₁R⁺neurons. Since NPY signaling regulates recurrent excitation in other brain regions, we hypothesized that Y₁R⁺neurons form interconnected local circuits in the IC and that NPY decreases the strength of recurrent excitation in this circuits. To test this hypothesis, we used optogenetics to activate Y₁R⁺neurons in mice of both sexes while recording from other neurons in the ipsilateral IC. We found that nearly 80% of glutamatergic IC neurons express the Y₁receptor, providing extensive opportunities for NPY signaling to regulate local circuits. Additionally, Y₁R⁺neuron synapses exhibited modest short-term synaptic plasticity, suggesting that local excitatory circuits maintain their influence over computations during sustained stimuli. We further found that application of LP-NPY decreased recurrent excitation in the IC, suggesting that NPY signaling strongly regulates local circuit function in the auditory midbrain. Our show that Y₁R⁺excitatory neurons form interconnected local circuits in the IC, and their influence over local circuits is regulated by NPY signaling.

   Significance Statement

   Local networks play fundamental roles in shaping neuronal computations in the brain. The inferior colliculus (IC), localized in the auditory midbrain, plays an essential role in sound processing, but the organization of local circuits in the IC is largely unknown. Here we show that IC neurons that express the Neuropeptide Y₁receptor (Y₁R⁺neurons) comprise most of the excitatory neurons in the IC and form interconnected local circuits. Additionally, we found that NPY, which is a powerful neuromodulator known to shape neuronal activity in other brain regions, decreases the extensive recurrent excitation mediated by Y₁R⁺neurons in local IC circuits. Thus, our results suggest that local NPY signaling is a key regulator of auditory computations in the IC.

    

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2. Mapping of neuropeptide Y expression in Octopus brains

   https://doi.org/10.1002/jmor.21141  

   Winters, Gabrielle C. ; Polese, Gianluca ; Di Cosmo, Anna ; Moroz, Leonid L. ( May 2020 , Journal of Morphology)

   Neuropeptide Y (NPY) is an evolutionarily conserved neurosecretory molecule implicated in a diverse complement of functions across taxa and in regulating feeding behavior and reproductive maturation inOctopus. However, little is known about the precise molecular circuitry of NPY‐mediated behaviors and physiological processes, which likely involve a complex interaction of multiple signal molecules in specific brain regions. Here, we examined the expression of NPY throughout theOctopuscentral nervous system. The sequence analysis ofOctopusNPY precursor confirmed the presence of both, signal peptide and putative active peptides, which are highly conserved across bilaterians.In situhybridization revealed distinct expression of NPY in specialized compartments, including potential “integration centers,” where visual, tactile, and other behavioral circuitries converge. These centers integrating separate circuits may maintain and modulate learning and memory or other behaviors not yet attributed to NPY‐dependent modulation inOctopus. Extrasomatic localization of NPY mRNA in the neurites of specific neuron populations in the brain suggests a potential demand for immediate translation at synapses and a crucial temporal role for NPY in these cell populations. We also documented the presence of NPY mRNA in a small cell population in the olfactory lobe, which is a component of theOctopusfeeding and reproductive control centers. However, the molecular mapping of NPY expression only partially overlapped with that produced by immunohistochemistry in previous studies. Our study provides a precise molecular map of NPY mRNA expression that can be used to design and test future hypotheses about molecular signaling in variousOctopusbehaviors.

    

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3. Structural basis of HIV-1 maturation inhibitor binding and activity

   https://doi.org/10.1038/s41467-023-36569-y  

   Sarkar, Sucharita ; Zadrozny, Kaneil K. ; Zadorozhnyi, Roman ; Russell, Ryan W. ; Quinn, Caitlin M. ; Kleinpeter, Alex ; Ablan, Sherimay ; Meshkin, Hamed ; Perilla, Juan R. ; Freed, Eric O. ; et al ( March 2023 , Nature Communications)

   HIV-1 maturation inhibitors (MIs), Bevirimat (BVM) and its analogs interfere with the catalytic cleavage of spacer peptide 1 (SP1) from the capsid protein C-terminal domain (CA_CTD), by binding to and stabilizing the CA_CTD-SP1 region. MIs are under development as alternative drugs to augment current antiretroviral therapies. Although promising, their mechanism of action and associated virus resistance pathways remain poorly understood at the molecular, biochemical, and structural levels. We report atomic-resolution magic-angle-spinning NMR structures of microcrystalline assemblies of CA_CTD-SP1 complexed with BVM and/or the assembly cofactor inositol hexakisphosphate (IP6). Our results reveal a mechanism by which BVM disrupts maturation, tightening the 6-helix bundle pore and quenching the motions of SP1 and the simultaneously bound IP6. In addition, BVM-resistant SP1-A1V and SP1-V7A variants exhibit distinct conformational and binding characteristics. Taken together, our study provides a structural explanation for BVM resistance as well as guidance for the design of new MIs.

    

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4. PRADA: Portable Reusable Accurate Diagnostics with nanostar Antennas for multiplexed biomarker screening

   https://doi.org/10.1002/btm2.10165  

   Wen, Xiaona ; Ou, Yu‐Chuan ; Zarick, Holly F. ; Zhang, Xin ; Hmelo, Anthony B. ; Victor, Quinton J. ; Paul, Eden P. ; Slocik, Joseph M. ; Naik, Rajesh R. ; Bellan, Leon M. ; et al ( May 2020 , Bioengineering & Translational Medicine)

   Precise monitoring of specific biomarkers in biological fluids with accurate biodiagnostic sensors is critical for early diagnosis of diseases and subsequent treatment planning. In this work, we demonstrated an innovative biodiagnostic sensor, portable reusable accurate diagnostics with nanostar antennas (PRADA), for multiplexed biomarker detection in small volumes (~50 μl) enabled in a microfluidic platform. Here, PRADA simultaneously detected two biomarkers of myocardial infarction, cardiac troponin I (cTnI), which is well accepted for cardiac disorders, and neuropeptide Y (NPY), which controls cardiac sympathetic drive. In PRADA immunoassay, magnetic beads captured the biomarkers in human serum samples, and gold nanostars (GNSs) “antennas” labeled with peptide biorecognition elements and Raman tags detected the biomarkers via surface‐enhanced Raman spectroscopy (SERS). The peptide‐conjugated GNS‐SERS barcodes were leveraged to achieve high sensitivity, with a limit of detection (LOD) of 0.0055 ng/ml of cTnI, and a LOD of 0.12 ng/ml of NPY comparable with commercially available test kits. The innovation of PRADA was also in the regeneration and reuse of the same sensor chip for ~14 cycles. We validated PRADA by testing cTnI in 11 de‐identified cardiac patient samples of various demographics within a 95% confidence interval and high precision profile. We envision low‐cost PRADA will have tremendous translational impact and be amenable to resource‐limited settings for accurate treatment planning in patients.

    

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5. Novel mutations in MYBPC1 are associated with myogenic tremor and mild myopathy

   https://doi.org/10.1002/ana.25494  

   Stavusis, Janis ; Lace, Baiba ; Schäfer, Jochen ; Geist, Janelle ; Inashkina, Inna ; Kidere, Dita ; Pajusalu, Sander ; Wright, Nathan T. ; Saak, Annika ; Weinhold, Manja ; et al ( May 2019 , Annals of Neurology)

   To define a distinct, dominantly inherited, mild skeletal myopathy associated with prominent and consistent tremor in two unrelated, three‐generation families.

   Clinical evaluations as well as exome and panel sequencing analyses were performed in affected and nonaffected members of two families to identify genetic variants segregating with the phenotype. Histological assessment of a muscle biopsy specimen was performed in 1 patient, and quantitative tremor analysis was carried out in 2 patients. Molecular modeling studies and biochemical assays were performed for both mutations.

   Two novel missense mutations inMYBPC1(p.E248K in family 1 and p.Y247H in family 2) were identified and shown to segregate perfectly with the myopathy/tremor phenotype in the respective families.MYBPC1encodes slow myosin binding protein‐C (sMyBP‐C), a modular sarcomeric protein playing structural and regulatory roles through its dynamic interaction with actin and myosin filaments. The Y247H and E248K mutations are located in the NH₂‐terminal M‐motif of sMyBP‐C. Both mutations result in markedly increased binding of the NH₂terminus to myosin, possibly interfering with normal cross‐bridge cycling as the first muscle‐based step in tremor genesis. The clinical tremor features observed in all mutation carriers, together with the tremor physiology studies performed in family 2, suggest amplification by an additional central loop modulating the clinical tremor phenomenology.

   Here, we link two novel missense mutations inMYBPC1with a dominant, mild skeletal myopathy invariably associated with a distinctive tremor. The molecular, genetic, and clinical studies are consistent with a unique sarcomeric origin of the tremor, which we classify as “myogenic tremor.” ANN NEUROL 2019

    

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