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In this issue of Neuron, Soria-Gomez et al. (2021) investigate whether activation of the type 1 cannabinoid receptor at specific subcellular locations within a single neural circuit produces multimodal behavior. Their results demonstrate that location matters striatonigral mitochondrial CB1 drives catalepsy while striatonigral plasma membrane CB1 receptors enable antinociception.How genetic loss of the sodium channel NaV1.7 results in painlessness is puzzling. MacDonald et al. (2021) demonstrate that instead of impairing peripheral excitability, NaV1.7 channels at central terminals of pain-sensing afferents play a pivotal role in the balance between pain and analgesia.Severe neuropsychiatric disorders are so genetically heterogeneous that virtually every unrelated patient harbors different clinically significant alleles. By studying schizophrenia in the Ashkenazi Jewish founder population, Lencz and co-authors identified rare severe alleles each shared by a few patients. Experimental evaluation of an implicated protocadherin allele revealed failure to form homophilic cellular aggregates as a possible mechanism for defective development of neural circuits.Making flexible decisions based on prior knowledge about causal environmental structures is a hallmark of goal-directed cognition in mammalian brains. Although several association brain regions, including the orbitofrontal cortex (OFC), have been implicated, the precise neuronal circuit mechanisms underlying knowledge-based decision-making remain elusive. Here, we established an inference-based auditory categorization task where mice performed within-session flexible stimulus re-categorization by inferring the changing task rules. We constructed a reinforcement learning model to recapitulate the inference-based flexible behavior and quantify the hidden variables associated with task structural knowledge. Combining two-photon population imaging and projection-specific optogenetics, we found that auditory cortex (ACx) neurons encoded the hidden task rule variable, which requires feedback input from the OFC. Silencing OFC-ACx input specifically disrupted re-categorization behavior. Direct imaging from OFC axons in the ACx revealed task state-related feedback signals, supporting the knowledge-based updating mechanism. Our data reveal a cortical circuit mechanism underlying structural knowledge-based flexible decision-making.Microspheres and injectable hydrogels derived from natural biopolymers have been extensively investigated as controlled local drug delivery systems. In this study, we prepared carboxymethyl chitin microspheres (CMCH-Ms) with a diameter of 10-100 μm through physical crosslinking by increasing temperature in an aqueous two-phase system without using organic solvents, surfactants and crosslinking agents. The stable microspheres keeping spherical shape with porous microstructure in different pH environments were embeded in thermosensitive hydroxypropyl chitin (HPCH) hydrogels. The morphology, gelation rate, swelling, rheological and mechanical properties, in vitro degradation and cytotoxicity, drug loading and drug release of the CMCH-Ms/HPCH gel scaffolds were examined. In vitro degradation and cytotoxicity test indicated that CMCH-Ms/HPCH gel scaffolds were biodegradable and non-cytotoxic. Moreover, no organic solvent was used in the preparation and drug loading process of CMCH-Ms/HPCH gel scaffold. Importantly, less burst drug release and long-term sustained-release from the CMCH-Ms/HPCH composite hydrogel was observed than those from only CMCH-Ms or HPCH hydrogel. Thus, the composite CMCH-Ms/HPCH hydrogel exhibited great potential application for loading different drugs and sustained drug release in controlled local drug delivery systems.The primary aim of the study was to investigate the semantic and syntactic aspects of verbal and aided single sentence productions in adults with aphasia and neurotypical adults to determine which mode allowed the exchange of information more effectively. The participants of this study included 20 adults with aphasia and 20 neurotypical adults who were native speakers of Malayalam, an Indo-Dravidian language spoken in the south-western state of Kerala in India. Thirteen action picture stimuli were constructed to elicit single sentences. The participants were expected to describe the action picture in a single sentence using spoken language as well as using Picture Communication Symbols (PCS). The semantic aspect of each sentence produced was analysed using Correct Information Unit (CIU) analyses, and the syntactic aspects were measured using (i) percentage of grammatically complete sentences, (ii) percentage of the correct number of verbs, and (iii) total number of syntactic errors. [https://www.selleckchem.com/products/GSK1904529A.html find more] A sentence production accuracy scale was constructed to obtain a combined score for semantic and syntactic aspects of each sentence produced. The results suggested that while both verbal and aided modes were effectively used for the exchange of information by neurotypical adults and adults with anomic aphasia, the aided mode was used more effectively by adults with Broca's aphasia. To conclude, the study highlights the importance of (a) using visual symbols even for those with mild aphasia as it tends to improve phonological and articulatory abilities, (b) use of symbols to construct simple sentences to communicate in adults with severe aphasia, (c) evaluation of the ability to use alternate modes of communication and also the preferred mode of communication in adults with aphasia.Critical to viral infection are the multiple interactions between viral proteins and host-cell counterparts. The first such interaction is the recognition of viral envelope proteins by surface receptors that normally fulfil other physiological roles, a hijacking mechanism perfected over the course of evolution. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), has successfully adopted this strategy using its spike glycoprotein to dock on the membrane-bound metalloprotease angiotensin-converting enzyme 2 (ACE2). The crystal structures of several SARS-CoV-2 proteins alone or in complex with their receptors or other ligands were recently solved at an unprecedented pace. This accomplishment is partly due to the increasing availability of data on other coronaviruses and ACE2 over the past 18 years. Likewise, other key intervening actors and mechanisms of viral infection were elucidated with the aid of biophysical approaches. link2 An understanding of the various structurally important motifs of the interacting partners provides key mechanistic information for the development of structure-based designer drugs able to inhibit various steps of the infective cycle, including neutralizing antibodies, small organic drugs, and vaccines. This review analyzes current progress and the outlook for future structural studies.Dyneins make up a family of AAA+ motors that move toward the minus end of microtubules. Cytoplasmic dynein is responsible for transporting intracellular cargos in interphase cells and mediating spindle assembly and chromosome positioning during cell division. Other dynein isoforms transport cargos in cilia and power ciliary beating. Dyneins were the least studied of the cytoskeletal motors due to challenges in the reconstitution of active dynein complexes in vitro and the scarcity of high-resolution methods for in-depth structural and biophysical characterization of these motors. link3 These challenges have been recently addressed, and there have been major advances in our understanding of the activation, mechanism, and regulation of dyneins. This review synthesizes the results of structural and biophysical studies for each class of dynein motors. We highlight several outstanding questions about the regulation of bidirectional transport along microtubules and the mechanisms that sustain self-coordinated oscillations within motile cilia.The phasor approach to fluorescence lifetime imaging has become a common method to analyze complicated fluorescence signals from biological samples. The appeal of the phasor representation of complex fluorescence decays in biological systems is that a visual representation of the decay of entire cells or tissues can be used to easily interpret fundamental biological states related to metabolism and oxidative stress. Phenotyping based on autofluorescence provides new avenues for disease characterization and diagnostics. The phasor approach is a transformation of complex fluorescence decays that does not use fits to model decays and therefore has the same information content as the original data. The phasor plot is unique for a given system, is highly reproducible, and provides a robust method to evaluate the existence of molecular interactions such as Förster resonance energy transfer or the response of ion indicators. Recent advances permitquantification of multiple components from phasor plots in fluorescence lifetime imaging microscopy, which is not presently possible using data fitting methods, especially in biological systems.Phycobilisomes (PBSs) are extremely large chromophore-protein complexes on the stromal side of the thylakoid membrane in cyanobacteria and red algae. The main function of PBSs is light harvesting, and they serve as antennas and transfer the absorbed energy to the reaction centers of two photosynthetic systems (photosystems I and II). PBSs are composed of phycobiliproteins and linker proteins. How phycobiliproteins and linkers are organized in PBSs and how light energy is efficiently harvested and transferred in PBSs are the fundamental questions in the study of photosynthesis. In this review, the structures of the red algae Griffithsia pacifica and Porphyridium purpureum are discussed in detail, along with the functions of linker proteins in phycobiliprotein assembly and in fine-tuning the energy state of chromophores.In eukaryotes, genomic DNA is packaged into chromatin in the nucleus. The accessibility of DNA is dependent on the chromatin structure and dynamics, which essentially control DNA-related processes, including transcription, DNA replication, and repair. All of the factors that affect the structure and dynamics of nucleosomes, the nucleosome-nucleosome interaction interfaces, and the binding of linker histones or other chromatin-binding proteins need to be considered to understand the organization and function of chromatin fibers. In this review, we provide a summary of recent progress on the structure of chromatin fibers in vitro and in the nucleus, highlight studies on the dynamic regulation of chromatin fibers, and discuss their related biological functions and abnormal organization in diseases.Cellular decision making is the process whereby cells choose one developmental pathway from multiple possible ones, either spontaneously or due to environmental stimuli. Examples in various cell types suggest an almost inexhaustible plethora of underlying molecular mechanisms. In general, cellular decisions rely on the gene regulatory network, which integrates external signals to drive cell fate choice. The search for general principles of such a process benefits from appropriate biological model systems that reveal how and why certain gene regulatory mechanisms drive specific cellular decisions according to ecological context and evolutionary outcomes. In this article, we review the historical and ongoing development of the phage lambda lysis-lysogeny decision as a model system to investigate all aspects of cellular decision making. The unique generality, simplicity, and richness of phage lambda decision making render it a constant source ofmathematical modeling-aided inspiration across all of biology. We discuss the origins and progress of quantitative phage lambda modeling from the 1950s until today, as well as its possible future directions.