Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based DHODH inhibitors through a scaffold hop from a pyrrole-based series.

Isosteric 3D Bicyclo[1.1.1]Pentane (BCP) Core-Based Lipids for mRNA Delivery and CRISPR/Cas Gene Editing.

Lipid nanoparticles (LNPs) are an essential component of messenger RNA (mRNA) vaccines and genome editing therapeutics. Ionizable amino lipids, which play the most crucial role in enabling mRNA to overcome delivery barriers, have, to date, been restricted to two-dimensional (2D) architectures. Inspired by improved physicochemical properties resulting from the incorporation of three-dimensionality (3D) into small-molecule drugs, we report the creation of 3D ionizable lipid designs through the introduction of bicyclo[1.

Three-dimensional saturated C(sp)-rich bioisosteres for benzene.

Benzenes, the most ubiquitous structural moiety in marketed small-molecule drugs, are frequently associated with poor 'drug-like' properties, including metabolic instability, and poor aqueous solubility. In an effort to overcome these limitations, recent developments in medicinal chemistry have demonstrated the improved physicochemical profiles of C(sp)-rich bioisosteric scaffolds relative to arenes. In the past two decades, we have witnessed an exponential increase in synthetic methods for accessing saturated bioisosteres of monosubstituted and para-substituted benzenes.

Direct binding to sterols accelerates endoplasmic reticulum-associated degradation of HMG CoA reductase.

The maintenance of cholesterol homeostasis is crucial for normal function at both the cellular and organismal levels. Two integral membrane proteins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and Scap, are key targets of a complex feedback regulatory system that operates to ensure cholesterol homeostasis. HMGCR catalyzes the rate-limiting step in the transformation of the 2-carbon precursor acetate to 27-carbon cholesterol.

Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates.

Modular functionalization enables versatile exploration of chemical space and has been broadly applied in structure-activity relationship (SAR) studies of aromatic scaffolds during drug discovery. Recently, the bicyclo[1.1.

Alkyl sulfinates as cross-coupling partners for programmable and stereospecific installation of C(sp) bioisosteres.

In recent years, a variety of cycloalkyl groups with quaternary carbons, in particular cyclopropyl and cyclobutyl trifluoromethyl groups, have emerged as promising bioisosteres in drug-like molecules. The modular installation of such bioisosteres remains challenging to synthetic chemists. Alkyl sulfinate reagents have been developed as radical precursors to prepare functionalized heterocycles with the desired alkyl bioisosteres.

Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in .

A prevalent feature of is a life-long and potentially lethal infection that is due to the nematode parasite's ability to autoinfect and, thereby, self-replicate within its host. Here, we investigated the role of the parasite's nuclear receptor, DAF-12, in governing infection. We identified Δ7-DA as the endogenous DAF-12 ligand and elucidated the hormone's biosynthetic pathway.

An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates.

Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry.

Practical and Modular Construction of C(sp)-Rich Alkyl Boron Compounds.

Alkyl boronic acids and esters play an important role in the synthesis of C(sp)-rich medicines, agrochemicals, and material chemistry. This work describes a new type of transition-metal-free mediated transformation to enable the construction of C(sp)-rich and sterically hindered alkyl boron reagents in a practical and modular manner. The broad generality and functional group tolerance of this method is extensively examined through a variety of substrates, including synthesis and late-stage functionalization of scaffolds relevant to medicinal chemistry.

Sulfur(IV)-Mediated Unsymmetrical Heterocycle Cross-Couplings.

Despite the tremendous utilities of metal-mediated cross-couplings in modern organic chemistry, coupling reactions involving nitrogenous heteroarenes remain a challenging undertaking - coordination of Lewis basic atoms into metal centers often necessitate elevated temperature, high catalyst loading, etc. Herein, we report a sulfur (IV) mediated cross-coupling amendable for the efficient synthesis of heteroaromatic substrates. Addition of heteroaryl nucleophiles to a simple, readily-accessible alkyl sulfinyl (IV) chloride allows formation of a trigonal bipyramidal sulfurane intermediate.

Functional Brain Connectivity Revealed by Sparse Coding of Large-Scale Local Field Potential Dynamics.

Exploration of brain dynamics patterns has attracted increasing attention due to its fundamental significance in understanding the working mechanism of the brain. However, due to the lack of effective modeling methods, how the simultaneously recorded LFP can inform us about the brain dynamics remains a general challenge. In this paper, we propose a novel sparse coding based method to investigate brain dynamics of freely-behaving mice from the perspective of functional connectivity, using super-long local field potential (LFP) recordings from 13 distinct regions of the mouse brain.

Large-Scale Circuitry Interactions Upon Earthquake Experiences Revealed by Recurrent Neural Networks.

Brain dynamics has recently received increasing interest due to its significant importance in basic and clinical neurosciences. However, due to inherent difficulties in both data acquisition and data analysis methods, studies on large-scale brain dynamics of mouse with local field potential (LFP) recording are very rare. In this paper, we did a series of works on modeling large-scale mouse brain dynamic activities responding to fearful earthquake.

Neural Coding of Appetitive Food Experiences in the Amygdala.

Real-life experiences involve the consumption of various foods, yet it is unclear how the brain distinguishes and categorizes such food experiences. Despite the crucial roles of the basolateral amygdala (BLA) in appetitive behavior and emotion, how BLA pyramidal cells and interneurons encode food experiences has not yet been well characterized. Here we employ large-scale tetrode recording techniques to investigate the coding properties of pyramidal neurons vs.

Building C(sp)-rich complexity by combining cycloaddition and C-C cross-coupling reactions.

Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres, cycloaddition reactions have featured in numerous total syntheses and are a key component in the education of chemistry students. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp manner.

Histone Deacetylase Inhibitor Alleviates the Neurodegenerative Phenotypes and Histone Dysregulation in Presenilins-Deficient Mice.

Histone acetylation has been shown to play a crucial role in memory formation, and histone deacetylase (HDAC) inhibitor sodium butyrate (NaB) has been demonstrated to improve memory performance and rescue the neurodegeneration of several Alzheimer's Disease (AD) mouse models. The forebrain presenilin-1 and presenilin-2 conditional double knockout (cDKO) mice showed memory impairment, forebrain degeneration, tau hyperphosphorylation and inflammation that closely mimics AD-like phenotypes. In this article, we have investigated the effects of systemic administration of NaB on neurodegenerative phenotypes in cDKO mice.

Neural Coding of Cell Assemblies via Spike-Timing Self-Information.

Cracking brain's neural code is of general interest. In contrast to the traditional view that enormous spike variability in resting states and stimulus-triggered responses reflects noise, here, we examine the "Neural Self-Information Theory" that the interspike-interval (ISI), or the silence-duration between 2 adjoining spikes, carries self-information that is inversely proportional to its variability-probability. Specifically, higher-probability ISIs convey minimal information because they reflect the ground state, whereas lower-probability ISIs carry more information, in the form of "positive" or "negative surprisals," signifying the excitatory or inhibitory shifts from the ground state, respectively.

Distinct retrosplenial cortex cell populations and their spike dynamics during ketamine-induced unconscious state.

Ketamine is known to induce psychotic-like symptoms, including delirium and visual hallucinations. It also causes neuronal damage and cell death in the retrosplenial cortex (RSC), an area that is thought to be a part of high visual cortical pathways and at least partially responsible for ketamine's psychotomimetic activities. However, the basic physiological properties of RSC cells as well as their response to ketamine in vivo remained largely unexplored.

Neural Code- on How Cell-Assembly Code Rises from Spike Time and Neuronal Variability.

A major stumbling block to cracking the real-time neural code is neuronal variability - neurons discharge spikes with enormous variability not only across trials within the same experiments but also in resting states. Such variability is widely regarded as a noise which is often deliberately averaged out during data analyses. In contrast to such a dogma, we put forth the that neural coding is operated based on the self-information principle under which variability in the time durations of inter-spike-intervals (ISI), or neuronal silence durations, is self-tagged with discrete information.

Discover mouse gene coexpression landscapes using dictionary learning and sparse coding.

Gene coexpression patterns carry rich information regarding enormously complex brain structures and functions. Characterization of these patterns in an unbiased, integrated, and anatomically comprehensive manner will illuminate the higher-order transcriptome organization and offer genetic foundations of functional circuitry. Here using dictionary learning and sparse coding, we derived coexpression networks from the space-resolved anatomical comprehensive in situ hybridization data from Allen Mouse Brain Atlas dataset.

Transcriptome Architecture of Adult Mouse Brain Revealed by Sparse Coding of Genome-Wide In Situ Hybridization Images.

Highly differentiated brain structures with distinctly different phenotypes are closely correlated with the unique combination of gene expression patterns. Using a genome-wide in situ hybridization image dataset released by Allen Mouse Brain Atlas, we present a data-driven method of dictionary learning and sparse coding. Our results show that sparse coding can elucidate patterns of transcriptome organization of mouse brain.

Camera-Based, Non-Contact, Vital-Signs Monitoring Technology May Provide a Way for the Early Prevention of SIDS in Infants.

Sudden infant death syndrome (SIDS) is the unexplained death, usually during sleep, of a baby younger than 1-year-old. Even though researchers have discovered some factors that may put babies at extra risk, SIDS remains unpredictable up until now. One hypothesis is that impaired cardiovascular control may play a role in the underlying mechanism of SIDS.

Brain Computation Is Organized via Power-of-Two-Based Permutation Logic.

There is considerable scientific interest in understanding how cell assemblies-the long-presumed computational motif-are organized so that the brain can generate intelligent cognition and flexible behavior. The proposes that the origin of intelligence is rooted in a power-of-two-based permutation logic ( = 2 -1), producing specific-to-general cell-assembly architecture capable of generating specific perceptions and memories, as well as generalized knowledge and flexible actions. We show that this power-of-two-based permutation logic is widely used in cortical and subcortical circuits across animal species and is conserved for the processing of a variety of cognitive modalities including appetitive, emotional and social information.

Dopamine Rebound-Excitation Theory: Putting Brakes on PTSD.

It is not uncommon for humans or animals to experience traumatic events in their lifetimes. However, the majority of individuals are resilient to long-term detrimental changes turning into anxiety and depression, such as post-traumatic stress disorder (PTSD). What underlying neural mechanism accounts for individual variability in stress resilience? Hyperactivity in fear circuits, such as the amygdalar system, is well-known to be the major pathophysiological basis for PTSD, much like a "stuck accelerator.