Chromosome-level subgenome-aware de novo assembly provides insight into genome divergence after hybridization.

Interspecies hybridization is prevalent in various eukaryotic lineages and plays important roles in phenotypic diversification, adaptation, and speciation. To better understand the changes that occurred in the different subgenomes of a hybrid species and how they facilitate adaptation, we have completed chromosome-level de novo assemblies of all chromosomes for a recently formed hybrid yeast, strain CBS380, using Oxford Nanopore Technologies' MinION long-read sequencing. We characterize the genome and compare it with its parent species, and , and other genomes to better understand genome evolution after a relatively recent hybridization event.

T-Cell Expression of CXCL13 is Associated with Immunotherapy Response in a Sex-Dependent Manner in Patients with Lung Cancer.

Emerging evidence in preclinical models demonstrates that antitumor immunity is not equivalent between males and females. However, more investigation in patients and across a wider range of cancer types is needed to fully understand sex as a variable in tumor immune responses. We investigated differences in T-cell responses between male and female patients with lung cancer by performing sex-based analysis of single cell transcriptomic datasets.

Chromosome-level Subgenome-aware Assembly of Provides Insight into Genome Divergence after Hybridization.

Interspecies hybridization is prevalent in various eukaryotic lineages and plays important roles in phenotypic diversification, adaption, and speciation. To better understand the changes that occurred in the different subgenomes of a hybrid species and how they facilitated adaptation, we completed chromosome-level assemblies of all 16 pairs chromosomes for a recently formed hybrid yeast, strain CBS380 (IFO11022), using Nanopore MinION long-read sequencing. Characterization of subgenomes and comparative analysis with the genomes of its parent species, and provide several new insights into understanding genome evolution after a relatively recent hybridization.

Metal coordinating inhibitors of Rift Valley fever virus replication.

Rift Valley fever virus (RVFV) is a veterinary and human pathogen and is an agent of bioterrorism concern. Currently, RVFV treatment is limited to supportive care, so new drugs to control RVFV infection are urgently needed. RVFV is a member of the order Bunyavirales, whose replication depends on the enzymatic activity of the viral L protein.

Single-cell analysis of peripheral CD8 T cell responses in patients receiving checkpoint blockade immunotherapy for cancer.

Checkpoint blockade immunotherapy has become a first-line treatment option for cancer patients, with success in increasingly diverse cancer types. Still, many patients do not experience durable responses and the reasons for clinical success versus failure remain largely undefined. Investigation of immune responses within the tumor microenvironment can be highly informative but access to tumor tissue is not always available, highlighting the need to identify biomarkers in the blood that correlate with clinical success.

Membrane Integrity Contributes to Resistance of Cryptococcus neoformans to the Cell Wall Inhibitor Caspofungin.

The fungal pathogen Cryptococcus neoformans causes up to 278 000 infections each year globally, resulting in up to 180,000 deaths annually, mostly impacting immunocompromised people. Therapeutic options for C. neoformans infections are very limited.

Repurposing and optimization of drugs for discovery of novel antifungals.

Although fungal diseases are a major and growing public health concern, there are only four major classes of drug to treat primary fungal pathogens. The pipeline of new antifungals in clinical development is relatively thin compared with other disease classes. One approach to rapidly identify and provide novel treatment options is to repurpose existing drugs as antifungals.

Discovery of 5-Nitro-6-thiocyanatopyrimidines as Inhibitors of and .

Opportunistic infections from pathogenic fungi present a major challenge to healthcare because of a very limited arsenal of antifungal drugs, an increasing population of immunosuppressed patients, and increased prevalence of resistant clinical strains due to overuse of the few available antifungals. Cryptococcal meningitis is a life-threatening opportunistic fungal infection caused by one of two species in the genus, and . Eighty percent of cryptococcosis diseases are caused by that is endemic in the environment.

Oxidized Lipoproteins Promote Resistance to Cancer Immunotherapy Independent of Patient Obesity.

Antitumor immunity is impaired in obese mice. Mechanistic insight into this observation remains sparse and whether it is recapitulated in patients with cancer is unclear because clinical studies have produced conflicting and controversial findings. We addressed this by analyzing data from patients with a diverse array of cancer types.

Fructose Promotes Cytoprotection in Melanoma Tumors and Resistance to Immunotherapy.

Checkpoint blockade immunotherapy relies on the empowerment of the immune system to fight cancer. Why some patients fail to achieve durable clinical responses is not well understood, but unique individual factors such as diet, obesity, and related metabolic syndrome could play a role. The link between obesity and patient outcomes remains controversial and has been mired by conflicting reports and limited mechanistic insight.

Amide-containing α-hydroxytropolones as inhibitors of hepatitis B virus replication.

The Hepatitis B Virus (HBV) ribonuclease H (RNaseH) is a promising but unexploited drug target. Here, we synthesized and analyzed a library of 57 amide-containing α-hydroxytropolones (αHTs) as potential leads for HBV drug development. Fifty percent effective concentrations ranged from 0.

The Aminoalkylindole BML-190 Negatively Regulates Chitosan Synthesis via the Cyclic AMP/Protein Kinase A1 Pathway in Cryptococcus neoformans.

can cause fatal meningoencephalitis in patients with AIDS or other immunocompromising conditions. Current antifungals are suboptimal to treat this disease; therefore, novel targets and new therapies are needed. Previously, we have shown that chitosan is a critical component of the cryptococcal cell wall and is required for survival in the mammalian host and that chitosan deficiency results in rapid clearance from the mammalian host.

Divergent synthesis of a thiolate-based α-hydroxytropolone library with a dynamic bioactivity profile.

Here we describe a rapid and divergent synthetic route toward structurally novel αHTs functionalized with either one or two thioether or sulfonyl appendages. Evaluation of this library against hepatitis B and herpes simplex virus, as well as the pathogenic fungus , and a human hepatoblastoma (HepDES19) revealed complementary biological profiles and new lead compounds with sub-micromolar activity against each pathogen.

Synthesis and Evaluation of Troponoids as a New Class of Antibiotics.

Novel antibiotics are urgently needed. The troponoids [tropones, tropolones, and α-hydroxytropolones (α-HT)] can have anti-bacterial activity. We synthesized or purchased 92 troponoids and evaluated their antibacterial activities against , , and .

Cryptococcus neoformans Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis.

Chitin is an essential component of the cell wall of conferring structural rigidity and integrity under diverse environmental conditions. Chitin deacetylase genes encode the enyzmes (chitin deacetylases [Cdas]) that deacetylate chitin, converting it to chitosan. The functional role of chitosan in the fungal cell wall is not well defined, but it is an important virulence determinant of Mutant strains deficient in chitosan are completely avirulent in a mouse pulmonary infection model.

Identification of 4-isopropyl-thiotropolone as a novel anti-microbial: regioselective synthesis, NMR characterization, and biological evaluation.

We have synthesized and separated tosylated thujaplicin isomers for the first time, and elucidated their structures using 1D, 2D-NMR techniques and X-ray crystallography. The tosylated isomers were used to synthesize 4-isopropyl-thiotropolone and 6-isopropyl-thiotropolone in a regioselective manner. H and C Chemical shifts of synthesized isomers were fully assigned using several NMR experiments, and their isotropic magnetic shielding was calculated using the GIAO (Gauge Including Atomic Orbitals) method and the B3LYP def2-TZVPP level of theory.

A fluorogenic C. neoformans reporter strain with a robust expression of m-cherry expressed from a safe haven site in the genome.

C. neoformans is an encapsulated fungal pathogen with defined asexual and sexual life cycles. Due to the availability of genetic and molecular tools for its manipulation, it has become a model organism for studies of fungal pathogens, even though it lacks a reliable system for maintaining DNA fragments as extrachromosomal plasmids.

Troponoids Can Inhibit Growth of the Human Fungal Pathogen Cryptococcus neoformans.

is a pathogen that is common in immunosuppressed patients. It can be treated with amphotericin B and fluconazole, but the mortality rate remains 15 to 30%. Thus, novel and more effective anticryptococcal therapies are needed.

Hepatitis B virus genetic diversity has minimal impact on sensitivity of the viral ribonuclease H to inhibitors.

Hepatitis B virus (HBV) causes hepatitis, cirrhosis, liver failure, and liver cancer, but the current therapies that employ either nucelos(t)ide analogs or (pegylated)interferon α do not clear the infection in the large majority of patients. Inhibitors of the HBV ribonuclease H (RNaseH) that are being developed with the goal of producing anti-HBV drugs are promising candidates for use in combination with the nucleos(t)ide analogs to improve therapeutic efficacy. HBV is genetically very diverse, with at least 8 genotypes that differ by ≥8% at the sequence level.

A Functional Interplay between Human Immunodeficiency Virus Type 1 Protease Residues 77 and 93 Involved in Differential Regulation of Precursor Autoprocessing and Mature Protease Activity.

HIV-1 protease (PR) is a viral enzyme vital to the production of infectious virions. It is initially synthesized as part of the Gag-Pol polyprotein precursor in the infected cell. The free mature PR is liberated as a result of precursor autoprocessing upon virion release.

Checkpoint blockade immunotherapy relies on T-bet but not Eomes to induce effector function in tumor-infiltrating CD8+ T cells.

Coinhibitory receptor blockade is a promising strategy to boost T-cell immunity against a variety of human cancers. However, many patients still do not benefit from this treatment, and responders often experience immune-related toxicities. These issues highlight the need for advanced mechanistic understanding to improve patient outcomes and uncover clinically relevant biomarkers of treatment efficacy.

Cross talk between the cell wall integrity and cyclic AMP/protein kinase A pathways in Cryptococcus neoformans.

Unlabelled: Cryptococcus neoformans is a fungal pathogen of immunocompromised people that causes fatal meningitis. The fungal cell wall is essential to viability and pathogenesis of C. neoformans, and biosynthesis and repair of the wall is primarily controlled by the cell wall integrity (CWI) signaling pathway.

HCV genome-wide genetic analyses in context of disease progression and hepatocellular carcinoma.

Hepatitis C virus (HCV) is a major cause of hepatitis and hepatocellular carcinoma (HCC) world-wide. Most HCV patients have relatively stable disease, but approximately 25% have progressive disease that often terminates in liver failure or HCC. HCV is highly variable genetically, with seven genotypes and multiple subtypes per genotype.