Microbial community composition predicts bacterial production across ocean ecosystems.

Microbial ecological functions are an emergent property of community composition. For some ecological functions, this link is strong enough that community composition can be used to estimate the quantity of an ecological function. Here, we apply random forest regression models to compare the predictive performance of community composition and environmental data for bacterial production (BP).

Enhancing Antibody-Specific Productivity: Unraveling the Impact of XBP1s Overexpression and Glutamine Availability in SP2/0 Cells.

Augmentation of glycoprotein synthesis requirements induces endoplasmic reticulum (ER) stress, activating the unfolded protein response (UPR) and triggering unconventional XBP1 splicing. As a result, XBP1s orchestrates the expression of essential genes to reduce stress and restore homeostasis. When this mechanism fails, chronic stress may lead to apoptosis, which is thought to be associated with exceeding a threshold in XBP1s levels.

Krill body size drives particulate organic carbon export in West Antarctica.

The export of carbon from the ocean surface and storage in the ocean interior is important in the modulation of global climate. The West Antarctic Peninsula experiences some of the largest summer particulate organic carbon (POC) export rates, and one of the fastest warming rates, in the world. To understand how warming may alter carbon storage, it is necessary to first determine the patterns and ecological drivers of POC export.

Fibroblast-derived PI16 sustains inflammatory pain via regulation of CD206 myeloid cells.

Originally identified in fibroblasts, Protease Inhibitor (PI)16 was recently shown to be crucial for the development of neuropathic pain via effects on blood-nerve barrier permeability and leukocyte infiltration, though its impact on inflammatory pain has not been established. Using the complete Freund's Adjuvant inflammatory pain model, we show that Pi16 mice are protected against sustained inflammatory pain. Accordingly, intrathecal delivery of a PI16 neutralizing antibody in wild-type mice prevented sustained CFA pain.

Depth drives the distribution of microbial ecological functions in the coastal western Antarctic Peninsula.

The Antarctic marine environment is a dynamic ecosystem where microorganisms play an important role in key biogeochemical cycles. Despite the role that microbes play in this ecosystem, little is known about the genetic and metabolic diversity of Antarctic marine microbes. In this study we leveraged DNA samples collected by the Palmer Long Term Ecological Research (LTER) project to sequence shotgun metagenomes of 48 key samples collected across the marine ecosystem of the western Antarctic Peninsula (wAP).

HDAC6 Inhibition Reverses Cisplatin-Induced Mechanical Hypersensitivity via Tonic Delta Opioid Receptor Signaling.

Peripheral neuropathic pain induced by the chemotherapeutic cisplatin can persist for months to years after treatment. Histone deacetylase 6 (HDAC6) inhibitors have therapeutic potential for cisplatin-induced neuropathic pain since they persistently reverse mechanical hypersensitivity and spontaneous pain in rodent models. Here, we investigated the mechanisms underlying reversal of mechanical hypersensitivity in male and female mice by a 2 week treatment with an HDAC6 inhibitor, administered 3 d after the last dose of cisplatin.

Sensory neuron dysfunction in orthotopic mouse models of colon cancer.

Reports of neurological sequelae related to colon cancer are largely restricted to rare instances of paraneoplastic syndromes, due to autoimmune reactions. Systemic inflammation associated with tumor development influences sensory neuron function in other disease models, though the extent to which this occurs in colorectal cancer is unknown. We induced orthotopic colorectal cancer via orthotopic injection of two colorectal cancer cell lines (MC38 and CT26) in two different mouse strains (C57BL/6 and Balb/c, respectively).

An HDAC6 inhibitor reverses chemotherapy-induced mechanical hypersensitivity via an IL-10 and macrophage dependent pathway.

Chemotherapy-induced peripheral neuropathy (CIPN) impacts a growing number of cancer survivors and treatment options are limited. Histone deacetylase 6 (HDAC6) inhibitors are attractive candidates because they reverse established CIPN and may enhance anti-tumor effects of chemotherapy. Before considering clinical application of HDAC6 inhibitors, the mechanisms underlying reversal of CIPN need to be identified.

Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer.

Neurodegenerative disorders, including chemotherapy-induced cognitive impairment, are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunction in vivo and in vitro. Astrocytes are key players in supporting neuronal development, synaptogenesis, axonal growth, metabolism and, potentially mitochondrial health.

The fibroblast-derived protein PI16 controls neuropathic pain.

Chronic pain is a major clinical problem of which the mechanisms are incompletely understood. Here, we describe the concept that PI16, a protein of unknown function mainly produced by fibroblasts, controls neuropathic pain. The spared nerve injury (SNI) model of neuropathic pain increases PI16 protein levels in fibroblasts in dorsal root ganglia (DRG) meninges and in the epi/perineurium of the sciatic nerve.

Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients with chronic HCV genotypes 1-6 and compensated cirrhosis: The EXPEDITION-8 trial.

Background & Aims: Eight-week glecaprevir/pibrentasvir leads to high rates of sustained virological response at post-treatment week 12 (SVR12) across HCV genotypes (GT) 1-6 in treatment-naïve patients without cirrhosis. We evaluated glecaprevir/pibrentasvir once daily for 8 weeks in treatment-naïve patients with compensated cirrhosis.

Methods: EXPEDITION-8 was a single-arm, multicenter, phase IIIb trial.

Cell-specific role of histone deacetylase 6 in chemotherapy-induced mechanical allodynia and loss of intraepidermal nerve fibers.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of cancer treatment with no Food and Drug Administration-approved medication for its prevention or management. Using RNA sequencing analysis of dorsal root ganglia (DRG), we identify critical contributions of histone deacetylase 6 (HDAC6) and mitochondrial damage to the establishment of CIPN in a mouse model of cisplatin-induced neuropathy. We show that pharmacological inhibition of HDAC6 using ACY-1215 or global deletion of HDAC6 is sufficient to prevent cisplatin-induced mechanical allodynia, loss of intraepidermal nerve fibers (IENFs), and mitochondrial bioenergetic deficits in DRG neurons and peripheral nerves in male and female mice.

Publisher Correction: Elastomeric sensor surfaces for high-throughput single-cell force cytometry.

In the version of this Article originally published, in Fig. 1a, all cells in the top schematic were missing, and in the bottom-left schematic showing multiple pattern shapes, two cells were missing in the bottom-right corner. This figure has now been updated in all versions of the Article.

Efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir with low-dose ribavirin in patients with chronic hepatitis C virus genotype 1a infection without cirrhosis.

Patients infected with hepatitis C virus (HCV) treated with interferon-free direct-acting antivirals may still require ribavirin. However, ribavirin is associated with adverse events that can limit its use. This open-label, multicentre, Phase 3 study evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir + dasabuvir (OBV/PTV/r + DSV) with low-dose ribavirin for 12 weeks in genotype 1a-infected patients without cirrhosis.

Safety and efficacy of glecaprevir/pibrentasvir for the treatment of chronic hepatitis C in patients aged 65 years or older.

Finding safe and effective treatments for chronic hepatitis C virus (HCV) infection in the elderly is of clinical interest given the comorbidities and associated polypharmacy in this population. However, the number of patients older than age 65 years enrolled into clinical trials of anti-HCV medications generally have been limited and thus reaching meaningful conclusions for this demographic has been difficult. Glecaprevir/pibrentasvir is a once-daily, all-oral, ribavirin-free, pangenotypic direct-acting antiviral (DAA) combination therapy that has demonstrated high sustained virologic response rates at post-treatment week 12 (SVR12) and a favorable safety profile in patients with chronic HCV infection.

Glecaprevir/Pibrentasvir in patients with chronic HCV genotype 3 infection: An integrated phase 2/3 analysis.

Glecaprevir coformulated with pibrentasvir (G/P) is approved to treat hepatitis C virus (HCV) infection and was highly efficacious in phase 2 and 3 studies. Treating HCV genotype (GT) 3 infection remains a priority, as these patients are harder to cure and at a greater risk for liver steatosis, fibrosis progression and hepatocellular carcinoma. Data were pooled from five phase 2 or 3 trials that evaluated 8-, 12- and 16-week G/P in patients with chronic HCV GT3 infection.

Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients With Hepatitis C Virus Infection.

Unlabelled: Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response at 12 weeks posttreatment (SVR12) across all major HCV genotypes (GTs). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant.

Efficacy and Safety of Glecaprevir/Pibrentasvir in Patients Coinfected With Hepatitis C Virus and Human Immunodeficiency Virus Type 1: The EXPEDITION-2 Study.

Background: Once-daily glecaprevir coformulated with pibrentasvir (glecaprevir/pibrentasvir) demonstrated high rates of sustained virologic response 12 weeks after treatment (SVR12) in patients with hepatitis C virus (HCV) genotype 1-6 infection. This phase 3 study evaluated the efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV genotype 1-6 and human immunodeficiency virus type 1 (HIV-1) coinfection, including patients with compensated cirrhosis.

Methods: EXPEDITION-2 was a phase 3, multicenter, open-label study evaluating glecaprevir/pibrentasvir (300 mg/120 mg) in HCV genotype 1-6/HIV-1-coinfected adults without and with compensated cirrhosis for 8 and 12 weeks, respectively.

A Phase 1 Study to Evaluate the Effect of Crushing, Cutting Into Half, or Grinding of Glecaprevir/Pibrentasvir Tablets on Exposures in Healthy Subjects.

Glecaprevir (GLE) and pibrentasvir (PIB) are direct-acting antivirals coformulated as a combination tablet for once-daily treatment of chronic hepatitis C virus infection. The objective of this study was to evaluate the effect of different methods of tablet manipulations-cutting in half, grinding into powder, or crushing-on the bioavailability of GLE and PIB relative to whole film-coated bilayer tablets. This was a phase 1, single-dose, open-label, randomized, 5-period, nonfasting crossover study in 25 healthy adult male and female subjects.

Elastomeric sensor surfaces for high-throughput single-cell force cytometry.

As cells with aberrant force-generating phenotypes can directly lead to disease, cellular force-generation mechanisms are high-value targets for new therapies. Here, we show that single-cell force sensors embedded in elastomers enable single-cell force measurements with ~100-fold improvement in throughput than was previously possible. The microtechnology is scalable and seamlessly integrates with the multi-well plate format, enabling highly parallelized time-course studies.

Glecaprevir-Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection.

Background: Glecaprevir and pibrentasvir are direct-acting antiviral agents with pangenotypic activity and a high barrier to resistance. We evaluated the efficacy and safety of 8-week and 12-week courses of treatment with 300 mg of glecaprevir plus 120 mg of pibrentasvir in patients without cirrhosis who had hepatitis C virus (HCV) genotype 1 or 3 infection.

Methods: We conducted two phase 3, randomized, open-label, multicenter trials.

Safety and Efficacy of Ombitasvir, Paritaprevir With Ritonavir ± Dasabuvir With or Without Ribavirin in Patients With Human Immunodeficiency Virus-1 and Hepatitis C Virus Genotype 1 or Genotype 4 Coinfection: TURQUOISE-I Part 2.

Background: Ombitasvir, paritaprevir with ritonavir, and dasabuvir (OBV/PTV/r ± DSV) ±ribavirin (RBV) are approved to treat hepatitis C virus (HCV) genotype 1 and 4 infection. Here, we investigate the safety and efficacy of OBV/PTV/r + DSV ±RBV for HCV genotype 1, and OBV/PTV/r + RBV for HCV genotype 4, in human immunodeficiency virus (HIV)-1 coinfected patients with or without compensated cirrhosis.

Methods: TURQUOISE-I, Part 2 is a phase 3 multicenter study.

Anti-VEGFR2-interferon-α2 regulates the tumor microenvironment and exhibits potent antitumor efficacy against colorectal cancer.

Interferon-α (IFNα) has multiple antitumor effects including direct antitumor toxicity and the ability to potently stimulate both innate and adaptive immunity. However, its clinical applications in the treatment of malignancies have been limited because of short half-life and serious adverse reactions when attempting to deliver therapeutically effective doses. To address these issues, we fused IFNα2a to the anti-vascular endothelial growth factor and receptor 2 (VEGFR2) antibody JZA00 with the goal of targeting it to the tumor microenvironment where it can stimulate the antitumor immune response.