Rebalancing TGFβ1/BMP signals in exhausted T cells unlocks responsiveness to immune checkpoint blockade therapy.

T cell dysfunctionality prevents the clearance of chronic infections and cancer. Furthermore, epigenetic programming in dysfunctional CD8 T cells limits their response to immunotherapies, including immune checkpoint blockade (ICB). However, it is unclear which upstream signals drive acquisition of dysfunctional epigenetic programs, and whether therapeutically targeting these signals can remodel terminally dysfunctional T cells to an ICB-responsive state.

"From Protein Toxins to Applied Toxicological Testing" virtual workshop identifies the need for a bioinformatic framework to assess novel food protein safety.

On October 21-22, 2020 the HESI (Health and Environmental Sciences Institute) Protein Allergens, Toxins, and Bioinformatics Committee, and the Society of Toxicology Food Safety Specialty Section co-hosted a virtual workshop titled "From Protein Toxins to Applied Toxicological Testing". The workshop focused on the safety assessment of novel proteins contained in foods and feeds, was globally represented by over 200 stakeholder attendees, and featured contributions from experts in academia, government and non-government organizations, and agricultural biotechnology developers from the private sector. A range of topics relevant to novel protein safety were discussed, including: the state of protein toxin biology, modes and mechanisms of action, structures and activity, use of bioinformatic analyses to assess the safety of a protein, and ways to leverage computational biology with in silico approaches for protein toxin identification/characterization.

Mass spectrometric analysis of digesta does not improve the allergenicity assessment of GM crops.

An investigation of the potential allergenicity of newly expressed proteins in genetically modified (GM) crops comprises part of the assessment of GM crop safety. However, allergenicity is not completely predictable from a definitive assay result or set of protein characteristics, and scientific opinions regarding the data that should be used to assess allergenicity are continuously evolving. Early studies supported a correlation between the stability of a protein exposed to digestive enzymes such as pepsin and the protein's status as a potential allergen, but over time the conclusions of these earlier studies were not confirmed.

Can Elite Dancers Return to Dance After Ultrasound-Guided Platelet-Rich Plasma (PRP) Injections?

Dancers exert tremendous stresses on the lower extremities rendering them prone to injuries that can curtail training and performance. The goal of this study was to evaluate clinical improvement in a population of elite dancers following treatment with ultrasound-guided platelet-rich plasma (PRP) injections of various lower extremity sites by assessing when they were able to return to dance. Nineteen dancers (13 female, 6 male; ages 15 to 42) were treated between 2009 and 2016 at sites that included: hamstring tendon (1), proximal iliotibial band (1), patellar tendon (3), posterior tibial tendon (5), peroneus brevis tendon (3), plantar fascia (3), and the first metatarsophalangeal (MTP) joint capsule (3).

Double-Mutated 5-Enol Pyruvylshikimate-3-phosphate Synthase Protein Expressed in MZHG0JG Corn (Zea mays L.) Has No Impact on Toxicological Safety and Nutritional Composition.

MZHG0JG corn will offer growers the flexibility to alternate between herbicides with two different modes of action in their weed-management programs, helping to mitigate and manage the evolution of herbicide resistance in weed populations. The proteins conferring herbicide tolerence in MZHG0JG corn, double-mutated 5-enol pyruvylshikimate-3-phosphate synthase protein (mEPSPS) and phosphinothricin acetyltransferase (PAT), as well as the MZHG0JG corn event, have been assessed by regulatory authorities globally and have been determined to be safe for humans, animals, and the environment. In addition to the safety data available for these proteins, further studies were conducted on MZHG0JG corn to assess levels of mEPSPS as compared to previously registered genetically modified (GM) corn.

Lower Extremity Injury Patterns in Elite Ballet Dancers: Ultrasound/MRI Imaging Features and an Institutional Overview of Therapeutic Ultrasound Guided Percutaneous Interventions.

Background: Altered biomechanics from repetitive microtrauma, such as long practice hours in en pointe (tip of the toes) or demi pointe (balls of the feet) predispose ballet dancers to a multitude of musculoskeletal pathologies particularly in the lower extremities. Both ultrasound and magnetic resonance imaging (MRI) are radiation-sparing modalities which can be used to confidently evaluate these injuries, with ultrasound (US) offering the added utility of therapeutic intervention at the same time in experienced hands.

Questions/purposes: The purposes of this paper were: (1) to illustrate the US and MRI features of lower extremity injury patterns in ballet dancers, focusing on pathologies commonly encountered at a single orthopedic hospital; (2) to present complementary roles of both ultrasound and MRI in the evaluation of these injuries whenever possible; (3) to review and present our institutional approach towards therapeutic ultrasound-guided interventions by presenting explicit cases.

Estimating viral titres in solutions with low viral loads.

An important consideration in the manufacture of products derived from animal or human sources is the virus reduction capacity of the manufacturing process as estimated using validated bench-scale models of relevant manufacturing steps. In these studies, manufacturing process intermediates are spiked with virus and processed using the bench-scale model and the resulting viral titres of input and output samples are typically determined using cell-based infectivity assays. In these assays, the Spearman-Kärber (SK) method is commonly used to estimate titres when there is one or more positive observation (i.

Critical factors influencing prion inactivation by sodium hydroxide.

Background And Objectives: Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases caused by aberrantly folded cellular proteins (PrP(Sc); prions) that are generally resistant to conventional pathogen-inactivation techniques. To ensure effective decontamination and inactivation of prions that could be present in source material, we investigated critical factors that influence prion inactivation by NaOH.

Materials And Methods: A decrease in prion infectivity correlates with the disappearance of the protease-resistant core of PrPSc (PrPRES) observed in biochemical assays.

A protein phosphatase-1gamma1 isoform selectivity determinant in dendritic spine-associated neurabin.

Protein phosphatase-1 (PP1) catalytic subunit isoforms interact with diverse proteins, typically containing a canonical (R/K)(V/I)XF motif. Despite sharing approximately 90% amino acid sequence identity, PP1beta and PP1gamma1 have distinct subcellular localizations that may be determined by selective interactions with PP1-binding proteins. Immunoprecipitation studies from brain and muscle extracts demonstrated that PP1gamma1 selectively interacts with spinophilin and neurabin, F-actin-targeting proteins, whereas PP1beta selectively interacted with G(M)/R(GL), the striated-muscle glycogen-targeting subunit.

Analysis of specific interactions of native protein phosphatase 1 isoforms with targeting subunits.

Expression of recombinant PP1 isoforms with fully authentic properties has proven to be a challenge for several laboratories. In order to circumvent this technical limitation in the investigation of isoform-specific roles for PP1, methods have been developed to analyze specific properties of native PP1 isoforms. The well-documented method of ethanol precipitation of tissue extracts has been used to dissociate phosphatase catalytic subunits from their endogenous regulatory subunits and other cellular proteins.

Determinants within the C-terminus of the human norepinephrine transporter dictate transporter trafficking, stability, and activity.

The function of the human norepinephrine transporter (hNET) depends on its presence at the cell surface. A role for the hNET C-terminus in trafficking the transporter to the surface has been suggested by the report of a bovine NET C-terminal splice variant that accumulates within heterologous host cells, and a human variant homolog has also been reported. We examined the relevance of the C-terminus of hNET to trafficking and function using transfected LLC-PK1 cells.

Masters athletes: factors affecting performance.

In recent years there has been an increase in interest in issues related to the enhancement of the performance of the masters athlete. Many of the changes in health status that have been thought to be the normal result of aging have been found to be actually the result of a long-standing sedentary lifestyle. Thus, masters athletes may be able to increase their athletic performance to higher levels than what was once thought.

Functional analysis of domains in the Byr2 kinase.

The activation of mitogen-activated protein (MAP) kinase cascades by the Ras GTPase is an evolutionarily conserved signal transduction mechanism. To better understand the interaction between Ras and its target kinase, we study the yeast Schizosaccharomyces pombe where the Ras1 GTPase activates the Byr2 kinase. The Byr2 kinase contains an N-terminal regulatory region and a C-terminal kinase region.

The Byr2 kinase translocates to the plasma membrane in a Ras1-dependent manner.

The activation of mitogen-activated protein kinase cascades by the Ras GTPase is an evolutionarily conserved signal transduction mechanism. To better understand the interaction between Ras and its target kinase, we study the yeast Schizosaccharomyces pombe where the Ras1 GTPase activates the Byr2 kinase. Cell fractionation and immunofluorescence showed that Ras1 was localized to the plasma membrane and that Byr2 was in the cytoplasm.

Cytokeratin expression results in a drug-resistant phenotype to six different chemotherapeutic agents.

The cytokeratin network is an abundant cytoplasmic system whose function is largely unknown. Recently, we have found that the introduction of a cytokeratin network into eukaryotic cells results in a drug resistance phenotype. The current study was undertaken to determine the universal nature of this phenomenon by investigating the survival response of two different cell lines to six different DNA-damaging agents using two different assays of cell survival.

Expression of cytokeratin confers multiple drug resistance.

The cytokeratin network is an extensive filamentous structure in the cytoplasm whose biological function(s) is unknown. Based upon previous data showing the modification of cytokeratin by mitoxantrone, we investigated the ability of cytokeratin networks to influence the survival response of cells to chemotherapeutic agents. We have compared the survival of mouse L fibroblasts lacking cytokeratins with that of L cells transfected with cytokeratins 8 and 18 in the presence of chemotherapeutic drugs.

Femoral neck anteversion in ballerinas.

The elite ballet dancer has greater-than-average turnout, or external rotation, in the hip. Anatomic constraints, such as the angle of version of the femoral neck, or the femoral neck anteversion (FNA) angle, may limit the amount of external rotation or turnout in the hip. The purpose of this study was to determine whether dancers who have better-than-average turnout have lower-than-average FNA angles.

Elevation of lung glutathione by oral supplementation of L-2-oxothiazolidine-4-carboxylate protects against oxygen toxicity in protein-energy malnourished rats.

The objectives of this study were to investigate whether oral supplementation of L-2-oxothiazolidine-4-carboxylate (OTC) is effective for increasing tissue glutathione (GSH) concentrations in rats fed a diet very low (0.5%) in protein-a model of wasting malnutrition-and to determine the efficacy of OTC for protection against pulmonary oxygen toxicity. Weanling rats, fed a 0.

Ribonuclease inhibits Ah receptor transformation in vitro.

The aryl hydrocarbon (Ah) receptor undergoes a ligand-dependent transformation to a heteromeric structure which has the ability to bind DNA sequence-specifically with high affinity. By this mechanism, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related xenobiotics modify gene expression. We observed that transformation was inhibited in vitro by the presence of ribonuclease A (RNAase) during incubation of rat hepatic cytosol with TCDD.

Prolactin-provoked alterations of cytosolic, membrane, and nuclear protein kinase C following partial hepatectomy.

The adenohypophyseal polypeptide hormone prolactin is a potent liver mitogen, stimulating cell cycle progression, an effect that appears coupled to increasing protein kinase C activity in membrane and nuclear fractions. Here, we examine whether hepatocyte proliferation, stimulated by partial hepatectomy, is associated with altered serum prolactin or protein kinase C activation. Within 5-15 min of liver resection, serum prolactin concentrations elevate significantly.

Effect of dietary protein deficiency and L-2-oxothiazolidine-4-carboxylate on the diurnal rhythm of hepatic glutathione in the rat.

Maximizing hepatic glutathione (GSH) concentration may provide greater protection against toxic compounds. A dietary supplement of L-2-oxothiazolidine-4-carboxylate (OTC), a stable derivative of cysteine, increased hepatic GSH in rats fed for 2 wk a diet deficient in protein (7.5%) but not in rats fed a diet adequate in protein (15%).

The effect of dietary protein and sulfur amino acids on hepatic glutathione concentration and glutathione-dependent enzyme activities in the rat.

Hepatic glutathione concentration and glutathione-dependent enzymes, glutathione S-transferase, glutathione peroxidase, and glutathione reductase, are important for protection against toxic compounds. Rats were fed diets containing 4, 7.5, 15, or 45% protein for 2 weeks.

Obturator hip dislocation with ipsilateral fractures of the femoral head and femoral neck. A case report.

A 28-year-old female pedestrians, struck by an automobile, sustained an obturator hip dislocation with concomitant ipsilateral fractures of both the femoral head and femoral neck. This unusual hip injury seems not to have been previously reported. The femoral neck fracture was widely separated from the shaft, and unfortunately, a 6-mm deep indentation fracture involved the anterosuperior portion of the articulating surface of the femoral head.