Engineering of the Recombinant Expression and PEGylation Efficiency of the Therapeutic Enzyme Human Thymidine Phosphorylase.

Human thymidine phosphorylase (HsTP) is an enzyme with important implications in the field of rare metabolic diseases. Defective mutations of HsTP lead to mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a disease with a high unmet medical need that is associated with severe neurological and gastrointestinal complications. Current efforts focus on the development of an enzyme replacement therapy (ERT) using the ortholog (EcTP).

Constraints on Cosmic Strings Using Data from the Third Advanced LIGO-Virgo Observing Run.

We search for gravitational-wave signals produced by cosmic strings in the Advanced LIGO and Virgo full O3 dataset. Search results are presented for gravitational waves produced by cosmic string loop features such as cusps, kinks, and, for the first time, kink-kink collisions. A template-based search for short-duration transient signals does not yield a detection.

Arginase Therapy Combines Effectively with Immune Checkpoint Blockade or Agonist Anti-OX40 Immunotherapy to Control Tumor Growth.

Metabolic dysregulation is a hallmark of cancer. Many tumors exhibit auxotrophy for various amino acids, such as arginine, because they are unable to meet the demand for these amino acids through endogenous production. This vulnerability can be exploited by employing therapeutic strategies that deplete systemic arginine in order to limit the growth and survival of arginine auxotrophic tumors.

Arginine depletion as a therapeutic approach for patients with COVID-19.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a source of significant morbidity and death worldwide, and effective treatments are urgently needed. Clinical trials have focused largely on direct antiviral therapies or on immunomodulation in patients with severe manifestations of COVID-19. One therapeutic approach that remains to be clinically investigated is disruption of the host-virus relationship through amino acid restriction, a strategy used successfully in the setting of cancer treatment.

Knowledge transfer for occupational health and safety: Cultivating health and safety learning culture in construction firms.

Within the last decades the incidence of workspace injuries and fatalities in the UK construction industry has declined markedly following the developments in occupational health and safety (OHS) management systems. However, safety statistics have reached a plateau and actions for further improvement of OHS management systems are called for. OHS is a form of organizational expertise that has both tacit and explicit dimensions and is situated in the ongoing practices.

Preclinical safety and antitumor activity of the arginine-degrading therapeutic enzyme pegzilarginase, a PEGylated, cobalt-substituted recombinant human arginase 1.

Metabolic remodeling contributes to the development and progression of some cancers and exposes them to vulnerabilities, including specific nutrient dependencies that can be targeted therapeutically. Arginine is a semiessential amino acid, and several cancers are unable to endogenously synthesize sufficient levels of arginine for survival and proliferation, most commonly due to reduced expression of argininosuccinate synthase (ASS1). Such cancers are dependent on arginine and they can be targeted via enzyme-mediated depletion of systemic arginine.

Targeting chemoresistant colorectal cancer via systemic administration of a BMP7 variant.

Despite intense research and clinical efforts, patients affected by advanced colorectal cancer (CRC) have still a poor prognosis. The discovery of colorectal (CR) cancer stem cell (CSC) as the cell compartment responsible for tumor initiation and propagation may provide new opportunities for the development of new therapeutic strategies. Given the reduced sensitivity of CR-CSCs to chemotherapy and the ability of bone morphogenetic proteins (BMP) to promote colonic stem cell differentiation, we aimed to investigate whether an enhanced variant of BMP7 (BMP7v) could sensitize to chemotherapy-resistant CRC cells and tumors.

Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine.

Cancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between nutrient supply and viability. In HME (human mammary epithelial) cells, deprivation of cystine led to increased cell death in cells expressing an activated epidermal growth factor receptor (EGFR) mutant.

The Impact of Transformational Leadership on Safety Climate and Individual Safety Behavior on Construction Sites.

Unsafe acts contribute dominantly to construction accidents, and increasing safety behavior is essential to reduce accidents. Previous research conceptualized safety behavior as an interaction between proximal individual differences (safety knowledge and safety motivation) and distal contextual factors (leadership and safety climate). However, relatively little empirical research has examined this conceptualization in the construction sector.

Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth.

Cancer cells experience higher oxidative stress from reactive oxygen species (ROS) than do non-malignant cells because of genetic alterations and abnormal growth; as a result, maintenance of the antioxidant glutathione (GSH) is essential for their survival and proliferation. Under conditions of elevated ROS, endogenous L-cysteine (L-Cys) production is insufficient for GSH synthesis. This necessitates uptake of L-Cys that is predominantly in its disulfide form, L-cystine (CSSC), via the xCT(-) transporter.

Climatic and psychosocial risks of heat illness incidents on construction site.

The study presented in this paper aims to identify prominent risks leading to heat illness in summer among construction workers that can be prioritised for developing effective interventions. Samples are 216 construction workers' cases at the individual level and 26 construction projects cases at the organisation level. A grounded theory is generated to define the climatic heat and psychosocial risks and the relationships between risks, timing and effectiveness of interventions.

Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency.

Arginase deficiency is caused by deficiency of arginase 1 (ARG1), a urea cycle enzyme that converts arginine to ornithine. Clinical features of arginase deficiency include elevated plasma arginine levels, spastic diplegia, intellectual disability, seizures and growth deficiency. Unlike other urea cycle disorders, recurrent hyperammonemia is typically less severe in this disorder.

A BMP7 Variant Inhibits Tumor Angiogenesis In Vitro and In Vivo through Direct Modulation of Endothelial Cell Biology.

Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have numerous biological activities including control of growth, differentiation, and vascular development. Using an in vitro co-culture endothelial cord formation assay, we investigated the role of a BMP7 variant (BMP7v) in VEGF, bFGF, and tumor-driven angiogenesis. BMP7v treatment led to disruption of neo-endothelial cord formation and regression of existing VEGF and bFGF cords in vitro.

Action at a distance: mutations of peripheral residues transform rapid reversible inhibitors to slow, tight binders of cyclooxygenase-2.

Cyclooxygenase enzymes (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin G2. The inhibitory activity of rapid, reversible COX inhibitors (ibuprofen, naproxen, mefenamic acid, and lumiracoxib) demonstrated a significant increase in potency and time dependence of inhibition against double tryptophan murine COX-2 mutants at the 89/90 and 89/119 positions. In contrast, the slow, time-dependent COX inhibitors (diclofenac, indomethacin, and flurbiprofen) were unaffected by those mutations.

Application of the predicted heat strain model in development of localized, threshold-based heat stress management guidelines for the construction industry.

Existing heat stress risk management guidelines recommended by international standards are not practical for the construction industry which needs site supervision staff to make instant managerial decisions to mitigate heat risks. The ability of the predicted heat strain (PHS) model [ISO 7933 (2004). Ergonomics of the thermal environment analytical determination and interpretation of heat stress using calculation of the predicted heat strain.

Management of climatic heat stress risk in construction: a review of practices, methodologies, and future research.

Climatic heat stress leads to accidents on construction sites brought about by a range of human factors emanating from heat induced illness, and fatigue leading to impaired capability, physical and mental. It is an occupational characteristic of construction work in many climates and the authors take the approach of re-engineering the whole safety management system rather than focusing on incremental improvement, which is current management practice in the construction industry. From a scientific viewpoint, climatic heat stress is determined by six key factors: (1) air temperature, (2) humidity, (3) radiant heat, and (4) wind speed indicating the environment, (5) metabolic heat generated by physical activities, and (6) "clothing effect" that moderates the heat exchange between the body and the environment.

Relational approach in managing construction project safety: a social capital perspective.

Existing initiatives in the management of construction project safety are largely based on normative compliance and error prevention, a risk management approach. Although advantageous, these approaches are not wholly successful in further lowering accident rates. A major limitation lies with the approaches' lack of emphasis on the social and team processes inherent in construction project settings.

A BMP7 variant inhibits the tumorigenic potential of glioblastoma stem-like cells.

Glioblastoma multiforme (GBM) is among the most aggressive tumor types and is essentially an incurable malignancy characterized by resistance to chemo-, radio-, and immunotherapy. GBM is maintained by a hierarchical cell organization that includes stem-like, precursor, and differentiated cells. Recurrence and maintenance of the tumor is attributed to a small population of undifferentiated tumor-initiating cells, defined as glioblastoma stem-like cells (GSLCs).

Knockdown of cancer testis antigens modulates neural stem cell marker expression in glioblastoma tumor stem cells.

The cancer stem cell hypothesis posits that a subpopulation of cancer stem cells is frequently responsible for a tumor's progression and resistance to treatment. The differential cellular morphology and gene expression between cancer stem cells and the majority of the tumor is becoming a point of attack for research into the next generation of therapeutic agents that may work through an induction of differentiation rather than apoptosis. Advances in the field of high-content imaging (HCI), combined with modern shRNA technology and subpopulation analysis tools, have created an ideal screening system to detect these morphological changes in a subset of cells upon gene knockdown.

An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway.

The growth and metabolic actions of growth hormone (GH) are believed to be mediated through the GH receptor (GHR) by JAK2 activation. The GHR exists as a constitutive homodimer, with signal transduction by ligand-induced realignment of receptor subunits. Based on the crystal structures, we identify a conformational change in the F'G' loop of the lower cytokine module, which results from binding of hGH but not G120R hGH antagonist.

Recurrent autonomic status epilepticus in Panayiotopoulos syndrome: video/EEG studies.

We describe a neurologically and developmentally normal child with infrequent seizures characterized by emetic symptoms and other autonomic phenomena and interictal spikes that satisfy the diagnostic criteria of Panayiotopoulos syndrome (PS). Two video/EEG recordings, taken a year apart, revealed prolonged autonomic seizures and other subtle behavioral changes, suggesting that episodes of nonconvulsive status epilepticus in PS may be more frequent than appreciated.

The contribution of the EEG technologists in the diagnosis of Panayiotopoulos syndrome (susceptibility to early onset benign childhood autonomic seizures).

Purpose: To assess the contribution of the EEG technologists in the diagnosis of children with epileptic seizures.

Methods: We analysed the clinical information obtained by the EEG technologists from children with epileptic seizures and their parents, and assessed its value for the generation of a clinically useful EEG report and a plausible electroclinical diagnosis. Interviews were based on a qualitative questionnaire, and were videotaped.

Recombinant expression of Munc18c in a baculovirus system and interaction with syntaxin4.

Two protein families that are critical for vesicle transport are the Syntaxin and Munc18/Sec1 families of proteins. These two molecules form a high affinity complex and play an essential role in vesicle docking and fusion. Munc18c was expressed as an N-terminally His-tagged fusion protein from recombinant baculovirus in Sf9 insect cells.