Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria.

Gram-positive bacteria do not produce lipopolysaccharide as a cell wall component. As such, the polymyxin class of antibiotics, which exert bactericidal activity against Gram-negative pathogens, are ineffective against Gram-positive bacteria. The safe-for-human-use hydroxyquinoline analog ionophore PBT2 has been previously shown to break polymyxin resistance in Gram-negative bacteria, independent of the lipopolysaccharide modification pathways that confer polymyxin resistance.

Increased thyroid malignancy in patients with primary hyperparathyroidism.

Background: Multiple studies have reported the increased incidence of thyroid cancer in patients with primary hyperparathyroidism (PHPT). However, the underlying risk factors of concomitant thyroid cancer in patients with PHPT remain unknown. The primary aim of this study was to examine the records of patients with PHPT to identify characteristics that correlated with the presence of coexisting thyroid nodules, and which may have an implication for the prediction of thyroid cancer.

Positive Thyroid Peroxidase Antibody and Thyroglobulin Antibody are Associated With Better Clinicopathologic Features of Papillary Thyroid Cancer.

Objective: To compare the thyroid autoantibody status of patients with papillary thyroid cancer (PTC) and benign nodular goiter as well as possible associations between thyroid autoantibodies and clinicopathologic features of PTC.

Methods: A total of 3934 participants who underwent thyroidectomy were enrolled in this retrospective study. Patients were divided into PTC and benign nodule groups according to pathological diagnosis.

Vegetation forcing modulates global land monsoon and water resources in a CO-enriched climate.

The global monsoon is characterised by transitions between pronounced dry and wet seasons, affecting food security for two-thirds of the world's population. Rising atmospheric CO influences the terrestrial hydrological cycle through climate-radiative and vegetation-physiological forcings. How these two forcings affect the seasonal intensity and characteristics of monsoonal precipitation and runoff is poorly understood.

Predicting factors for central or lateral lymph node metastasis in conventional papillary thyroid microcarcinoma.

Background: Optimal management for papillary thyroid microcarcinoma (PTMC) remains controversial. The purpose of this study was to explore risk factors predictive of cervical lymph node metastasis in conventional PTMCs.

Methods: Conventional PTMC patients (n = 2,404) undergoing surgery between 2010 and 2017 were grouped and analyzed according to the positivity of cervical lymph node.

Discovery of glycerol phosphate modification on streptococcal rhamnose polysaccharides.

Cell wall glycopolymers on the surface of Gram-positive bacteria are fundamental to bacterial physiology and infection biology. Here we identify gacH, a gene in the Streptococcus pyogenes group A carbohydrate (GAC) biosynthetic cluster, in two independent transposon library screens for its ability to confer resistance to zinc and susceptibility to the bactericidal enzyme human group IIA-secreted phospholipase A. Subsequent structural and phylogenetic analysis of the GacH extracellular domain revealed that GacH represents an alternative class of glycerol phosphate transferase.

Group A co-ordinates manganese import and iron efflux in response to hydrogen peroxide stress.

Bacterial pathogens encounter a variety of adverse physiological conditions during infection, including metal starvation, metal overload and oxidative stress. Here, we demonstrate that group A (GAS) utilises Mn(II) import via MtsABC during conditions of hydrogen peroxide stress to optimally metallate the superoxide dismutase, SodA, with Mn. MtsABC expression is controlled by the DtxR family metalloregulator MtsR, which also regulates the expression of Fe uptake systems in GAS.

Mammary-specific ablation of Cyp24a1 inhibits development, reduces proliferation and increases sensitivity to vitamin D.

Active vitamin D (1,25(OH)2D) has been shown to regulate numerous cell processes in mammary cells. Degradation of 1,25(OH)2D is initiated by the mitochondrial enzyme, 25-hydroxyvitamin D 24-hydroxylase (CYP24 A1), and provides local control of 1,25(OH)2D bioactivity. Several reports of the association between elevated CYP24 A1 activity and breast cancer incidence, suggest that CYP24 A1 may be a target for therapeutic intervention.

Vitamin D signaling and breast cancer: Insights from transgenic mouse models.

The biologically active form of vitamin D (1,25(OH)D) regulates epithelial cell differentiation, proliferation, and apoptosis, lending weight to clinical evidence linking vitamin D insufficiency to breast cancer incidence and mortality. Local dysregulation of vitamin D metabolism has been identified in patients with breast cancer, implying that disruption of 1,25(OH)D signaling may contribute to breast cancer development in an autocrine or paracrine manner. Mouse mammary glands express the critical enzymes responsible for 1,25(OH)D synthesis (Cyp2r1 and Cyp27b1), degradation (Cyp24a1), as well as the vitamin D receptor (Vdr), and genetically modified mouse models have revealed a great deal about the role of vitamin D in cancer initiation and progression.

Transition Metal Homeostasis in Streptococcus pyogenes and Streptococcus pneumoniae.

Trace metals such as Fe, Mn, Zn and Cu are essential for various biological functions including proper innate immune function. The host immune system has complicated and coordinated mechanisms in place to either starve and/or overload invading pathogens with various metals to combat the infection. Here, we discuss the roles of Fe, Mn and Zn in terms of nutritional immunity, and also the roles of Cu and Zn in metal overload in relation to the physiology and pathogenesis of two human streptococcal species, Streptococcus pneumoniae and Streptococcus pyogenes.

The PerR-Regulated P-Type ATPase (PmtA) Acts as a Ferrous Iron Efflux Pump in Streptococcus pyogenes.

(group A [GAS]) is an obligate human pathogen responsible for a broad spectrum of human disease. GAS has a requirement for metal homeostasis within the human host and, as such, tightly modulates metal uptake and efflux during infection. Metal acquisition systems are required to combat metal sequestration by the host, while metal efflux systems are essential to protect against metal overload poisoning.

New Peptidomimetic Boronates for Selective Inhibition of the Chymotrypsin-like Activity of the 26S Proteasome.

Proteasome is a large proteinase complex that degrades proteins via its three catalytic activities. Among these activities, the "chymotrypsin-like" activity has emerged as the focus of drug discovery in cancer therapy. Here, we report new peptidomimetic boronates that are highly specific for the chymotrypsin-like catalytic activity of the proteasome.

Comparison of the biological effects of exogenous and endogenous 1,25-dihydroxyvitamin D on the mature osteoblast cell line MLO-A5.

Clinical and animal data indicate that serum 25-hydroxyvitamin D (25D) exerts an anabolic effect on bone while serum 1α,25-dihydroxyvitamin D (1,25D) stimulates bone mineral loss, although the mechanism responsible for these divergent actions is unknown. Biological effects of 25D on bone cells are dependent on the local conversion to 1,25D by the 25-hydroxyvitamin D-1α-hydroxylase enzyme, CYP27B1. Therefore, identification of possible differential activities of locally produced and exogenously supplied 1,25D in bone is likely to be informative for guiding optimal administration of vitamin D supplements for bone health.

Identification of vitamin D target genes in human breast cancer tissue.

Multiple epidemiological studies have shown that high vitamin D status is strongly associated with improved breast cancer survival. To determine the molecular pathways influenced by 1 alpha, 25-dihydroxyvitamin D (1,25D) in breast epithelial cells we isolated RNA from normal human breast and cancer tissues treated with 1,25D in an ex vivo explant system. RNA-Seq revealed 523 genes that were differentially expressed in breast cancer tissues in response to 1,25D treatment, and 127 genes with altered expression in normal breast tissues.

Keratomycosis in five dogs.

Five cases of canine keratomycosis were diagnosed and treated at a private Veterinary Ophthalmology Practice in Melbourne, Australia. Clinical presentations varied between dogs. Predisposing factors were identified in 4 of 5 cases.

Diamond burr debridement of 34 canine corneas with presumed corneal calcareous degeneration.

Objectives: To describe the signalment, presence of systemic and/or ocular comorbidities, times to detected healing and probabilities of recurrence after diamond burr debridement (DBD) of eyes with presumed corneal calcareous degeneration and secondary ulceration and/or ocular pain.

Animals Studied: Twenty-six dogs with 42 eyes affected, 34 eyes treated with DBD.

Methods: A case series was conducted using medical records from a private veterinary ophthalmology referral practice.

1,25-Dihydroxyvitamin D3 and extracellular calcium promote mineral deposition via NPP1 activity in a mature osteoblast cell line MLO-A5.

While vitamin D supplementation is common, the anabolic mechanisms that improve bone status are poorly understood. Under standard mineralising conditions including media ionised calcium of 1.1 mM, 1,25-dihydroxyvitamin D3 (1,25D) enhanced differentiation and mineral deposition by the mature osteoblast/pre-osteocyte cell line, MLO-A5.

Manganese homeostasis in group A Streptococcus is critical for resistance to oxidative stress and virulence.

Unlabelled: Streptococcus pyogenes (group A Streptococcus [GAS]) is an obligate human pathogen responsible for a spectrum of human disease states. Metallobiology of human pathogens is revealing the fundamental role of metals in both nutritional immunity leading to pathogen starvation and metal poisoning of pathogens by innate immune cells. Spy0980 (MntE) is a paralog of the GAS zinc efflux pump CzcD.

Management of canine corneal squamous cell carcinoma with lamellar keratectomy and strontium 90 plesiotherapy: 3 cases.

Purpose: To report three cases of canine corneal squamous cell carcinoma (SCC) treated with strontium 90 beta radiation as an adjunct to surgical excision.

Methods: Corneal SCC was excised with lamellar keratectomy. This was followed by local application of strontium 90 beta radiation.

The local production of 1,25(OH)2D3 promotes osteoblast and osteocyte maturation.

Maintenance of an adequate vitamin D status, as indicated by the level of circulating 25-hydroxyvitamin D (25(OH)D), is associated with higher bone mass and decreased risk of fracture. However, the molecular actions of vitamin D hormone (1,25(OH)2D3) in bone are complex, and include stimulation of osteoclastogenesis via RANK-ligand up-regulation, as well as the inhibition of mineralisation. We hypothesise that these divergent data may be reconciled by autocrine actions of 1,25(OH)2D3 which effect skeletal maintenance, as opposed to endocrine 1,25(OH)2D3 which acts to maintain serum calcium homeostasis.

Novel targets of vitamin D activity in bone: action of the vitamin D receptor in osteoblasts, osteocytes and osteoclasts.

The active form of vitamin D, 1,25-dihydroxyvitamin D3, carries out its diverse range of biological activities by binding to the nuclear vitamin D receptor, present in almost every cell of the body. It is well established that adequate serum 25-hydroxyvitamin D levels correlate with a reduction in the incidence of osteoporosis; however, the physiological basis for this relationship remains elusive. Although, the endocrine actions of vitamin D are thoroughly appreciated, the effect of vitamin D on bone tissue and bone cells is yet to be completely understood.

Vitamin D activities and metabolic bone disease.

Vitamin D activity requires an adequate vitamin D status as indicated by the serum level of 25-hydroxyvitamin D and appropriate expression of genes coding for vitamin D receptor and 25-hydroxyvitamin D 1α-hydroxylase, the enzyme which converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Vitamin D deficiency contributes to the aetiology of osteomalacia and osteoporosis. The key element of osteomalacia, or rickets in children, is a delay in mineralization.

The pleiotropic effects of vitamin D in bone.

A current controversial question related to vitamin D supplementation is what level of serum 25-hydroxyvitamin D3 (25(OH)D3) is required to reduce the incidence of osteoporotic fractures. The reasoning behind vitamin D supplementation has been mostly derived from the role of vitamin D to promote intestinal calcium absorption and reduce bone resorption. While minimum 25(OH)D3 levels of 20nmol/L are required for sufficient intestinal calcium absorption to prevent osteomalacia, the mechanistic details of how higher 25(OH)D3 levels, well beyond that required for optimal calcium absorption, are able to prevent fractures and increase bone mineral density is unclear.

Vitamin D and bone health.

Current data demonstrate that vitamin D deficiency contributes to the aetiology of at least two metabolic bone diseases, osteomalacia and osteoporosis. Osteomalacia, or rickets in children, results from a delay in mineralization and can be resolved by normalization of plasma calcium and phosphate homeostasis independently of vitamin D activity. The well characterized endocrine pathway of vitamin D metabolism and activities is solely responsible for vitamin D regulating plasma calcium and phosphate homeostasis and therefore for protecting against osteomalacia.