Enteropathogenic
and enterohemorrhagic
are diarrheagenic bacterial human pathogens that cause severe gastroenteritis. These enteric pathotypes, together with the mouse pathogen
, belong to the family ...of attaching and effacing pathogens that form a distinctive histological lesion in the intestinal epithelium. The virulence of these bacteria depends on a type III secretion system (T3SS), which mediates the translocation of effector proteins from the bacterial cytosol into the infected cells. The core architecture of the T3SS consists of a multi-ring basal body embedded in the bacterial membranes, a periplasmic inner rod, a transmembrane export apparatus in the inner membrane, and cytosolic components including an ATPase complex and the C-ring. In addition, two distinct hollow appendages are assembled on the extracellular face of the basal body creating a channel for protein secretion: an approximately 23 nm needle, and a filament that extends up to 600 nm. This filamentous structure allows these pathogens to get through the host cells mucus barrier. Upon contact with the target cell, a translocation pore is assembled in the host membrane through which the effector proteins are injected. Assembly of the T3SS is strictly regulated to ensure proper timing of substrate secretion. The different type III substrates coexist in the bacterial cytoplasm, and their hierarchical secretion is determined by specialized chaperones in coordination with two molecular switches and the so-called sorting platform. In this review, we present recent advances in the understanding of the T3SS in attaching and effacing pathogens.
Summary
The purpose of this systematic review and meta‐analysis was to estimate the prevalence of personal weight control attempts (weight loss and/or maintenance) worldwide and to identify ...correlates, personal strategies used and the underlying motives. We included epidemiological/observational studies of adults (≥18 years) reporting prevalence of weight control attempts in the past‐year. Seventy‐two studies (n = 1,184,942) met eligibility criteria. Results from high quality studies showed that 42% of adults from general populations and 44% of adults from ethnic‐minority populations reported trying to lose weight, and 23% of adults from general populations reported trying to maintain weight annually. In general population studies, higher prevalence of weight loss attempts was observed in the decade of 2000–2009 (48.2%), in Europe/Central Asia (61.3%) and in overweight/obese individuals and in women (p < 0.01). Of the 37 strategies (grouped in 10 domains of the Oxford Food and Activity Behaviours Taxonomy) and 12 motives reported for trying to control weight, exercising and dieting (within the energy compensation and restraint domains, respectively) and wellbeing and long‐term health were the most prevalent. To our knowledge, this is the first systematic review to investigate weight control attempts worldwide. Key strategies and motives were identified which have implications for future public health initiatives on weight control.
The lack of a functional vascular supply has, to a large extent, hampered the whole range of clinical applications of ‘successful’ laboratory‐based bone tissue engineering strategies. To the present, ...grafts have been dependent on post‐implant vascularization, which jeopardizes graft integration and often leads to its failure. For this reason, the development of strategies that could effectively induce the establishment of a microcirculation in the engineered constructs has become a major goal for the tissue engineering research community. This review addresses the role and importance of the development of a vascular network in bone tissue engineering and provides an overview of the most up to date research efforts to develop such a network.
The lack of a functional vasculature is recognized by the tissue engineering scientific community as the major hurdle for the clinical success of the field. Although this problem is common to most the engineered tissues there are differences inherent to the different physiologies and regenerative strategies. Therefore, this paper addresses the vascularization problem but specifically focuses on the context of bone tissue engineering.
Pancreatic cancer (PC) is the third most common type of gastrointestinal tract cancer in Europe and the fourth leading cause of death by cancer. Its initial stage is asymptomatic Therefore, the ...diagnosis tends to be late leading to locally advanced stages that presuppose late and debilitating symptoms, which consequently makes the Nutritional Status (NS) get worse. The weight loss (WL), malnutrition, and oncologic cachexia, which are quite prevalent in PC patients, reflect a poor prognosis. We aimed to track and evaluate the NS and Functional Status (FS) of PC patients (hospitalized patients – HP and Day Hospital patients – DHP) and associate NS with symptoms with nutritional impact and FS.
Observational cohort study in PC patients from Garcia de Orta Hospital. NS was tracked and evaluated using Nutritional Risk Screening (NRS-2002) and Patient-Generated Subjective Global Assessment (PG-SGA). To assess FS we used the Eastern Cooperative Oncology Group (ECOG), Karnofsky Performance Scale Index (KPSI) and Handgrip Dynamometer (HGD).
41 PC patients (30-HP and 11-DHP). 29 patients in stage IV of the tumor. 24 with a WL >10% in the last 6 months. 37 manifest symptoms with nutritional impact. 30 to 34 malnourished according to the GLIM criteria and PG-SGA, respectively. 11 in ECOG level 2 and corresponding KPSI, 10 in level 3 and 8 in level 4. 28 patients had a value of HGD below the 10th percentile. NRS-2002, PG-SGA and GLIM criteria were positively correlated with the symptoms (p < 0.01), % WL (p < 0.01) and ECOG (p < 0.01) and negatively correlated with HGS (p < 0.05 – NRS-2002; p < 0.01 – PG-SGA and GLIM criteria).
PC patients manifest debilitating symptoms with nutritional impact, namely severe WL and anorexia, which in turn lead to deterioration of the NS and FS. It is an oncology population with high nutritional risk and a higher prevalence of malnutrition, associated with severe % WL and symptoms and a sharp decline in FS.
KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of ...covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients
. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.
Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a‐synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with ...Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019: Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.
This article is related to the Special Issue Synuclein which was solicited from the Synuclein Meeting 2019. Every 2 years for about 12 years, the Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. Alpha‐synuclein (aSyn) is implicated in several neurodegenerative disorders of the brain and in this review we cover various aspects of aSyn biology and pathobiology, as depicted in the various circles.
This article is related to the Special Issue "Synuclein"
A majority of the global net primary production of mangroves is unaccounted for by current carbon budgets. It has been hypothesized that this “missing carbon” is exported as dissolved inorganic ...carbon (DIC) from subsurface respiration and groundwater (or pore-water) exchange driven by tidal pumping. We tested this hypothesis by measuring concentrations and δ
13C values of DIC, dissolved organic carbon (DOC), and particulate organic carbon (POC), along with radon (222Rn, a natural submarine groundwater discharge tracer), in a tidal creek in Moreton Bay, Australia. Concentrations and δ
13C values displayed consistent tidal variations, and mirrored the trend in 222Rn in summer and winter. DIC and DOC were exported from, and POC was imported to, the mangroves during all tidal cycles. The exported DOC had a similar δ13C value in summer and winter (∼ −30‰). The exported δ
13C-DIC showed no difference between summer and winter and had a δ
13C value slightly more enriched (∼ −22.5‰) than the exported DOC. The imported POC had differing values in summer (∼ −16‰) and winter (∼ −22‰), reflecting a combination of seagrass and estuarine particulate organic matter (POM) in summer and most likely a dominance of estuarine POM in winter. A coupled 222Rn and carbon model showed that 93–99% of the DIC and 89–92% of the DOC exports were driven by groundwater advection. DIC export averaged 3 g C m−2 d−1 and was an order of magnitude higher than DOC export, and similar to global estimates of the mangrove missing carbon (i.e., ∼ 1.9–2.7 g C m−2 d−1).
Aims
The biofilm produced by Staphylococcus aureus isolates involved in clinical or subclinical bovine mastitis and the activity of nisin and lysostaphin against the preformed biofilm produced by ...these strains were investigated.
Methods and Results
Eighteen strains were tested and all produced biofilm. Eight strains with distinct biofilm composition were selected for the antimicrobial activity assays. The minimal inhibitory concentration of each bacteriocin was determined against the planktonic cells and ranged from 15·6 to 500 μg ml−1 for nisin, and from 3·9 to 50 μg ml−1, for lysostaphin. Lysostaphin treatment (0·4 μg ml−1) for 4 h caused a strong Staph. aureus 4181 biofilm detachment and death of the majority of the sessile cells, while nisin treatment (100 μg ml−1) for the same time caused only a great reduction in cell viability. Additionally, combination of both bacteriocins for 4 h resulted in significant death of the sessile cells but no biofilm detachment.
Conclusions
The treatment with lysostaphin alone or in combination with nisin was effective in killing most biofilm sessile cells.
Significance and Impact of the Study
The action of lysostaphin, either alone or in combination with nisin, against established staphylococcal biofilm may represent an alternative to bovine mastitis control. However, the duration of the treatment should be considered for its application so that the best effectiveness can be achieved.
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