IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress

When unfolded proteins accumulate to irremediably high levels within the endoplasmic reticulum (ER), intracellular signaling pathways called the unfolded protein response (UPR) become hyperactivated to?cause programmed cell death. We discovered that?thioredoxin-interacting protein (TXNIP) is?a critical node in this "terminal UPR." TXNIP becomes rapidly induced by IRE1α, an ER bifunctional kinase/endoribonuclease (RNase). Hyperactivated IRE1α increases TXNIP mRNA stability by reducing levels of a TXNIP destabilizing microRNA, miR-17. In turn, elevated TXNIP protein activates the NLRP3 inflammasome, causing procaspase-1 cleavage and interleukin 1β (IL-1β) secretion. Txnip gene deletion reduces pancreatic β cell death during ER stress and suppresses diabetes caused by proinsulin misfolding in the Akita mouse. Finally, small molecule?IRE1α RNase inhibitors suppress TXNIP production to block IL-1β secretion. In summary, the IRE1α-TXNIP pathway is used in the terminal UPR to promote sterile inflammation and programmed cell death and may be targeted to develop effective treatments for cell degenerative diseases.     

Diapause affects cuticular hydrocarbon composition and mating behavior of both sexes in Drosophila montana

Envipnmental cues,mainly photoperiod and temperature,are known to control female adult reproductive diapause in several insect species.Diapause enhances female survival during adverse conditions and postpones progeny production to the favorable season.Male diapause(a reversible inability to inseminate receptive females)has been studied much less than female diapause.However,if the males maximized their chances to fertilize females while minimizing their energy expenditure,they would be expected to be in diapause at the same time as females.We investigated Drosophila montana male mating bchavior under short-day conditions that induce diapause in females and found the males to be reproductively inactive.We also found that males reared under long-day conditions(reproducing individuals)court reproducing postdiapause fermales,but not diapausing ones.The diapausing fies of both sexes had more long-chain and less short-chain hydrocarbons on their cuticle than the reproducing ones,which presumably increase their survival under stressful conditions,but at the same time decrease their attractiveness.Our study shows that the mating behavior of females and males is well coordinated during and afier overwintering and it also gives support to the dual role of insect cuticular hydrocarbons in adaptation and mate choice.     

Synthesis,characterization, and cellular localization of a fluorescent probe of the antimalarial 8-aminoquinoline primaquine

Primaquine (PQ) is the only commercially available drug that clears dormant liver stages of malaria and blocks transmission to mosquito vectors. Although an old drug, much remains to be known about the mechanism(s) of action. Herein we develop a fluorescent tagged PQ to discover cellular localization in the human malaria parasite, Plasmodium falciparum. Successful synthesis and characterization of a primaquine-coumarin fluorescent probe (PQCP) demonstrated potency equivalent to the parent drug and the probe was not cytotoxic to HepG2 carcinoma cells. Cellular localization was found primarily in the cytosol of the asexual erythrocytic and gametocyte stages of parasite development.     

Isothiazolidinone inhibitors of PTP1B containing imidazoles and imidazolines

The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I complexed with PTP1B were solved and revealed the inhibitors are interacting extensively with the B site of the enzyme.     

Evaluation of the Clinical and Cost Effectiveness of Intermediate Care Clinics for Diabetes (ICCD): A Multicentre Cluster Randomised Controlled Trial

Background

Configuring high quality care for the rapidly increasing number of people with type 2 diabetes (T2D) is a major challenge worldwide for both providers and commissioners. In the UK, about two thirds of people with T2D are managed entirely in primary care, with wide variation in management strategies and achievement of targets. Pay for performance, introduced in 2004, initially resulted in improvements but disparities exist in ethnic minorities and the improvements are levelling off. Community based, intermediate care clinics for diabetes (ICCDs) were considered one solution and are functioning across the UK. However, there is no randomised trial evidence for the effectiveness of such clinics.

Trial Design, Methods and Findings

This is a cluster-randomised trial, involving 3 primary care trusts, with 49 general practices randomised to usual care (n = 25) or intervention (ICCDs; n = 24). All eligible adult patients with T2D were invited; 1997 were recruited and 1280 followed-up after 18-months intervention. Primary outcome: achievement of all three of the NICE targets [(HbA1c≤7.0%/53 mmol/mol; Blood Pressure <140/80 mmHg; cholesterol <154 mg/dl (4 mmol/l)]. Primary outcome was achieved in 14.3% in the intervention arm vs. 9.3% in the control arm (p = 0.059 after adjustment for covariates). The odds ratio (95% CI) for achieving primary outcome in the intervention group was 1.56 (0.98, 2.49). Primary care and community clinic costs were significantly higher in the intervention group, but there were no significant differences in hospital costs or overall healthcare costs. An incremental cost-effectiveness ratio (ICER) of +£7,778 per QALY gained, indicated ICCD was marginally more expensive at producing health gain.

Conclusions

Intermediate care clinics can contribute to improving target achievement in patients with diabetes. Further work is needed to investigate the optimal scale and organisational structure of ICCD services and whether, over time, their role may change as skill levels in primary care increase.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00945204","term_id":"NCT00945204"}}NCT00945204; National Research Register (NRR) M0014178167.     

Climate‐induced warming imposes a threat to north European spring ecosystems

Interest in climate change effects on groundwater has increased dramatically during the last decade. The mechanisms of climate‐related groundwater depletion have been thoroughly reviewed, but the influence of global warming on groundwater‐dependent ecosystems (GDEs) remains poorly known. Here we report long‐term water temperature trends in 66 northern European cold‐water springs. A vast majority of the springs (82%) exhibited a significant increase in water temperature during 1968–2012. Mean spring water temperatures were closely related to regional air temperature and global radiative forcing of the corresponding year. Based on three alternative climate scenarios representing low (RCP2.6), intermediate (RCP6) and high‐emission scenarios (RCP8.5), we estimate that increase in mean spring water temperature in the region is likely to range from 0.67 °C (RCP2.6) to 5.94 °C (RCP8.5) by 2086. According to the worst‐case scenario, water temperature of these originally cold‐water ecosystems (regional mean in the late 1970s: 4.7 °C) may exceed 12 °C by the end of this century. We used bryophyte and macroinvertebrate species data from Finnish springs and spring‐fed streams to assess ecological impacts of the predicted warming. An increase in spring water temperature by several degrees will likely have substantial biodiversity impacts, causing regional extinction of native, cold‐stenothermal spring specialists, whereas species diversity of headwater generalists is likely to increase. Even a slight (by 1 °C) increase in water temperature may eliminate endemic spring species, thus altering bryophyte and macroinvertebrate assemblages of spring‐fed streams. Climate change‐induced warming of northern regions may thus alter species composition of the spring biota and cause regional homogenization of biodiversity in headwater ecosystems.     

Parasitic Bacteria and Fungi on Common Mistletoe (Viscum album L.) and Their Potential Application in Biocontrol

This study was carried out to identify pathogenic bacteria and fungi on mistletoe (Viscum album L.) and investigate their potential use in biological control of this parasitic plant. For this purpose, a total of 48 fungal isolate and 193 bacterial strains were isolated from contaminated V. album during the summers 2005–2006. The isolated bacterial strains and fungal isolates were identified by using the Sherlock Microbial Identification System (MIS; Microbial ID, Newark) and microscopic methods, respectively. The bacterial strains that induced hypersensitive reaction (HR) on tobacco (Nicotiana tabacum L.) and fungal isolates were tested for pathogenicity on young shoots of mistletoe by using injection methods. The pathogenic bacterial strains and fungal isolates were also tested for their activity against mistletoe using spray methods. Five bacterial strains (two Burkholderia cepacia, one each of Bacillus megaterium, Bacillus pumilus and Pandoraea pulminicola) were HR and pathogenicity positive when injected but none of them when sprayed on mistletoe. When fungi were injected, 32 isolates were pathogenic but only thirteen when sprayed on mistletoe. Alternaria alternata VA?‐202, VA?‐205, VA?‐217 and Acremonium kiliense VA‐11 fungal isolates were the most effective ones and caused strong disease symptoms on mistletoe. The present study is the first report on the efficiency of potential biocontrol agents against mistletoe in Turkey.     

Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma

The orphan nuclear receptor NR4A1 exhibits pro-oncogenic activity in cancer cell lines. NR4A1 activates mTOR signaling, regulates genes such as thioredoxin domain containing 5 and isocitrate dehydrogenase 1 that maintain low oxidative stress, and coactivates specificity protein 1 (Sp1)-regulated pro-survival and growth promoting genes. Transfection of renal cell carcinoma (RCC) ACHN and 786-O cells with oligonucleotides that target NR4A1 results in a 40–60% decrease in cell proliferation and induction of apoptosis. Moreover, knockdown of NR4A1 in RCC cells decreased bcl-2, survivin and epidermal growth factor receptor expression, inhibited of mTOR signaling, induced oxidative and endoplasmic reticulum stress, and decreased TXNDC5 and IDH1. We have recently demonstrated that selected 1,1-bis(3''-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds including the p-hydroxyphenyl (DIM-C-pPhOH) and p-carboxymethyl (DIM-C-pPhCO₂Me) analogs bind NR4A1 and act as antagonists. Both DIM-C-pPhOH and DIM-C-pPhCO₂Me inhibited growth and induced apoptosis in ACHN and 786-O cells, and the functional and genomic effects of the NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. These results indicate that NR4A1 antagonists target multiple growth promoting and pro-survival pathways in RCC cells and in tumors (xenograft) and represent a novel chemotherapy for treating RCC.