Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease.

Glucocerebrosidase (GBA1) gene mutations increase the risk of Parkinson disease (PD). While the cellular mechanisms associating GBA1 mutations and PD are unknown, loss of the glucocerebrosidase enzyme (GCase) activity, inhibition of autophagy and increased α-synuclein levels have been implicated. Here we show that autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase. ALR is a cellular process controlled by mTOR which regenerates functional lysosomes from autolysosomes formed during macroautophagy. A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models of GCase deficiency, including primary mouse neurons and the PD patient derived fibroblasts with GBA1 mutations, suggesting that ALR is compromised. Importantly Rab7, a GTPase crucial for endosome-lysosome trafficking and ALR, accumulated in GCase deficient cells, supporting the notion that lysosomal recycling is impaired. Recombinant GCase treatment reversed ALR inhibition and lysosomal dysfunction. Moreover, ALR dysfunction was accompanied by impairment of macroautophagy and chaperone-mediated autophagy, increased levels of total and phosphorylated (S129) monomeric α-synuclein, evidence of amyloid oligomers and increased α-synuclein release. Concurrently, we found increased cholesterol and altered glucosylceramide homeostasis which could compromise ALR. We propose that GCase deficiency in PD inhibits lysosomal recycling. Consequently neurons are unable to maintain the pool of mature and functional lysosomes required for the autophagic clearance of α-synuclein, leading to the accumulation and spread of pathogenic α-synuclein species in the brain. Since GCase deficiency and lysosomal dysfunction occur with ageing and sporadic PD pathology, the decrease in lysosomal reformation may be a common feature in PD

Who Meets Whom: Access and Lobbying During the Coalition Years

In 2010, the incoming Coalition government announced that it would publish details of meetings between ministers and outside interests. We have collated and coded these data and, in this article, describe patterns of access between 2010 and 2015. In some respects, access is notably fragmented. No single organisation attends more than 2.5% of the 6292 meetings held by ministers. On the contrary, business, collectively, attends fully 45% of all meetings: more than twice the share of any other category of organisation. We also find evidence of distinctive policy communities characterised by high levels of access between particular interests and ministers within specific departments

Modulation of Global Low-Frequency Motions Underlies Allosteric Regulation: Demonstration in CRP/FNR Family Transcription Factors

Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distinct site. There is growing evidence that allosteric cooperativity can be communicated by modulation of protein dynamics without conformational change. The mechanisms, however, for communicating dynamic fluctuations between sites are debated. We provide a foundational theory for how allostery can occur as a function of low-frequency dynamics without a change in structure. We have generated coarse-grained models that describe the protein backbone motions of the CRP/FNR family transcription factors, CAP of Escherichia coli and GlxR of Corynebacterium glutamicum. The latter we demonstrate as a new exemplar for allostery without conformation change. We observe that binding the first molecule of cAMP ligand is correlated with modulation of the global normal modes and negative cooperativity for binding the second cAMP ligand without a change in mean structure. The theory makes key experimental predictions that are tested through an analysis of variant proteins by structural biology and isothermal calorimetry. Quantifying allostery as a free energy landscape revealed a protein ‘‘design space’’ that identified the inter- and intramolecular regulatory parameters that frame CRP/FNR family allostery. Furthermore, through analyzing CAP variants from diverse species, we demonstrate an evolutionary selection pressure to conserve residues crucial for allosteric control. This finding provides a link between the position of CRP/FNR transcription factors within the allosteric free energy landscapes and evolutionary selection pressures. Our study therefore reveals significant features of the mechanistic basis for allostery. Changes in low-frequency dynamics correlate with allosteric effects on ligand binding without the requirement for a defined spatial pathway. In addition to evolving suitable three-dimensional structures, CRP/FNR family transcription factors have been selected to occupy a dynamic space that fine-tunes biological activity and thus establishes the means to engineer allosteric mechanisms driven by low-frequency dynamics

A Four-Antigen Mixture for Rapid Assessment of Onchocerca volvulus Infection

Caused by the filarial parasite Onchocerca volvulus, onchocerciasis is a neglected tropical disease associated with blindness and severe dermatitis. Available diagnostic methods are either invasive, require hours or days to perform, and/or need sophisticated equipment to be conducted. Thus, there is an urgent need for simple and rapid technologies for the specific diagnosis of Onchocerca volvulus infection. Here we investigated whether luciferase immunoprecipitation systems (LIPS) can produce a more rapid and specific test for diagnosis of O. volvulus infection. Using modified versions of previously identified Onchocerca-specific antigens, LIPS tests detected antibodies to all four O. volvulus antigens and easily distinguished the O. volvulus-infected samples from uninfected samples. We also tested these four different antigens in a simpler format as a combined mixture and distinguished 100% of the confirmed cases from the uninfected controls. A rapid 15-minute version of this mixture test (QLIPS) also allowed distinction of 100% of the cases from those uninfected and performed even better in identifying Onchocerca from other cross-reactive parasitic infections. This study suggests that this rapid LIPS test (QLIPS) has the potential to be used in point-of-care detection of onchocerciasis and thereby may provide a new tool for diagnosis and the monitoring of transmission control measures

Synergistic Antibacterial Effects of Metallic Nanoparticle Combinations

© The Author(s) 2019.Metallic nanoparticles have unique antimicrobial properties that make them suitable for use within medical and pharmaceutical devices to prevent the spread of infection in healthcare. The use of nanoparticles in healthcare is on the increase with silver being used in many devices. However, not all metallic nanoparticles can target and kill all disease-causing bacteria. To overcome this, a combination of several different metallic nanoparticles were used in this study to compare effects of multiple metallic nanoparticles when in combination than when used singly, as single elemental nanoparticles (SENPs), against two common hospital acquired pathogens (Staphylococcus aureus and Pseudomonas. aeruginosa). Flow cytometry LIVE/DEAD assay was used to determine rates of cell death within a bacterial population when exposed to the nanoparticles. Results were analysed using linear models to compare effectiveness of three different metallic nanoparticles, tungsten carbide (WC), silver (Ag) and copper (Cu), in combination and separately. Results show that when the nanoparticles are placed in combination (NPCs), antimicrobial effects significantly increase than when compared with SENPs (P < 0.01). This study demonstrates that certain metallic nanoparticles can be used in combination to improve the antimicrobial efficiency in destroying morphologically distinct pathogens within the healthcare and pharmaceutical industry.Peer reviewe

Sex-Specific Differences in Shoaling Affect Parasite Transmission in Guppies

Background: Individuals have to trade-off the costs and benefits of group membership during shoaling behaviour. Shoaling can increase the risk of parasite transmission, but this cost has rarely been quantified experimentally. Guppies (Poecilia reticulata) are a model system for behavioural studies, and they are commonly infected by gyrodactylid parasites, notorious fish pathogens that are directly transmitted between guppy hosts. Methodology/Principal Findings:Parasite transmission in single sex shoals of male and female guppies were observed using an experimental infection of Gyrodactylus turnbulli. Parasite transmission was affected by sex-specific differences in host behaviour, and significantly more parasites were transmitted when fish had more frequent and more prolonged contact with each other. Females shoaled significantly more than males and had a four times higher risk to contract an infection. Conclusions/Significance: Intersexual differences in host behaviours such as shoaling are driven by differences in natural and sexual selection experienced by both sexes. Here we show that the potential benefits of an increased shoaling tendency are traded off against increased risks of contracting an infectious parasite in a group-living species

Getting into hot water:sick guppies frequent warmer thermal conditions

Ectotherms depend on the environmental temperature for thermoregulation and exploit thermal regimes that optimise physiological functioning. They may also frequent warmer conditions to up-regulate their immune response against parasite infection and/or impede parasite development. This adaptive response, known as ‘behavioural fever’, has been documented in various taxa including insects, reptiles and fish, but only in response to endoparasite infections. Here, a choice chamber experiment was used to investigate the thermal preferences of a tropical freshwater fish, the Trinidadian guppy (Poecilia reticulata), when infected with a common helminth ectoparasite Gyrodactylus turnbulli, in female-only and mixed-sex shoals. The temperature tolerance of G. turnbulli was also investigated by monitoring parasite population trajectories on guppies maintained at a continuous 18, 24 or 32 °C. Regardless of shoal composition, infected fish frequented the 32 °C choice chamber more often than when uninfected, significantly increasing their mean temperature preference. Parasites maintained continuously at 32 °C decreased to extinction within 3 days, whereas mean parasite abundance increased on hosts incubated at 18 and 24 °C. We show for the first time that gyrodactylid-infected fish have a preference for warmer waters and speculate that sick fish exploit the upper thermal tolerances of their parasites to self medicate

Distributed model predictive control of linear systems with coupled constraints based on collective neurodynamic optimization

© Springer Nature Switzerland AG 2018. Distributed model predictive control explores an array of local predictive controllers that synthesize the control of subsystems independently yet they communicate to efficiently cooperate in achieving the closed-loop control performance. Distributed model predictive control problems naturally result in sequential distributed optimization problems that require real-time solution. This paper presents a collective neurodynamic approach to design and implement the distributed model predictive control of linear systems in the presence of globally coupled constraints. For each subsystem, a neurodynamic model minimizes its cost function using local information only. According to the communication topology of the network, neurodynamic models share information to their neighbours to reach consensus on the optimal control actions to be carried out. The collective neurodynamic models are proven to guarantee the global optimality of the model predictive control system

Factors affecting the use of patient survey data for quality improvement in the Veterans Health Administration

<p>Abstract</p> <p>Background</p> <p>Little is known about how to use patient feedback to improve experiences of health care. The Veterans Health Administration (VA) conducts regular patient surveys that have indicated improved care experiences over the past decade. The goal of this study was to assess factors that were barriers to, or promoters of, efforts to improve care experiences in VA facilities.</p> <p>Methods</p> <p>We conducted case studies at two VA facilities, one with stable high scores on inpatient reports of emotional support between 2002 and 2006, and one with stable low scores over the same period. A semi-structured interview was used to gather information from staff who worked with patient survey data at the study facilities. Data were analyzed using a previously developed qualitative framework describing organizational, professional and data-related barriers and promoters to data use.</p> <p>Results</p> <p>Respondents reported more promoters than barriers to using survey data, and particularly support for improvement efforts. Themes included developing patient-centered cultures, quality improvement structures such as regular data review, and training staff in patient-centered behaviors. The influence of incentives, the role of nursing leadership, and triangulating survey data with other data on patients' views also emerged as important. It was easier to collect data on current organization and practice than those in the past and this made it difficult to deduce which factors might influence differing facility performance.</p> <p>Conclusions</p> <p>Interviews with VA staff provided promising examples of how systematic processes for using survey data can be implemented as part of wider quality improvement efforts. However, prospective studies are needed to identify the most effective strategies for using patient feedback to improve specific aspects of patient-centered care.</p

Survival trends of cancer amongst the south Asian and non-south Asian population under 30 years of age in Yorkshire, UK.

Introduction: Several studies have shown differences in survival trends between ethnic groups across adults with cancer in the UK. It is unclear whether these differences exist exclusively in the older adult population or whether they begin to emerge in children and young adults. Methods: Subjects (n = 3534) diagnosed with cancer under 30 years of age in Yorkshire between 1990 and 2005 were analysed. Differences in survival rates for diagnostic subgroups were estimated by ethnic group (south Asian or not) using Kaplan–Meier estimation and Cox regression. Results: When compared to non-south Asians (all other ethnic groups excluding south Asians) a significant increased risk of death was seen for south Asians with leukaemia (hazard ratio (HR) = 1.75; 95% confidence interval (CI) = 1.11–2.76) and lymphoma (HR = 2.05; 95% CI = 1.09–3.87), whereas south Asians with solid tumours other than central nervous system tumours had a significantly reduced risk of death(HR = 0.50; 95% CI = 0.28–0.89). This was independent of socioeconomic deprivation. Conclusion: We found evidence of poorer survival outcomes for south Asians compared to non-south Asian children and young adults with leukaemia and lymphoma, but better outcomes for south Asian children and young adults with other solid tumours. This needs to be explained, and carefully addressed in the on-going development of cancer services