Guanylyl cyclase sees the light

Cyclic guanosine monophosphate (cGMP) is a critical second messenger that regulates cardiovascular function and vision in humans. Two recent papers, including one in BMC Structural Biology, have revealed atomic structures of the enzymes that catalyze the synthesis of cGMP providing new clues about the molecular basis of substrate specificity and allosteric regulation in nucleotide cyclases

In search of a modelling strategy for projecting internal migration in European countries - Demographic versus economic-geographical approaches

Internal migration is the most volatile and difficult to predict component of regional demographic change. A pure demographic approach using age and sex-specific parameters of migration intensities cannot fully capture the migration trends over time. One of the approaches that can be used for a better description of past trends and forecasting of future trends is to use additional non-demographic information such as regional economic indicators. In this paper we compare the predictive performance of pure demographic and extended economic-geographical models using data of four European countries at the so-called NUTS 2 level. The models are nested within a GLM specification%2C that allows both demographic and extended models to be written as specific cases of loglinear models. Therefore model fit and performance can be compared directly.

The role of research in viral disease eradication and elimination programs: Lessons for malaria eradication

By examining the role research has played in eradication or regional elimination initiatives for three viral diseases-smallpox, poliomyelitis, and measles-we derive nine cross-cutting lessons applicable to malaria eradication. In these initiatives, some types of research commenced as the programs began and proceeded in parallel. Basic laboratory, clinical, and field research all contributed notably to progress made in the viral programs. For each program, vaccine was the lynchpin intervention, but as the programs progressed, research was required to improve vaccine formulations, delivery methods, and immunization schedules. Surveillance was fundamental to all three programs, whilst polio eradication also required improved diagnostic methods to identify asymptomatic infections. Molecular characterization of pathogen isolates strengthened surveillance and allowed insights into the geographic source of infections and their spread. Anthropologic, sociologic, and behavioural research were needed to address cultural and religious beliefs to expand community acceptance. The last phases of elimination and eradication became increasingly difficult, as a nil incidence was approached. Any eradication initiative for malaria must incorporate flexible research agendas that can adapt to changing epidemiologic contingencies and allow planning for posteradication scenarios. © 2011 Breman et al

Using immersive audio and vibration to enhance remote diagnosis of mechanical failure in uncrewed vessels.

There is increasing interest in the maritime industry in the potential use of uncrewed vessels to improve the efficiency and safety of maritime operations. This leads to a number of questions relating to the maintenance and repair of mechanical systems, in particular, critical propulsion systems which if a failure occurs could endanger the vessel. While control data is commonly monitored remotely, engineers on board ship also employ a wide variety of sensory feedback such as sound and vibration to diagnose the condition of systems, and these are often not replicated in remote monitoring. In order to assess the potential for enhancement of remote monitoring and diagnosis, this project simulated an engine room (ER) based on a real vessel in Unreal Engine 4 for the HTC ViveTM VR headset. Audio was recorded from the vessel, with mechanical faults synthesized to create a range of simulated failures. In order to simulate operational requirements, the system was remotely fed data from an external server. The system allowed users to view normal control room data, listen to the overall sound of the space presented spatially over loudspeakers, isolate the sound of particular machinery components, and feel the vibration of machinery through a body worn vibration transducer. Users could scroll through a 10-hour time history of system performance, including audio, vibration and data for snapshots at hourly intervals. Seven experienced marine engineers were asked to assess several scenarios for potential faults in different elements of the ER. They were assessed both quantitatively regarding correct fault identification, and qualitatively in order to assess their perception of usability of the system. Users were able to diagnose simulated mechanical failures with a high degree of accuracy, mainly utilising audio and vibration stimuli, and reported specifically that the immersive audio and vibration improved realism and increased their ability to diagnose system failures from a remote location

Korn's second inequality and geometric rigidity with mixed growth conditions

Geometric rigidity states that a gradient field which is $L^p$-close to the set of proper rotations is necessarily $L^p$-close to a fixed rotation, and is one key estimate in nonlinear elasticity. In several applications, as for example in the theory of plasticity, energy densities with mixed growth appear. We show here that geometric rigidity holds also in $L^p+L^q$ and in $L^{p,q}$ interpolation spaces. As a first step we prove the corresponding linear inequality, which generalizes Korn's inequality to these spaces

Endovenous laser ablation therapy in children: applications and outcomes

BACKGROUND: Endovenous laser ablation is well recognized as the first-line treatment for superficial venous reflux with varicose veins in adults. It is not widely reported and is not an established practice in pediatric patients. OBJECTIVE: To illustrate a variety of pediatric venous conditions in which endovenous laser ablation can be utilized and to demonstrate its feasibility and safety in children. MATERIALS AND METHODS: We conducted a retrospective review of endovenous laser ablation procedures performed between January 2007 and July 2014 at two large pediatric institutions. RESULTS: We included 35 patients (17 males) who underwent endovenous laser ablation to 43 veins. Median age at first treatment was 14 years (range: 3-18 years). Median weight was 56 kg (range: 19-97 kg). Underlying diagnoses were common venous malformation (15), Klippel-Trenaunay syndrome (8), superficial venous reflux with varicose veins (5), verrucous hemangioma-related phlebectasia (4), venous varix (2) and arteriovenous fistula (1). The most common aim of treatment was to facilitate sclerotherapy. Thirty-four patients had treatment in the lower limbs and one patient in an upper limb. Ten of the veins treated with endovenous laser ablation had an additional procedure performed to close the vein. Complications attributable to endovenous laser ablation occurred in two patients (6%). One patient experienced post-procedural pain and one patient developed a temporary sensory nerve injury. Median clinical follow-up was 13 months (range: 28 days-5.7 years). The aim of the treatment was achieved in 29 of the 35 (83%) patients. CONCLUSION: Endovenous laser ablation is technically feasible and safe in children. It can be used in the management of a range of pediatric venous diseases with good outcomes

Estimation of the economic burden of COVID-19 using disability-adjusted life years (DALYs) and productivity losses in Kerala, India: a model-based analysis

OBJECTIVES: From the beginning of the COVID-19 pandemic, clinical practice and research globally have centred on the prevention of transmission and treatment of the disease. The pandemic has had a huge impact on the economy and stressed healthcare systems worldwide. The present study estimates disability-adjusted life years (DALYs), years of potential productive life lost (YPPLL) and cost of productivity lost (CPL) due to premature mortality and absenteeism secondary to COVID-19 in the state of Kerala, India. SETTING: Details on sociodemographics, incidence, death, quarantine, recovery time, etc were derived from public sources and the Collective for Open Data Distribution-Keralam. The working proportion for 5-year age–gender cohorts and the corresponding life expectancy were obtained from the 2011 Census of India. PRIMARY AND SECONDARY OUTCOME MEASURES: The impact of the disease was computed through model-based analysis on various age–gender cohorts. Sensitivity analysis was conducted by adjusting six variables across 21 scenarios. We present two estimates, one until 15 November 2020 and later updated to 10 June 2021. RESULTS: Severity of infection and mortality were higher among the older cohorts, with men being more susceptible than women in most subgroups. DALYs for males and females were 15 954.5 and 8638.4 until 15 November 2020, and 83 853.0 and 56 628.3 until 10 June 2021. The corresponding YPPLL were 1323.57 and 612.31 until 15 November 2020, and 6993.04 and 3811.57 until 10 June 2021, and the CPL (premature mortality) were 263 780 579.94 and 41 836 001.82 until 15 November 2020, and 1 419 557 903.76 and 278 275 495.29 until 10 June 2021. CONCLUSIONS: Most of the COVID-19 burden was contributed by years of life lost. Losses due to YPPLL were reduced as the impact of COVID-19 infection was lesser among the productive cohorts. The CPL values for individuals aged 40–49 years old were the highest. These estimates provide the data necessary for policymakers to work on reducing the economic burden of COVID-19 in Kerala

Human cytomegalovirus latency-associated proteins elicit immune-suppressive IL-10 producing CD4⁺ T cells.

Human cytomegalovirus (HCMV) is a widely prevalent human herpesvirus, which, after primary infection, persists in the host for life. In healthy individuals, the virus is well controlled by the HCMV-specific T cell response. A key feature of this persistence, in the face of a normally robust host immune response, is the establishment of viral latency. In contrast to lytic infection, which is characterised by extensive viral gene expression and virus production, long-term latency in cells of the myeloid lineage is characterised by highly restricted expression of viral genes, including UL138 and LUNA. Here we report that both UL138 and LUNA-specific T cells were detectable directly ex vivo in healthy HCMV seropositive subjects and that this response is principally CD4⁺ T cell mediated. These UL138-specific CD4⁺ T cells are able to mediate MHC class II restricted cytotoxicity and, importantly, show IFNγ effector function in the context of both lytic and latent infection. Furthermore, in contrast to CDCD4⁺ T cells specific to antigens expressed solely during lytic infection, both the UL138 and LUNA-specific CD4⁺ T cell responses included CD4⁺ T cells that secreted the immunosuppressive cytokine cIL-10. We also show that cIL-10 expressing CD4⁺ T-cells are directed against latently expressed US28 and UL111A. Taken together, our data show that latency-associated gene products of HCMV generate CD4⁺ T cell responses in vivo, which are able to elicit effector function in response to both lytic and latently infected cells. Importantly and in contrast to CD4⁺ T cell populations, which recognise antigens solely expressed during lytic infection, include a subset of cells that secrete the immunosuppressive cytokine cIL-10. This suggests that HCMV skews the T cell responses to latency-associated antigens to one that is overall suppressive in order to sustain latent carriage in vivo

Search algorithms as a framework for the optimization of drug combinations

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms, originally developed for digital communication, modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs with only one third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio