Enumerating and indexing many-body intramolecular interactions:a graph theoretic approach

The central idea observes a recursive mapping of -body intramolecular interactions to -body terms that is consistent with the molecular topology. Iterative application of the line graph transformation is identified as a natural and elegant tool to accomplish the recursion. The procedure readily generalizes to arbitrary -body potentials. In particular, the method yields a complete characterization of -body interactions. The hierarchical structure of atomic index lists for each interaction order is compactly expressed as a directed acyclic graph. A pseudo-code description of the generating algorithm is given. With suitable data structures (e.g., edge lists or adjacency matrices), automatic enumeration and indexing of -body interactions can be implemented straightforwardly to handle large bio-molecular systems. Explicit examples are discussed, including a chemically relevant effective potential model of taurocholate bile salt

Femtosecond X-ray emission study of the spin cross-over dynamics in haem proteins

In haemoglobin (consisting of four globular myoglobin-like subunits), the change from the low-spin (LS) hexacoordinated haem to the high spin (HS) pentacoordinated domed form upon ligand detachment and the reverse process upon ligand binding, represent the transition states that ultimately drive the respiratory function. Visible-ultraviolet light has long been used to mimic the ligand release from the haem by photodissociation, while its recombination was monitored using time-resolved infrared to ultraviolet spectroscopic tools. However, these are neither element- nor spin-sensitive. Here we investigate the transition state in the case of Myoglobin-NO (MbNO) using femtosecond Fe Kalpha and Kbeta non-resonant X-ray emission spectroscopy (XES) at an X-ray free-electron laser upon photolysis of the Fe-NO bond. We find that the photoinduced change from the LS (S = 1/2) MbNO to the HS (S = 2) deoxy-myoglobin (deoxyMb) haem occurs in ca. 800 fs, and that it proceeds via an intermediate (S = 1) spin state. The XES observables also show that upon NO recombination to deoxyMb, the return to the planar MbNO ground state is an electronic relaxation from HS to LS taking place in ca. 30 ps. Thus, the entire ligand dissociation-recombination cycle in MbNO is a spin cross-over followed by a reverse spin cross-over process

HCMV pUL135 remodels the actin cytoskeleton to impair immune recognition of infected cells

Immune evasion genes help human cytomegalovirus (HCMV) establish lifelong persistence. Without immune pressure, laboratory-adapted HCMV strains have undergone genetic alterations. Among these, the deletion of the UL/b’ domain is associated with loss of virulence. In a screen of UL/b’, we identified pUL135 as a protein responsible for the characteristic cytopathic effect of clinical HCMV strains that also protected from natural killer (NK) and T cell attack. pUL135 interacted directly with abl interactor 1 (ABI1) and ABI2 to recruit the WAVE2 regulatory complex to the plasma membrane, remodel the actin cytoskeleton and dramatically reduce the efficiency of immune synapse (IS) formation. An intimate association between F-actin filaments in target cells and the IS was dispelled by pUL135 expression. Thus, F-actin in target cells plays a critical role in synaptogenesis, and this can be exploited by pathogens to protect against cytotoxic immune effector cells. An independent interaction between pUL135 and talin disrupted cell contacts with the extracellular matrix

Variations in hospital standardised mortality ratios (HSMR) as a result of frequent readmissions

BACKGROUND: We investigated the impact that variations in the frequency of readmissions had upon a hospital's standardised mortality ratio (HSMR). An adapted HSMR model was used in the study. Our calculations were based on the admissions of 70 hospitals in The Netherlands during the years 2005 to 2009. METHODS: Through a retrospective analysis of routinely collected hospital data, we calculated standardised in-hospital mortality ratios both by hospital and by diagnostic group (H/SMRs) using two different models. The first was the Dutch 2010 model while the second was the same model but with an additional adjustment for the readmission frequency. We compared H/SMR outcomes and the corresponding quality metrics in order to test discrimination (c-statistics), calibration (Hosmer-Lemeshow) and explanatory power (pseudo-R2 statistic) for both models. RESULTS: The SMR outcomes for model 2 compared to model 1, varied between -39% and +110%. On the HSMR level these variations ranged from -12% to +11%. There was a substantial disagreement between the models with respect to significant death on the SMR level as well as the HSMR level (~ 20%). All quality metrics comparing both models were in favour of model 2. The susceptibility to adjustment for readmission increased for longer review periods. CONCLUSIONS: The 2010 HSMR model for the Netherlands was sensitive to adjustment for the frequency of readmissions. A model without this adjustment, as opposed to a model with the adjustment, produced substantially different HSMR outcomes. The uncertainty introduced by these differences exceeded the uncertainty indicated by the 95% confidence intervals. Therefore an adjustment for the frequency of readmissions should be considered in The Netherlands, since such a model showed more favourable quality metric characteristics compared to a model without such an adjustment. Other countries could well benefit from a similar adjustment to their models. A review period of the data collected over the last three years, at least, is advisable. (aut.ref.

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

The effects of COVID-19 on cognitive performance in a community-based cohort: a COVID symptom study biobank prospective cohort study

BACKGROUND: Cognitive impairment has been reported after many types of infection, including SARS-CoV-2. Whether deficits following SARS-CoV-2 improve over time is unclear. Studies to date have focused on hospitalised individuals with up to a year follow-up. The presence, magnitude, persistence and correlations of effects in community-based cases remain relatively unexplored. METHODS: Cognitive performance (working memory, attention, reasoning, motor control) was assessed in a prospective cohort study of participants from the United Kingdom COVID Symptom Study Biobank between July 12, 2021 and August 27, 2021 (Round 1), and between April 28, 2022 and June 21, 2022 (Round 2). Participants, recruited from the COVID Symptom Study smartphone app, comprised individuals with and without SARS-CoV-2 infection and varying symptom duration. Effects of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated using multivariable ordinary least squares linear regression models weighted for inverse probability of participation, adjusting for potential confounders and mediators. The role of ongoing symptoms after COVID-19 infection was examined stratifying for self-perceived recovery. Longitudinal analysis assessed change in cognitive performance between rounds. FINDINGS: 3335 individuals completed Round 1, of whom 1768 also completed Round 2. At Round 1, individuals with previous positive SARS-CoV-2 tests had lower cognitive accuracy (N = 1737, β = −0.14 standard deviations, SDs, 95% confidence intervals, CI: −0.21, −0.07) than negative controls. Deficits were largest for positive individuals with ≥12 weeks of symptoms (N = 495, β = −0.22 SDs, 95% CI: −0.35, −0.09). Effects were comparable to hospital presentation during illness (N = 281, β = −0.31 SDs, 95% CI: −0.44, −0.18), and 10 years age difference (60–70 years vs. 50–60 years, β = −0.21 SDs, 95% CI: −0.30, −0.13) in the whole study population. Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive individuals who did not feel recovered from COVID-19, whereas individuals who reported full recovery showed no deficits. Longitudinal analysis showed no evidence of cognitive change over time, suggesting that cognitive deficits for affected individuals persisted at almost 2 years since initial infection. INTERPRETATION: Cognitive deficits following SARS-CoV-2 infection were detectable nearly two years post infection, and largest for individuals with longer symptom durations, ongoing symptoms, and/or more severe infection. However, no such deficits were detected in individuals who reported full recovery from COVID-19. Further work is needed to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms. FUNDING: Chronic Disease Research Foundation, Wellcome Trust, National Institute for Health and Care Research, Medical Research Council, British Heart Foundation, Alzheimer's Society, European Union, COVID-19 Driver Relief Fund, French National Research Agency

Sophorolipid biosurfactants: Possible uses as antibacterial and antibiofilm agent.

Biosurfactants are amphipathic, surface-active molecules of microbial origin which accumulate at interfaces reducing interfacial tension and leading to the formation of aggregated micellular structures in solution. Some biosurfactants have been reported to have antimicrobial properties, the ability to prevent adhesion and to disrupt biofilm formation. We investigated antimicrobial properties and biofilm disruption using sophorolipids at different concentrations. Growth of Gram negative Cupriavidus necator ATCC 17699 and Gram positive Bacillus subtilis BBK006 were inhibited by sophorolipids at concentrations of 5% v/v with a bactericidal effect. Sophorolipids (5% v/v) were also able to disrupt biofilms formed by single and mixed cultures of B. subtilis BBK006 and Staphylococcus aureus ATCC 9144 under static and flow conditions, as was observed by scanning electron microscopy. The results indicated that sophorolipids may be promising compounds for use in biomedical application as adjuvants to other antimicrobial against some pathogens through inhibition of growth and/or biofilm disruption

Mosquito Feeding Affects Larval Behaviour and Development in a Moth

Organisms are attacked by different natural enemies present in their habitat. While enemies such as parasitoids and predators will kill their hosts/preys when they successfully attack them, enemies such as micropredators will not entirely consume their prey. However, they can still have important consequences on the performance and ecology of the prey, such as reduced growth, increased emigration, disease transmission