A systematic investigation of tobacco industry sourced data relating to illicit tobacco trade featured in Pakistan's media coverage (2015-2020).

INTRODUCTION: Previous evidence suggests the tobacco industry uses media to disseminate misleading narratives relating to illicit tobacco trade (ITT) as part of efforts to influence policy outcomes. Such evidence is largely High-Income Countries (HIC) focussed, resulting in a literature gap for Low- and Middle-Income Countries (LMICs). Pakistan and its annual budget cycle is used as a case study for addressing this gap. METHODS: Electronic English-language articles from newspapers in Pakistan (328) were sourced from LexisNexis and a sub-sample of Urdu-language electronic articles (12) were identified through internet searches.The articles were published between 2015- 2020and included claims/estimates relating to ITT, which were coded to identify cited data sources. Changes in media coverage before and after Pakistan's annual budget announcements were explored via Wilcoxon signed rank and Poisson regression tests. RESULTS: Of the 357 claims/estimates analysed, 66 (20%) were industry funded. The most prevalent sources were national government bodies (36.6%) and tobacco companies or their representatives (15.1%). Wilcoxon signed-rank and Poisson regression tests on the frequency of English-language articles both created a p-value of < 0.05 for the frequency of relevant articles between the months of April and May, compared to the other months, indicating statistical significance. CONCLUSIONS: There was a statistically significant increase in the number of English-language articles featuring claims/estimates relating to Pakistan's ITT in the months leading up to the annual budget each year. The government should consider measures to improve transparency standards within media coverage and promote factcheck journalism to safeguard against industry tactics to manipulate public discourses. IMPLICATIONS: This paper is, to our knowledge, the largest exploration of the use of data sourced from the tobacco industry within a country's media that has been undertaken to date, utilising a team of seven coders across the UK and Pakistan. Our findings reveal weaknesses within media coverage of ITT in Pakistan, both in English and Urdu language publications. We encourage the government to consider new standards to enhance transparency and promote factcheck journalism within media coverage in the country.

Cyclic Ion Mobility for Hydrogen/Deuterium Exchange-Mass Spectrometry Applications.

Hydrogen/deuterium exchange-mass spectrometry (HDX-MS) has emerged as a powerful tool to probe protein dynamics. As a bottom-up technique, HDX-MS provides information at peptide-level resolution, allowing structural localization of dynamic changes. Consequently, the HDX-MS data quality is largely determined by the number of peptides that are identified and monitored after deuteration. Integration of ion mobility (IM) into HDX-MS workflows has been shown to increase the data quality by providing an orthogonal mode of peptide ion separation in the gas phase. This is of critical importance for challenging targets such as integral membrane proteins (IMPs), which often suffer from low sequence coverage or redundancy in HDX-MS analyses. The increasing complexity of samples being investigated by HDX-MS, such as membrane mimetic reconstituted and in vivo IMPs, has generated need for instrumentation with greater resolving power. Recently, Giles et al. developed cyclic ion mobility (cIM), an IM device with racetrack geometry that enables scalable, multipass IM separations. Using one-pass and multipass cIM routines, we use the recently commercialized SELECT SERIES Cyclic IM spectrometer for HDX-MS analyses of four detergent solubilized IMP samples and report its enhanced performance. Furthermore, we develop a novel processing strategy capable of better handling multipass cIM data. Interestingly, use of one-pass and multipass cIM routines produced unique peptide populations, with their combined peptide output being 31 to 222% higher than previous generation SYNAPT G2-Si instrumentation. Thus, we propose a novel HDX-MS workflow with integrated cIM that has the potential to enable the analysis of more complex systems with greater accuracy and speed.

Fasting to stop suffering in advanced dementia.

Many healthcare providers think withholding food and fluids from advance dementia patients, even if those patients requested that when competent, is immoral. This means such patients suffer unnecessarily long. Patients have the ethical right when capacitated to specify that they want assistance with food and drink stopped when they have advanced dementia. Physicians should implement these patient choices when advance dementia patients can no longer feed themselves. In some states there may be legal barriers to this practice. The perpetual placement of food and drink within reach of patients who are unable to feed themselves is futile, so there is no need for it. The best way for persons concerned about suffering in advanced dementia is to add a supplement to one's advance directive specifying under what circumstances one wants food and fluids assistance stopped.

Racial disparities in rates of invasiveness of resected intraductal papillary mucinous neoplasms in the United States.

BACKGROUND: Racial and ethnic disparities have been observed in the multidisciplinary management of pancreatic ductal adenocarcinoma. Intraductal papillary mucinous neoplasm is the most common identifiable precursor to pancreatic ductal adenocarcinoma, where early surgical intervention before the development of an invasive intraductal papillary mucinous neoplasm improves survival. The association of race/ethnicity with the risk of identifying invasive intraductal papillary mucinous neoplasms during resection has not been previously defined. METHODS: The American College of Surgeons National Quality Improvement Program targeted pancreatectomy database (2014-2021) was queried for patients with race/ethnicity data who underwent resection of an intraductal papillary mucinous neoplasm. Backward Wald logistic regression modeling (P ≤ 0.05 for entry; P > .10 for removal) was used to identify independent predictors of invasion. RESULTS: A total of 4,505 cases of resected intraductal papillary mucinous neoplasms were identified, with 923 (20.5%) demonstrating invasive intraductal papillary mucinous neoplasms. The cohort of individuals other than non-Hispanic Whites were significantly more likely to have invasive intraductal papillary mucinous neoplasms (White, 19.9%; Black, 24.2%; Asian, 23.7%; Hispanic, 22.6%; P = .026). Such disparity could not be explained by greater comorbidity, as non-White patients were significantly younger (age <65 years: 41.7% vs 33.2%, P < .001) and had better physical status (American Society of Anesthesiologists score ≤2: 28.8% vs 25.2%, P = .053). After controlling for clinicodemographic variables, being an individual of race/ethnicity other than White was independently associated with higher odds of invasive intraductal papillary mucinous neoplasms (odds ratio, 1.280; 95% confidence interval, 1.046-1.566; P = .017). No differences in postoperative morbidity were observed. CONCLUSION: In a national cohort of patients with resected intraductal papillary mucinous neoplasms, individuals who identified as being of race/ethnicity other than White were significantly more likely to have invasive intraductal papillary mucinous neoplasms during surgical resection.

Dynamic coupling of fast channel gating with slow ATP-turnover underpins protein transport through the Sec translocon.

The Sec translocon is a highly conserved membrane assembly for polypeptide transport across, or into, lipid bilayers. In bacteria, secretion through the core channel complex-SecYEG in the inner membrane-is powered by the cytosolic ATPase SecA. Here, we use single-molecule fluorescence to interrogate the conformational state of SecYEG throughout the ATP hydrolysis cycle of SecA. We show that the SecYEG channel fluctuations between open and closed states are much faster (~20-fold during translocation) than ATP turnover, and that the nucleotide status of SecA modulates the rates of opening and closure. The SecY variant PrlA4, which exhibits faster transport but unaffected ATPase rates, increases the dwell time in the open state, facilitating pre-protein diffusion through the pore and thereby enhancing translocation efficiency. Thus, rapid SecYEG channel dynamics are allosterically coupled to SecA via modulation of the energy landscape, and play an integral part in protein transport. Loose coupling of ATP-turnover by SecA to the dynamic properties of SecYEG is compatible with a Brownian-rachet mechanism of translocation, rather than strict nucleotide-dependent interconversion between different static states of a power stroke.

A community effort in SARS-CoV-2 drug discovery.

The COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against COVID-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find 'consensus compounds'. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding-, cleavage-, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS-CoV-2 treatments.

Optimising the colour of traps requires an insect's eye view.

Colour is a critical property of many traps used to control or monitor insect pests, and applied entomologists continue to devote time and effort to improving colour for greater trapping efficiency. This work has often been guided by human colour perceptions, which differ greatly from those of the pests being studied. As a result, trap development can be a laborious process that is heavily reliant on trial and error. However, the responses of an insect's photoreceptors to a given trap colour can be calculated using well-established procedures. Photoreceptor responses represent sensory inputs that drive insect behaviour, and if their relationship to insect attraction can be determined or hypothesised, they provide metrics that can guide the rational optimisation of trap colour. This approach has recently been used successfully in separate studies of tsetse flies and thrips, but could be applied to a wide diversity of pest insects. Here we describe this approach to facilitate its use by applied entomologists. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Neural landscape diffusion resolves conflicts between needs across time.

Animals perform flexible goal-directed behaviours to satisfy their basic physiological needs1-12. However, little is known about how unitary behaviours are chosen under conflicting needs. Here we reveal principles by which the brain resolves such conflicts between needs across time. We developed an experimental paradigm in which a hungry and thirsty mouse is given free choices between equidistant food and water. We found that mice collect need-appropriate rewards by structuring their choices into persistent bouts with stochastic transitions. High-density electrophysiological recordings during this behaviour revealed distributed single neuron and neuronal population correlates of a persistent internal goal state guiding future choices of the mouse. We captured these phenomena with a mathematical model describing a global need state that noisily diffuses across a shifting energy landscape. Model simulations successfully predicted behavioural and neural data, including population neural dynamics before choice transitions and in response to optogenetic thirst stimulation. These results provide a general framework for resolving conflicts between needs across time, rooted in the emergent properties of need-dependent state persistence and noise-driven shifts between behavioural goals.

Association between SMAD4 Mutations and GATA6 Expression in Paired Pancreatic Ductal Adenocarcinoma Tumor Specimens: Data from Two Independent Molecularly-Characterized Cohorts.

Several molecular biomarkers have been identified to guide induction treatment selection for localized pancreatic ductal adenocarcinoma (PDAC). SMAD4 alterations and low GATA6 expression/modified "Moffitt" basal-like phenotype have each been associated with inferior survival uniquely for patients receiving 5-FU-based therapies. SMAD4 may directly regulate the expression of GATA6 in PDAC, pointing to a common predictive biomarker. To evaluate the relationship between SMAD4 mutations and GATA6 expression in human PDAC tumors, patients with paired SMAD4 mutation and GATA6 mRNA expression data in the TCGA and CPTAC were identified. In 321 patients (TCGA: n = 180; CPTAC: n = 141), the rate of SMAD4 alterations was 26.8%. The rate of SMAD4 alteration did not vary per tertile of normalized GATA6 expression (TCGA: p = 0.928; CPTAC: p = 0.828). In the TCGA, SMAD4 alterations and the basal-like phenotype were each associated with worse survival (log rank p = 0.077 and p = 0.080, respectively), but their combined presence did not identify a subset with uniquely inferior survival (p = 0.943). In the CPTAC, the basal-like phenotype was associated with significantly worse survival (p < 0.001), but the prognostic value was not influenced by the combined presence of SMAD4 alterations (p = 0.960). SMAD4 alterations were not associated with poor clinico-pathological features such as poor tumor grade, advanced tumor stage, positive lymphovascular invasion (LVI), or positive perineural invasion (PNI), compared with SMAD4-wildtype. Given that SMAD4 mutations were not associated with GATA6 expression or Moffitt subtype in two independent molecularly characterized PDAC cohorts, distinct biomarker-defined clinical trials are necessary.

A unifying mechanism for protein transport through the core bacterial Sec machinery.

Encapsulation and compartmentalization are fundamental to the evolution of cellular life, but they also pose a challenge: how to partition the molecules that perform biological functions-the proteins-across impermeable barriers into sub-cellular organelles, and to the outside. The solution lies in the evolution of specialized machines, translocons, found in every biological membrane, which act both as gate and gatekeeper across and into membrane bilayers. Understanding how these translocons operate at the molecular level has been a long-standing ambition of cell biology, and one that is approaching its denouement; particularly in the case of the ubiquitous Sec system. In this review, we highlight the fruits of recent game-changing technical innovations in structural biology, biophysics and biochemistry to present a largely complete mechanism for the bacterial version of the core Sec machinery. We discuss the merits of our model over alternative proposals and identify the remaining open questions. The template laid out by the study of the Sec system will be of immense value for probing the many other translocons found in diverse biological membranes, towards the ultimate goal of altering or impeding their functions for pharmaceutical or biotechnological purposes.

Association between N-Terminal Pyrenes Stabilizes the Collagen Triple Helix.

Collagen model peptides featuring the fluorophore pyrene at their N-termini have been synthesized, and their thermal denaturation has been examined using circular dichroism (CD) and fluorescence spectroscopies. Flanking the (Pro-Hyp-Gly)7 core of the peptide monomers at positions 1 and/or 23 in the primary sequence, Lys residues were introduced to ensure water solubility. Triple helices derived from such peptides show a broad excimer emission at ∼480 nm, indicative of interaction between the pyrene units. CD experiments show that the fluorophores enhance helix stability primarily through entropic effects. Unfolding temperatures (Tm) increase by up to 7 °C for systems with N-terminal lysine residues and by up to 21 °C for systems in which the first-position Lys is replaced by Ala. Tm values derived from fluorescence measurements (at 50 µM) typically lie within ∼1 °C of those obtained using CD (at 200 µM). Computational modeling in a water continuum using B3LYP-GD3 and M06-2X functionals predicts that face-to-face association of fluorophores can occur while H-bonding within the [(POG)n]3 assembly is retained. Such parallel stacking is consistent with hydrophobically driven stabilization. Labeling collagen peptides with pyrene is a synthetically simple way to promote triple helicity while providing a means to obtain Tm data on relatively dilute samples.

Body size and life history shape the historical biogeography of tetrapods.

Dispersal across biogeographic barriers is a key process determining global patterns of biodiversity as it allows lineages to colonize and diversify in new realms. Here we demonstrate that past biogeographic dispersal events often depended on species' traits, by analysing 7,009 tetrapod species in 56 clades. Biogeographic models incorporating body size or life history accrued more statistical support than trait-independent models in 91% of clades. In these clades, dispersal rates increased by 28-32% for lineages with traits favouring successful biogeographic dispersal. Differences between clades in the effect magnitude of life history on dispersal rates are linked to the strength and type of biogeographic barriers and intra-clade trait variability. In many cases, large body sizes and fast life histories facilitate dispersal success. However, species with small bodies and/or slow life histories, or those with average traits, have an advantage in a minority of clades. Body size-dispersal relationships were related to a clade's average body size and life history strategy. These results provide important new insight into how traits have shaped the historical biogeography of tetrapod lineages and may impact present-day and future biogeographic dispersal.

In vivo noninvasive mitochondrial redox assessment of the optic nerve head to predict disease.

Eye diseases are diagnosed by visualizing often irreversible structural changes occurring late in disease progression, such as retinal ganglion cell loss in glaucoma. The retina and optic nerve head have high mitochondrial energy need. Early mitochondrial/energetics dysfunction may predict vulnerability to permanent structural changes. In the in vivo murine eye, we used light-based resonance Raman spectroscopy (RRS) to assess noninvasively the redox states of mitochondria and hemoglobin which reflect availability of electron donors (fuel) and acceptors (oxygen). As proof of principle, we demonstrated that the mitochondrial redox state at the optic nerve head correlates with later retinal ganglion loss after acute intraocular pressure (IOP) elevation. This technology can potentially map the metabolic health of eye tissue in vivo complementary to optical coherence tomography, defining structural changes. Early detection (and normalization) of mitochondrial dysfunction before irreversible damage could lead to prevention of permanent neural loss.

The evolution and ecology of multiple antipredator defences.

Prey seldom rely on a single type of antipredator defence, often using multiple defences to avoid predation. In many cases, selection in different contexts may favour the evolution of multiple defences in a prey. However, a prey may use multiple defences to protect itself during a single predator encounter. Such "defence portfolios" that defend prey against a single instance of predation are distributed across and within successive stages of the predation sequence (encounter, detection, identification, approach (attack), subjugation and consumption). We contend that at present, our understanding of defence portfolio evolution is incomplete, and seen from the fragmentary perspective of specific sensory systems (e.g., visual) or specific types of defences (especially aposematism). In this review, we aim to build a comprehensive framework for conceptualizing the evolution of multiple prey defences, beginning with hypotheses for the evolution of multiple defences in general, and defence portfolios in particular. We then examine idealized models of resource trade-offs and functional interactions between traits, along with evidence supporting them. We find that defence portfolios are constrained by resource allocation to other aspects of life history, as well as functional incompatibilities between different defences. We also find that selection is likely to favour combinations of defences that have synergistic effects on predator behaviour and prey survival. Next, we examine specific aspects of prey ecology, genetics and development, and predator cognition that modify the predictions of current hypotheses or introduce competing hypotheses. We outline schema for gathering data on the distribution of prey defences across species and geography, determining how multiple defences are produced, and testing the proximate mechanisms by which multiple prey defences impact predator behaviour. Adopting these approaches will strengthen our understanding of multiple defensive strategies.

Unraveling attributes of COVID-19 vaccine acceptance and uptake in the U.S.: a large nationwide study.

SARS-CoV-2 vaccines are useful tools to combat the Coronavirus Disease 2019 (COVID-19) pandemic, but vaccine reluctance threatens these vaccines' effectiveness. To address COVID-19 vaccine reluctance and ensure equitable distribution, understanding the extent of and factors associated with vaccine acceptance and uptake is critical. We report the results of a large nationwide study in the US conducted December 2020-May 2021 of 36,711 users from COVID-19-focused smartphone-based app How We Feel on their willingness to receive a COVID-19 vaccine. We identified sociodemographic and behavioral factors that were associated with COVID-19 vaccine acceptance and uptake, and we found several vulnerable groups at increased risk of COVID-19 burden, morbidity, and mortality were more likely to be reluctant to accept a vaccine and had lower rates of vaccination. Our findings highlight specific populations in which targeted efforts to develop education and outreach programs are needed to overcome poor vaccine acceptance and improve equitable access, diversity, and inclusion in the national response to COVID-19.