Genotype-environment associations reveal genes potentially linked to avian malaria infection in populations of an endemic island bird.

Patterns of pathogen prevalence are, at least partially, the result of coevolutionary host-pathogen interactions. Thus, exploring the distribution of host genetic variation in relation to infection by a pathogen within and across populations can provide important insights into mechanisms of host defence and adaptation. Here, we use a landscape genomics approach (Bayenv) in conjunction with genome-wide data (ddRADseq) to test for associations between avian malaria (Plasmodium) prevalence and host genetic variation across 13 populations of the island endemic Berthelot's pipit (Anthus berthelotii). Considerable and consistent spatial heterogeneity in malaria prevalence was observed among populations over a period of 15 years. The prevalence of malaria infection was also strongly positively correlated with pox (Avipoxvirus) prevalence. Multiple host loci showed significant associations with malaria prevalence after controlling for genome-wide neutral genetic structure. These sites were located near to or within genes linked to metabolism, stress response, transcriptional regulation, complement activity and the inflammatory response, many previously implicated in vertebrate responses to malarial infection. Our findings identify diverse genes - not just limited to the immune system - that may be involved in host protection against malaria and suggest that spatially variable pathogen pressure may be an important evolutionary driver of genetic divergence among wild animal populations, such as Berthelot's pipit. Furthermore, our data indicate that spatio-temporal variation in multiple different pathogens (e.g. malaria and pox in this case) may have to be studied together to develop a more holistic understanding of host pathogen-mediated evolution.

Replication-dependent histone biosynthesis is coupled to cell-cycle commitment.

The current model of replication-dependent (RD) histone biosynthesis posits that RD histone gene expression is coupled to DNA replication, occurring only in S phase of the cell cycle once DNA synthesis has begun. However, several key factors in the RD histone biosynthesis pathway are up-regulated by E2F or phosphorylated by CDK2, suggesting these processes may instead begin much earlier, at the point of cell-cycle commitment. In this study, we use both fixed- and live-cell imaging of human cells to address this question, revealing a hybrid model in which RD histone biosynthesis is first initiated in G1, followed by a strong increase in histone production in S phase of the cell cycle. This suggests a mechanism by which cells that have committed to the cell cycle build up an initial small pool of RD histones to be available for the start of DNA replication, before producing most of the necessary histones required in S phase. Thus, a clear distinction exists at completion of mitosis between cells that are born with the intention of proceeding through the cell cycle and replicating their DNA and cells that have chosen to exit the cell cycle and have no immediate need for histone synthesis.

Attuning to a changing ocean.

The ocean is a lifeline for human existence, but current practices risk severely undermining ocean sustainability. Present and future social-ecological challenges necessitate the maintenance and development of knowledge and action by stimulating collaboration among scientists and between science, policy, and practice. Here we explore not only how such collaborations have developed in the Nordic countries and adjacent seas but also how knowledge from these regions contributes to an understanding of how to obtain a sustainable ocean. Our collective experience may be summarized in three points: 1) In the absence of long-term observations, decision-making is subject to high risk arising from natural variability; 2) in the absence of established scientific organizations, advice to stakeholders often relies on a few advisors, making them prone to biased perceptions; and 3) in the absence of trust between policy makers and the science community, attuning to a changing ocean will be subject to arbitrary decision-making with unforeseen and negative ramifications. Underpinning these observations, we show that collaboration across scientific disciplines and stakeholders and between nations is a necessary condition for appropriate actions.

Engineered Chimeras Unveil Swappable Modular Features of Fatty Acid and Polyketide Synthase Acyl Carrier Proteins.

The strategic redesign of microbial biosynthetic pathways is a compelling route to access molecules of diverse structure and function in a potentially environmentally sustainable fashion. The promise of this approach hinges on an improved understanding of acyl carrier proteins (ACPs), which serve as central hubs in biosynthetic pathways. These small, flexible proteins mediate the transport of molecular building blocks and intermediates to enzymatic partners that extend and tailor the growing natural products. Past combinatorial biosynthesis efforts have failed due to incompatible ACP-enzyme pairings. Herein, we report the design of chimeric ACPs with features of the actinorhodin polyketide synthase ACP (ACT) and of the Escherichia coli fatty acid synthase (FAS) ACP (AcpP). We evaluate the ability of the chimeric ACPs to interact with the E. coli FAS ketosynthase FabF, which represents an interaction essential to building the carbon backbone of the synthase molecular output. Given that AcpP interacts with FabF but ACT does not, we sought to exchange modular features of ACT with AcpP to confer functionality with FabF. The interactions of chimeric ACPs with FabF were interrogated using sedimentation velocity experiments, surface plasmon resonance analyses, mechanism-based cross-linking assays, and molecular dynamics simulations. Results suggest that the residues guiding AcpP-FabF compatibility and ACT-FabF incompatibility may reside in the loop I, α-helix II region. These findings can inform the development of strategic secondary element swaps that expand the enzyme compatibility of ACPs across systems and therefore represent a critical step toward the strategic engineering of "un-natural" natural products.

Genomic associations with poxvirus across divergent island populations in Berthelot's pipit.

Understanding the mechanisms and genes that enable animal populations to adapt to pathogens is important from an evolutionary, health and conservation perspective. Berthelot's pipit (Anthus berthelotii) experiences extensive and consistent spatial heterogeneity in avian pox infection pressure across its range of island populations, thus providing an excellent system with which to examine how pathogen-mediated selection drives spatial variation in immunogenetic diversity. Here, we test for evidence of genetic variation associated with avian pox at both an individual and population-level. At the individual level, we find no evidence that variation in MHC class I and TLR4 (both known to be important in recognising viral infection) was associated with pox infection within two separate populations. However, using genotype-environment association (Bayenv) in conjunction with genome-wide (ddRAD-seq) data, we detected strong associations between population-level avian pox prevalence and allele frequencies of single nucleotide polymorphisms (SNPs) at a number of sites across the genome. These sites were located within genes involved in cellular stress signalling and immune responses, many of which have previously been associated with responses to viral infection in humans and other animals. Consequently, our analyses indicate that pathogen-mediated selection may play a role in shaping genomic variation among relatively recently colonised island bird populations and highlight the utility of genotype-environment associations for identifying candidate genes potentially involved in host-pathogen interactions.

Valuing high-seas ecosystem conservation.

The high seas provide a variety of ecosystem services that benefit society. There have, however, been few attempts to quantify the human welfare impacts of changes to the delivery of these benefits. We assessed the values of several key ecosystem service benefits derived from protecting ecosystems in the high seas of the Flemish Cap through choice experiments conducted in Canada, Norway, and Scotland. Rather than solely eliciting public willingness to pay, we also explored the determinants of variance in the estimates of willingness to pay. We aimed to determine how much respondents were willing to pay for high-seas ecosystems conservation, which factors influence individuals' willingness to pay, and whether individuals in Canada had a higher willingness to pay relative to those living in Norway and Scotland. This latter point captures distance-decay effects. On average, the public placed positive value on conserving high-seas ecosystems and on developing economic activities related to the exploitation and exploration of marine resources, despite a lack of awareness and familiarity with these environments. Distance-decay effects on willingness to pay were not clear. Scots had the highest willingness to pay and the Norwegians the lowest willingness to pay for all attributes, with the only exception being willingness to pay for a large increase in new jobs, in which case Canadians' willingness to pay was higher than Scots'. The public's willingness to pay was influenced by sociodemographic characteristics and their perceptions of high-seas ecosystems. Our results provide evidence of the impacts of high-seas governance on human welfare and that improved governance could increase the value people place on high-seas ecosystems and the services they produce.

La alta mar proporciona una variedad de servicios ambientales que benefician a la sociedad. Sin embargo, ha habido pocos intentos por cuantificar los impactos al bienestar humano ocasionados por los cambios en la entrega de estos beneficios. Analizamos los valores de varios beneficios importantes de los servicios ambientales derivados de la protección al ecosistema en la alta mar del Cabo Flamenco por medio de experimentos de elección realizados en Canadá, Noruega y Escocia. En lugar de sólo suscitar la voluntad pública para pagar, también exploramos las determinantes de la varianza en las estimaciones de la voluntad para pagar. Nuestro objetivo fue determinar cuánto están dispuestos a pagar los respondientes por la conservación de los ecosistemas de alta mar, cuáles factores influyen sobre la voluntad para pagar de cada individuo y si los individuos en Canadá tenían una mayor voluntad para pagar que aquellos individuos que viven en Noruega y en Escocia. Este último punto captura los efectos de la descomposición por distancia. En promedio, el público le colocó un valor positivo a la conservación de los ecosistemas de alta mar y al desarrollo de actividades económicas relacionadas con la explotación y la exploración de los recursos marinos, a pesar de la falta de conocimiento y familiaridad con estos ambientes. Los efectos de la descomposición por distancia sobre la voluntad para pagar no estuvieron claros. Los escoceses tuvieron la mayor voluntad para pagar y los noruegos la menor voluntad para pagar por todos los atributos, siendo la única excepción la voluntad para pagar por un incremento de trabajos nuevos, en cuyo caso, la voluntad de los canadienses fue más alta que la de los escoceses. La voluntad del público para pagar estuvo influenciada por las características sociodemográficas y su percepción de los ecosistemas de alta mar. Nuestros resultados proporcionan una evidencia de los impactos que tiene la gestión de alta mar sobre el bienestar humano y que la gestión mejorada podría incrementar el valor que las personas le ponen a los ecosistemas de alta mar y a los servicios que producen.

Have environmental preferences and willingness to pay remained stable before and during the global Covid-19 shock?

This study tests the stability of environmental preferences and willingness to pay (WTP) values using a discrete choice experiment (DCE) across three countries pre and post the peak of the first wave of the Covid-19 pandemic. A DCE examining the public's preferences for alternative environmental management plans on the high seas, in the area of the Flemish Cap, was carried out in Canada, Scotland and Norway in late 2019 and was rerun in early May 2020 shortly after the Covid-19 pandemic had officially peaked in the three countries. The same choice set sequence is tested across the two periods, using different but nationally representative samples in each case. Entropy balancing, a multivariate reweighting method, is used to achieve covariate balance between the pre and post Covid samples in the analysis. The results suggest that both preferences and WTP remain relatively stable in the face of a major public health crisis and economic upheaval.

The FtsLB subcomplex of the bacterial divisome is a tetramer with an uninterrupted FtsL helix linking the transmembrane and periplasmic regions.

In Escherichia coli, FtsLB plays a central role in the initiation of cell division, possibly transducing a signal that will eventually lead to the activation of peptidoglycan remodeling at the forming septum. The molecular mechanisms by which FtsLB operates in the divisome, however, are not understood. Here, we present a structural analysis of the FtsLB complex, performed with biophysical, computational, and in vivo methods, that establishes the organization of the transmembrane region and proximal coiled coil of the complex. FRET analysis in vitro is consistent with formation of a tetramer composed of two FtsL and two FtsB subunits. We predicted subunit contacts through co-evolutionary analysis and used them to compute a structural model of the complex. The transmembrane region of FtsLB is stabilized by hydrophobic packing and by a complex network of hydrogen bonds. The coiled coil domain probably terminates near the critical constriction control domain, which might correspond to a structural transition. The presence of strongly polar amino acids within the core of the tetrameric coiled coil suggests that the coil may split into two independent FtsQ-binding domains. The helix of FtsB is interrupted between the transmembrane and coiled coil regions by a flexible Gly-rich linker. Conversely, the data suggest that FtsL forms an uninterrupted helix across the two regions and that the integrity of this helix is indispensable for the function of the complex. The FtsL helix is thus a candidate for acting as a potential mechanical connection to communicate conformational changes between periplasmic, membrane, and cytoplasmic regions.

Willingness to pay to protect cold water corals.

There is increasing pressure to use currently untapped resources in the deep sea, raising questions regarding ecosystem service trade-offs in these often unknown areas. We assessed the trade-offs between protection of cold-water coral reefs and economic activities, such as fisheries and petroleum extraction, through a survey of a representative sample of the populations of Norway and Ireland. Choice-experiment surveys were conducted in workshop settings and through the internet. Both survey approaches provided some similar results, such as preferences for protection. Our cross-country comparison showed the general public in Norway and Ireland was willing, despite possible conflict with extractive and consumptive economic activities in the deep sea, to protect cold-water corals as habitat for fish. On average, people were willing to pay NKr 341 and NKr 424 for a small and large increase in protected areas respectively, and NKr 880 if the area is important habitat for fish, all else held equal. However, there was large variation across individuals and countries. Norwegian respondents valued pure existence of cold-water corals more than the Irish respondents, and the latter were less willing to trade off industrial activities than the former. Nonetheless, the findings support conservation of cold-water corals and more generally of ocean environments that provide habitat for fish, which the current deep sea governance systems are not adequately designed or sufficiently well-structured to secure.

RESUMEN: Existe una creciente presión por el uso correcto de recursos NO EXPLOTADOS en los mares profundos, lo que genera preguntas con respecto a las compensaciones de los servicios ambientales en los ecosistemas de estas áreas comúnmente desconocidas. Evaluamos las compensaciones entre la protección de los arrecifes de coral de aguas frías y las actividades económicas, como las pesquerías y la extracción de petróleo, por medio de un censo de muestras representativas de las poblaciones de Noruega e Irlanda. Las encuestas de experimento de elección se realizaron dentro de talleres y por medio del internet. Ambas estrategias de encuesta proporcionaron algunos resultados similares, como la preferencia por la protección. Nuestra comparación entre países mostró que el público en general en Noruega y en Irlanda estaba dispuesto, a pesar del posible conflicto con las actividades económicas de extracción y de consumo en el mar profundo, a proteger los corales de aguas frías como hábitat para peces. En promedio, las personas estuvieron dispuestas a pagar 341 coronas noruegas (NKr) y NKr 424 por un incremento menor y mayor respectivamente de las áreas protegidas y NKr 880 si el área es un hábitat importante para los peces, todo lo demás se mantuvo igual. Sin embargo, hubo una gran variación entre individuos y países. Los respondientes noruegos valoraron la pura existencia de los corales de aguas frías más que los respondientes irlandeses, y estos últimos tuvieron menos disposición que los primeros para compensar las actividades industriales. Sin embargo, nuestros resultados respaldan la conservación de los corales de aguas frías y, con mayor generalidad, de los ambientes oceánicos que proporcionan un hábitat para los peces, para lo cual los sistemas de la actual gobernanza del mar profundo no están diseñados adecuadamente o estructurados suficientemente para asegurar esto.

The Pillow Project, Infant Choking, and Basic Life Support Training for Prospective Parents: A Low-Cost Intervention for Widespread Application.

Dissemination of pediatric basic life support skills, while recommended, is not done routinely for pregnant women and their partners within the maternity services. This study evaluates an e-learning program coupled with the use of a novel infant pillow mannequin to determine whether a low-cost intervention with potential for widespread application could enable training in the event of an infant choking and the provision of basic life support. A prospective cohort study with an uncontrolled pre- and posttest design was used following institutional ethical approval. A 4-week cycle of antenatal education classes in a regional Maternity Hospital in Ireland and a purposive sample of pregnant women and their partners attending the antenatal education classes were used. The following measures were assessed: (1) confidence in knowing what to do in the event of an infant choking; (2) confidence in performing infant cardiopulmonary resuscitation (CPR); (3) ability to perform the requisite skills; and (4) the perceived acceptability of the infant pillow mannequin as a means of practice. Twenty-four individuals completed a pre- and postprogram questionnaire. The e-learning program along with practice on the pillow mannequin significantly affected confidence (P < .001) in the actions to take in the event of an infant choking and in performing infant CPR. Forty-four participants used the pillow mannequin for practice and volunteered to have their skills assessed. More than 90% demonstrated correct positioning of the infant in the event of choking, correctly identified the correct ratio of chest compressions to breaths, and conducted chest compressions to the required depth. Three distinct categories of comment were identified: usefulness of the program; simplicity of the program/pillow mannequin; and accessibility for practice at home. A self-instructional e-learning program coupled with an infant pillow mannequin enables parents to learn the procedure in the event of an infant choking and to demonstrate basic life support. This low-cost intervention has the potential for widespread application within developed and developing countries.

Screening for transmembrane association in divisome proteins using TOXGREEN, a high-throughput variant of the TOXCAT assay.

TOXCAT is a widely used genetic assay to study interactions of transmembrane helices within the inner membrane of the bacterium Escherichia coli. TOXCAT is based on a fusion construct that links a transmembrane domain of interest with a cytoplasmic DNA-binding domain from the Vibrio cholerae ToxR protein. Interaction driven by the transmembrane domain results in dimerization of the ToxR domain, which, in turn, activates the expression of the reporter gene chloramphenicol acetyl transferase (CAT). Quantification of CAT is used as a measure of the ability of the transmembrane domain to self-associate. Because the quantification of CAT is relatively laborious, we developed a high-throughput variant of the assay, TOXGREEN, based on the expression of super-folded GFP and detection of fluorescence directly in unprocessed cell cultures. Careful side-by-side comparison of TOXCAT and TOXGREEN demonstrates that the methods have comparable response, dynamic range, sensitivity and intrinsic variability both in LB and minimal media. The greatly enhanced workflow makes TOXGREEN much more scalable and ideal for screening, since hundreds of constructs can be rapidly assessed in 96 well plates. Even for small scale investigations, TOXGREEN significantly reduces time, labor and cost associated with the procedure. We demonstrate applicability with a large screening for self-association among the transmembrane domains of bitopic proteins of the divisome (FtsL, FtsB, FtsQ, FtsI, FtsN, ZipA and EzrA) belonging to 11 bacterial species. The analysis confirms a previously reported tendency for FtsB to self-associate, and suggests that the transmembrane domains of ZipA, EzrA and FtsN may also possibly oligomerize.

Acute multi-level response to defective de novo chromatin assembly in S-phase.

Long-term perturbation of de novo chromatin assembly during DNA replication has profound effects on epigenome maintenance and cell fate. The early mechanistic origin of these defects is unknown. Here, we combine acute degradation of Chromatin Assembly Factor 1 (CAF-1), a key player in de novo chromatin assembly, with single-cell genomics, quantitative proteomics, and live-microscopy to uncover these initiating mechanisms in human cells. CAF-1 loss immediately slows down DNA replication speed and renders nascent DNA hyperaccessible. A rapid cellular response, distinct from canonical DNA damage signaling, is triggered and lowers histone mRNAs. As a result, histone variants usage and their modifications are altered, limiting transcriptional fidelity and delaying chromatin maturation within a single S-phase. This multi-level response induces a cell-cycle arrest after mitosis. Our work reveals the immediate consequences of defective de novo chromatin assembly during DNA replication, explaining how at later times the epigenome and cell fate can be altered.

Primary care and youth mental health in Ireland: qualitative study in deprived urban areas.

BACKGROUND: Mental disorders account for six of the 20 leading causes of disability worldwide with a very high prevalence of psychiatric morbidity in youth aged 15-24 years. However, healthcare professionals are faced with many challenges in the identification and treatment of mental and substance use disorders in young people (e.g. young people's unwillingness to seek help from healthcare professionals, lack of training, limited resources etc.) The challenge of youth mental health for primary care is especially evident in urban deprived areas, where rates of and risk factors for mental health problems are especially common. There is an emerging consensus that primary care is well placed to address mental and substance use disorders in young people especially in deprived urban areas. This study aims to describe healthcare professionals' experience and attitudes towards screening and early intervention for mental and substance use disorders among young people (16-25 years) in primary care in deprived urban settings in Ireland. METHODS: The chosen method for this qualitative study was inductive thematic analysis which involved semi-structured interviews with 37 healthcare professionals from primary care, secondary care and community agencies at two deprived urban centres. RESULTS: We identified three themes in respect of interventions to increase screening and treatment: (1) Identification is optimised by a range of strategies, including raising awareness, training, more systematic and formalised assessment, and youth-friendly practices (e.g. communication skills, ensuring confidentiality); (2) Treatment is enhanced by closer inter-agency collaboration and training for all healthcare professionals working in primary care; (3) Ongoing engagement is enhanced by motivational work with young people, setting achievable treatment goals, supporting transition between child and adult mental health services and recognising primary care's longitudinal nature as a key asset in promoting treatment engagement. CONCLUSIONS: Especially in deprived areas, primary care is central to early intervention for youth mental health. Identification, treatment and continuing engagement are likely to be enhanced by a range of strategies with young people, healthcare professionals and systems. Further research on youth mental health and primary care, including qualitative accounts of young people's experience and developing complex interventions that promote early intervention are priorities.

"What she told us made the world of difference": carers' perspectives on a hospice at home service.

UNLABELLED: This paper explores the expectations and needs of current and bereaved carers whose relatives received care at home from a palliative care team. AIM: A hospice at home service was established in 2006 to provide patients with care in their own homes. We examined whether this model of care was helpful in mitigating carers' burden and in enabling terminally ill patients to be cared for and die at home. METHODS: This study utilized a survey and interviews. Participants were carers in the midwest of Ireland. Survey responses from 122 carers were analyzed using SPSS 18.0 (SPSS Inc., 2009); interviews with 15 carers were also conducted. RESULTS: Carers' expectations of the service were often exceeded, and quality of care dimensions were rated highly. Future improvements could include facilitating discussions on place of death and offering bereavement support. CONCLUSION: The service is supporting carers in facilitating their relatives' choice to die at home.

Youth advancing anti-racism in the 2020s.

In this review, we highlight articles on youth anti-racist action undertaken alongside the COVID-19 pandemic. Three contexts for youth anti-racism development are reviewed: educational settings, out-of-school programs, and youth-led participatory action research. The burden and costs of these undertakings are substantial for youth (particularly racially and ethnically marginalized youth), and pandemic-related stressors have exacerbated the costs and toll of this work. Accordingly, the current review centers opportunities to better scaffold and support youth-led anti-racist action with a focus on systemic and programmatic supports including engaging youth in research as a vehicle for racial justice. We conclude with a call to action for adult activists, scholars, and allies committed to partnering with youth to envision and create a more equitable and just future as we collectively emerge from a global pandemic.

Cyclin E/CDK2 and feedback from soluble histone protein regulate the S phase burst of histone biosynthesis.

Faithful DNA replication requires that cells fine-tune their histone pool in coordination with cell-cycle progression. Replication-dependent histone biosynthesis is initiated at a low level upon cell-cycle commitment, followed by a burst at the G1/S transition, but it remains unclear how exactly the cell regulates this burst in histone biosynthesis as DNA replication begins. Here, we use single-cell time-lapse imaging to elucidate the mechanisms by which cells modulate histone production during different phases of the cell cycle. We find that CDK2-mediated phosphorylation of NPAT at the restriction point triggers histone transcription, which results in a burst of histone mRNA precisely at the G1/S phase boundary. Excess soluble histone protein further modulates histone abundance by promoting the degradation of histone mRNA for the duration of S phase. Thus, cells regulate their histone production in strict coordination with cell-cycle progression by two distinct mechanisms acting in concert.

Cyclin E/CDK2 and feedback from soluble histone protein regulate the S phase burst of histone biosynthesis.

Faithful DNA replication requires that cells fine-tune their histone pool in coordination with cell-cycle progression. Replication-dependent histone biosynthesis is initiated at a low level upon cell-cycle commitment, followed by a burst at the G1/S transition, but it remains unclear how exactly the cell regulates this change in histone biosynthesis as DNA replication begins. Here, we use single-cell timelapse imaging to elucidate the mechanisms by which cells modulate histone production during different phases of the cell cycle. We find that CDK2-mediated phosphorylation of NPAT at the Restriction Point triggers histone transcription, which results in a burst of histone mRNA precisely at the G1/S phase boundary. Excess soluble histone protein further modulates histone abundance by promoting the degradation of histone mRNA for the duration of S phase. Thus, cells regulate their histone production in strict coordination with cell-cycle progression by two distinct mechanisms acting in concert.

Use of Machine Learning with Fused Spectral Data for Prediction of Product Sensory Characteristics: The Case of Grape to Wine.

Generations of sensors have been developed for predicting food sensory profiles to circumvent the use of a human sensory panel, but a technology that can rapidly predict a suite of sensory attributes from one spectral measurement remains unavailable. Using spectra from grape extracts, this novel study aimed to address this challenge by exploring the use of a machine learning algorithm, extreme gradient boosting (XGBoost), to predict twenty-two wine sensory attribute scores from five sensory stimuli: aroma, colour, taste, flavour, and mouthfeel. Two datasets were obtained from absorbance-transmission and fluorescence excitation-emission matrix (A-TEEM) spectroscopy with different fusion methods: variable-level data fusion of absorbance and fluorescence spectral fingerprints, and feature-level data fusion of A-TEEM and CIELAB datasets. The results for externally validated models showed slightly better performance using only A-TEEM data, predicting five out of twenty-two wine sensory attributes with R2 values above 0.7 and fifteen with R2 values above 0.5. Considering the complex biotransformation involved in processing grapes to wine, the ability to predict sensory properties based on underlying chemical composition in this way suggests that the approach could be more broadly applicable to the agri-food sector and other transformed foodstuffs to predict a product's sensory characteristics from raw material spectral attributes.

Machine learning for classifying and predicting grape maturity indices using absorbance and fluorescence spectra.

Absorbance-transmission and fluorescence excitation-emission matrix (A-TEEM) spectroscopy was investigated as a rapid method for predicting maturity indices using Cabernet Sauvignon grapes produced under four viticulture treatments during two growing seasons. Machine learning models were developed with fused spectral data to predict 3-isobutyl-2-methoxypyrazine (IBMP), pH, total tannins (Tannin), total soluble solids (TSS), and malic and tartaric acids based on the results from traditional analysis methods. Extreme gradient boosting (XGB) regression yielded R2 values of 0.92-0.96 for IBMP, malic acid, pH, and TSS for externally validated (Test) models, with partial least squares regression being superior for TSS prediction (R2 = 0.97). R2 values of 0.64-0.81 were achieved with either approach for tartaric acid and Tannin predictions. Classification of grape maturity, defined by quantile ranges for red colour, IBMP, malic acid, and TSS, was investigated using XGB discriminant analysis, providing an average of 78 % correctly classified samples for the Test model.

Multiple cancers escape from multiple MAPK pathway inhibitors and use DNA replication stress signaling to tolerate aberrant cell cycles.

Many cancers harbor pro-proliferative mutations of the mitogen-activated protein kinase (MAPK) pathway. In BRAF-driven melanoma cells treated with BRAF inhibitors, subpopulations of cells escape drug-induced quiescence through a nongenetic manner of adaptation and resume slow proliferation. Here, we found that this phenomenon is common to many cancer types driven by EGFR, KRAS, or BRAF mutations in response to multiple, clinically approved MAPK pathway inhibitors. In 2D cultures and 3D spheroid models of various cancer cell lines, a subset of cells escaped drug-induced quiescence within 4 days to resume proliferation. These "escapee" cells exhibited DNA replication deficits, accumulated DNA lesions, and mounted a stress response that depended on the ataxia telangiectasia and RAD3-related (ATR) kinase. We further identified that components of the Fanconi anemia (FA) DNA repair pathway are recruited to sites of mitotic DNA synthesis (MiDAS) in escapee cells, enabling successful completion of cell division. Analysis of patient tumor samples and clinical data correlated disease progression with an increase in DNA replication stress response factors. Our findings suggest that many MAPK pathway-mutant cancers rapidly escape drug action and that suppressing early stress tolerance pathways may achieve more durable clinical responses to MAPK pathway inhibitors.