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The invasive spotted-wing drosophila,Drosophila suzukii,is a major pest of fruit crops worldwide. Management ofD. suzukiirelies heavily on chemical control in both organic and conventional systems, and there is a need to develop more sustainable management practices. We evaluated the efficacy of three colors of plastic mulches at reducing populations ofD. suzukiiin fall-bearing raspberry and assessed the mulches’ impacts on canopy microclimate factors relevant toD. suzukii. Black, white, and metallic plastic mulches reduced adultD. suzukiipopulations by 42–51% and larval populations by 52–72% compared to the grower standard. The mulches did not change canopy temperature or relative humidity, but metallic mulches increased canopy light intensity compared to the black mulch. Radiance in the visible spectrum (401–680 nm) was higher for the white and metallic mulch plots, but the black mulch plots did not differ from the control. In the UV spectrum (380–400 nm), all three plastic mulches had higher radiance than the control plots. Future studies will determine whether changes in radiance are associated with the observed reduction inD. suzukiipopulations. Plastic mulches are a promising cultural practice for managingD. suzukiisince they can reduce adult and larval populations and could be incorporated into an integrated pest management program in both organic and conventional systems.

Circadian disruption increased insulin resistance and decreased mammary development in late gestation, nonlactating (dry) cows. The objective was to measure the effect of circadian disruption on transcriptomes of the liver and mammary gland. At 35 days before expected calving (BEC), multiparous dry cows were assigned to either control (CON) or phase-shifted treatments (PS). CON was exposed to 16-h light and 8-h dark. PS was exposed to 16-h light to 8-h dark, but phase of the light-dark cycle was shifted 6 h every 3 days. On day 21 BEC, liver and mammary were biopsied. RNA was isolated ( n = 6 CON, n = 6 PS per tissue), and libraries were prepared and sequenced using paired-end reads. Reads mapping to bovine genome averaged 27 ± 2 million and aligned to 14,222 protein-coding genes in liver and 15,480 in mammary analysis. In the liver, 834 genes, and in the mammary gland, 862 genes were different (nominal P < 0.05) between PS and CON. In the liver, genes upregulated in PS functioned in cholesterol biosynthesis, endoplasmic reticulum stress, wound healing, and inflammation. Genes downregulated in liver function in cholesterol efflux. In the mammary gland, genes upregulated functioned in mRNA processing and transcription and downregulated genes encoded extracellular matrix proteins and proteases, cathepsins and lysosomal proteases, lipid transporters, and regulated oxidative phosphorylation. Increased cholesterol synthesis and decreased efflux suggest that circadian disruption potentially increases the risk of fatty liver in cows. Decreased remodeling and lipid transport in mammary may decrease milk production capacity during lactation.

Background Japanese knotweed (R. japonica var japonica) is one of the world’s 100 worst invasive species, causing crop losses, damage to infrastructure, and erosion of ecosystem services. In the UK, this species is an all-female clone, which spreads by vegetative reproduction. Despite this genetic continuity, Japanese knotweed can colonise a wide variety of environmental habitats. However, little is known about the phenotypic plasticity responsible for the ability of Japanese knotweed to invade and thrive in such diverse habitats. We have used attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy, in which the spectral fingerprint generated allows subtle differences in composition to be clearly visualized, to examine regional differences in clonal Japanese knotweed. Results We have shown distinct differences in the spectral fingerprint region (1800–900 cm− 1) of Japanese knotweed from three different regions in the UK that were sufficient to successfully identify plants from different geographical regions with high accuracy using support vector machine (SVM) chemometrics. Conclusions These differences were not correlated with environmental variations between regions, raising the possibility that epigenetic modifications may contribute to the phenotypic plasticity responsible for the ability of R. japonica to invade and thrive in such diverse habitats.

INTRODUCTION The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020. METHODS We identified 1442 publications using ADNI data by conventional search methods and selected impactful studies for inclusion. RESULTS Disease progression studies supported pivotal roles for regional amyloid beta (Aβ) and tau deposition, and identified underlying genetic contributions to Alzheimer's disease (AD). Vascular disease, immune response, inflammation, resilience, and sex modulated disease course. Biologically coherent subgroups were identified at all clinical stages. Practical algorithms and methodological changes improved determination of Aβ status. Plasma Aβ, phosphorylated tau181, and neurofilament light were promising noninvasive biomarkers. Prognostic and diagnostic models were externally validated in ADNI but studies are limited by lack of ethnocultural cohort diversity. DISCUSSION ADNI has had a profound impact in improving clinical trials for AD.

Soil microbial communities are important for biogeochemical processes, along with the cycling of nutrients in an ecosystem. Their enzymatic activities are key indicators of their responses to stress. The objective of this research was to assess the effect of land reclamation on microbial biomass and activities in soils impacted by metal contamination. Phospholipid fatty acid analysis (PLFA) (PLFA) results revealed a significant increase in total microbial biomass, fungi, actinomycetes, and bacteria when limed soils were compared to unlimed samples. This change in microbial biomass was associated with a significant increase of pH. The overall level of the β-glucosidase (BG), cellobiohydrolase (CBH), and aryl sulfatase (AS) activities was significantly higher in the dolomitic limestone treated soils than in the untreated samples. However, the activity of glycine aminopeptidase (GAP) was significantly lower in the limed soil than in unlimed samples used as reference. No significant differences (P ≥ 0.05) were observed between the two types of lands (limed vs unlimed) for other enzymes tested, which includes β-N-acetylglucosaminidase (NAGase), acid phosphatase (AP), alkaline phosphatase (ALP), leucine aminopeptidase (LAP), and peroxidase (PER). The levels of enzymatic responses also varied among sites. Overall, this study revealed for the first time the effects of liming on soil microbial activities in recently reclaimed sites damaged by metals.

In our earlier work, we demonstrated that the oxidases tyrosinase (TYR), laccase (LAC), and a heme peroxidase (POX) occur widely in lichens. Here we report on the occurrence of another oxidoreductase enzyme, quinone reductase (QR) (EC 1.6.5.5). While QR has been reported to occur widely in other organisms, there is currently no information on QR activities in lichens. Here we present a survey of QR activity in 14 species of lichens. Results demonstrate that QR activity is readily detectable in all lichen species tested. However, activities vary greatly, with ‘jelly’ lichens in the genera Collema and Leptogium having the highest activities. QR, LAC and POX are all believed to have a role in extracellular hydroxyl radical production. However, in this study no correlation was found between the activities of these enzymes and the rates at which hydroxyl radicals were produced. Possible roles for QR in lichen biology are discussed.

The SARS-CoV-2 lineage B.1.1.7, designated variant of concern (VOC) 202012/01 by Public Health England1, was first identified in the UK in late summer to early autumn 20202. Whole-genome SARS-CoV-2 sequence data collected from community-based diagnostic testing for COVID-19 show an extremely rapid expansion of the B.1.1.7 lineage during autumn 2020, suggesting that it has a selective advantage. Here we show that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S gene target failures (SGTF) in community-based diagnostic PCR testing. Analysis of trends in SGTF and non-SGTF case numbers in local areas across England shows that B.1.1.7 has higher transmissibility than non-VOC lineages, even if it has a different latent period or generation time. The SGTF data indicate a transient shift in the age composition of reported cases, with cases of B.1.1.7 including a larger share of under 20-year-olds than non-VOC cases. We estimated time-varying reproduction numbers for B.1.1.7 and co-circulating lineages using SGTF and genomic data. The best-supported models did not indicate a substantial difference in VOC transmissibility among different age groups, but all analyses agreed that B.1.1.7 has a substantial transmission advantage over other lineages, with a 50% to 100% higher reproduction number.

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.

Major sensory innervation to the uterus is provided by spinal afferent nerves, whose cell bodies lie predominantly in thoracolumbar dorsal root ganglia (DRG). While the origin of the cell bodies of uterine spinal afferents is clear, the identity of their sensory endings has remained unknown. Hence, our major aim was to identify the location, morphology, and calcitonin gene-related peptide (CGRP)-immunoreactivity of uterine spinal afferent endings supplied by thoracolumbar DRG. We also sought to determine the degree of uterine afferent innervation provided by the vagus nerve. Using an anterograde tracing technique, nulliparous female C57BL/6 mice were injected unilaterally with biotinylated dextran into thoracolumbar DRG (T13-L3). After 7-9 days, uterine horns were stained to visualize traced nerve axons and endings immunoreactive to CGRP. Whole uteri from a separate cohort of animals were injected with retrograde neuronal tracer (DiI) and dye uptake in nodose ganglia was examined. Anterogradely labeled axons innervated each uterine horn, these projected rostrally or caudally from their site of entry, branching to form varicose endings in the myometrium and/or vascular plexus. Most spinal afferent endings were CGRP-immunoreactive and morphologically classified as "simple-type." Rarely, uterine nerve cell bodies were labeled in nodose ganglia. Here, we provide the first detailed description of spinal afferent nerve endings in the uterus of a vertebrate. Distinct morphological types of spinal afferent nerve endings were identified throughout multiple anatomical layers of the uterine wall. Compared to other visceral organs, uterine spinal afferent endings displayed noticeably less morphological diversity. Few neurons in nodose ganglia innervate the uterus.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder that is associated with repetitive head impacts. Neuropathologically, it is defined by the presence of perivascular hyperphosphorylated tau aggregates in cortical tissue (McKee et al., 2016, Acta Neuropathologica, 131, 75–86). Although many pathological and assumed clinical correlates of CTE have been well characterized, its effects on cortical dendritic arbors are still unknown. Here, we quantified dendrites and dendritic spines of supragranular pyramidal neurons in tissue from human frontal and occipital lobes, in 11 cases with (M(age) = 79 ± 7 years) and 5 cases without (M(age) = 76 ± 11 years) CTE. Tissue was stained with a modified rapid Golgi technique. Dendritic systems of 20 neurons per region in each brain (N = 640 neurons) were quantified using computer-assisted morphometry. One key finding was that CTE neurons exhibited increased variability and distributional changes across six of the eight dendritic system measures, presumably due to ongoing degeneration and compensatory reorganization of dendritic systems. However, despite heightened variation among CTE neurons, CTE cases exhibited lower mean values than Control cases in seven of the eight dendritic system measures. These dendritic alterations may represent a new pathological marker of CTE, and further examination of dendritic changes could contribute to both mechanistic and functional understandings of the disease.

Background Sexually transmitted infections (STIs) and Human immunodeficiency virus (HIV) share a complex bidirectional relationship, however, population prevalence and the association between the presence of STIs and HIV in a high HIV burden district in KwaZulu-Natal, South Africa is not known. Methods A total of 9812 participants aged 15–49 years were enrolled in a cross-sectional population-based household survey. Participants completed a structured questionnaire and provided first-pass urine (males) or self-collected vulvo-vaginal swabs (females) for the detection of STIs. Results Prevalence of herpes simplex virus type-2 (HSV-2) was 57.8%, syphilis was 1.6%, Neisseria gonorrhoeae was 2.8%, Chlamydia trachomatis was 7.1%, Trichomonas vaginalis was 9.0%, Mycoplasma genitalium was 5.5% and HIV was 36.3%. HIV positive status was associated with an increased probability of having M. genitalium (aPR = 1.49, 95% CI 1.02–2.19) among males and syphilis (aPR = 2.54, 95% CI 1.32–4.86), N. gonorrhoeae (aPR = 2.39, 95% CI 1.62–3.52), T. vaginalis (aPR = 1.70, 95% CI 1.43–2.01) and M. genitalium (aPR = 1.60, 95% CI 1.15–2.22) among females. HIV viral load ≥400 copies per mL was associated with an increased probability of N. gonorrhoeae (aPR = 1.91, 95% CI 1.36–2.70), C. trachomatis (aPR = 1.52, 95% CI 1.12–2.05) and M. genitalium (aPR = 1.83, 95% CI 1.27–2.63). Conclusions The high prevalence of STIs and the association between STIs and HIV, and HIV viral load underscores the public health implications of sustained transmission risk of STIs and HIV. These findings highlight the urgent need for expanding STI surveillance and implementing interventions to monitor and reduce the STI burden.

The desiccation tolerant (DT) fern species Crepidomanes inopinatum and Loxogramme abyssinica often grow together in the understory of KwaZulu-Natal Afromontane forests. Crepidomanes inopinatum is a “filmy” fern that dries rapidly because it lacks a cuticle; by contrast L. abyssinica possesses a cuticle, and therefore dries slowly. It was predicted that because C. inopinatum dries quickly, this species would have little time available to induce DT mechanisms, and therefore mainly relies on constitutive mechanisms. By comparison, the slow-drying L. abyssinica has time to put DT mechanism in place, and therefore may depend more on inducible mechanisms. Here we tested whether a drying-rehydration cycle induces two mechanisms often suggested to contribute DT, specifically increases in the activity of two reactive oxygen species (ROS) scavenging enzymes and the concentration of soluble sugars. Measurement of chlorophyll fluorescence parameters showed that both species recover rapidly during rehydration after desiccation, confirming that both are genuinely poikilohydric. In both species slow desiccation increased the activity of the ROS scavenging enzyme superoxide dismutase (SOD), and the concentrations of soluble sugars. Desiccation had little effect on the activity of the (ROS) scavenging enzyme peroxidases (POX) in either species, suggesting that maintenance of POX activity is a constitutive DT mechanism. However, the main difference between the two species was that de-acclimation occurred in the filmy fern; moist storage under cool dim light for a week reduced DT. By contrast, in the fern with a cuticle no de-acclimation occurred. However, overall, results suggest that counter to our original hypothesis, inducible DT mechanisms occur even in filmy ferns that desiccate rapidly.

Hit anti-leishmanial saponin structures selected following primary and secondary screening., Leishmaniasis is a neglected tropical disease caused by insect-vector borne protozoan parasites of the, Leishmania species. Whilst infection threatens and affects millions of the global poor, vaccines are absent and drug therapy limited. Extensive efforts have recently been made to discover new leads from small molecule synthetic compound libraries held by industry; however, the number of new chemical entities identified and entering development as anti-leishmanials has been very low. This has led to increased interest in the possibility of discovering naturally derived compounds with potent antileishmanial activity which may be developed towards clinical applications. Plant-derived triterpenoid and steroidal saponins have long been considered as anti-microbials and here we describe an investigation of a library of 137 natural (9) and semi-synthetic saponins (128) for activity against Leishmania mexicana, a causative agent of cutaneous leishmaniasis. The triterpenoid sapogenin, hederagenin, readily obtained in large quantities from Hedera helix (common ivy), was converted into a range of 128 derivatives. These semi-synthetic compounds, as well as saponins isolated from ivy, were examined with a phenotypic screening approach to identify potent and selective anti-leishmanial hits. This led to the identification of 12 compounds, including the natural saponin gypsogenin, demonstrating high potency (ED50 < 10.5 μM) against axenic L. mexicana amastigotes, the mammalian pathogenic form. One of these, hederagenin disuccinate, was sufficiently non-toxic to the macrophage host cell to facilitate further analyses, selectivity index (SI) > 10. Whilst this was not active in an infected cell model, the anti-leishmanial properties of hederagenin-derivatives have been demonstrated, and the possibility of improving the selectivity of natural hederagenin through chemical modification has been established.

Lichens are symbiotic photosynthesizing organisms with thalli formed by fungi and algae/cyanobacteria that possess high stress tolerance. One of the factors that contributes to the ability of a lichen to tolerate harsh environmental conditions is the presence of unique metabolites, including high-molecular-weight dark pigments termed melanins. The chemical composition and structure of lichen melanins remain poorly studied. We analyzed the elemental composition, the main functional groups, and the physicochemical properties of melanin extracted from Cetraria islandica and Pseudevernia furfuracea lichens. Based on the C/N ratio, this pigment is allomelanin. We also identified functional groups that provide photoprotective and antioxidant properties of melanin. Melanin synthesis might be an essential defense mechanism contributing to the survival of lichens under exposure to UV radiation.

The peritrophic matrix of blood-feeding insects is a chitinous structure that forms a protective barrier against oral pathogens and abrasive particles1. Tsetse flies transmit Trypanosoma brucei, which is the parasite that causes human sleeping sickness and is also partially responsible for animal trypanosomiasis in Sub-Saharan Africa. For this parasite to establish an infection in flies, it must first colonize the area between the peritrophic matrix and gut epithelium called the ectoperitrophic space. Although unproven, it is generally accepted that trypanosomes reach the ectoperitrophic space by penetrating the peritrophic matrix in the anterior midgut2,3,4. Here, we revisited this event using fluorescence- and electron-microscopy methodologies. We show that trypanosomes penetrate the ectoperitrophic space in which the newly made peritrophic matrix is synthesized by the proventriculus. Our model describes how these proventriculus-colonizing parasites can either migrate to the ectoperitrophic space or become trapped within peritrophic matrix layers to form cyst-like bodies that are passively pushed along the gut as the matrix gets remodelled. Furthermore, early proventricular colonization seems to be promoted by factors in trypanosome-infected blood that cause higher salivary gland infections and potentially increase parasite transmission.

The use of wastewater for irrigation in agroforestry is cost-effective for water management. It is well established that rhizospheric microorganisms such as N2-fixing bacteria are able to modulate rhizobioaugmention and to boost phyoremediation process. To date, no study has been conducted to evaluate biological effects of rhizobioaugmentation in Casuarina glauca trees induced by their symbiont N-fixing actinobacteria of the genus Frankia. The objective of the present study was to evaluate the main effects of rhizobioaugmentation on the biological activity in the C. glauca’s rhizosphere and on C. glauca growth in soils irrigated with industrial wastewater. Two Frankia strains (BMG5.22 and BMG5.23) were used in a single or dual inoculations of C. glauca seedlings irrigated with industrial wastewater. Soil enzymes activity related to carbon, phosphorus, sulfur and nitrogen cycling were measured. Results revealed that the BMG5.22 Frankia strain increases significantly the size (dry weight) of C. glauca shoots and roots while dual inoculation increased significantly the root length. Surprisingly, β-glucosidase (BG), cellobiohydrolase (CBH), β-N-acetylglucosaminidase (NAGase), aryl sulfatase (AS), acid phosphatase (AP), alkaline phosphatase (AlP), glycine aminopeptidase (GAP), leucine aminopeptidase (LAP), and peroxidase (PER) activity in the rhizosphere decreased significantly in soils treated with the two strains of symbionts. This suggests no positive correlations between enzymatic activity and C. glauca growth.

It has been hypothesized that the Neolithic transition towards an agricultural and pastoralist economy facilitated the emergence of human adapted pathogens. Here, we recovered eight Salmonella enterica subsp. enterica genomes from human skeletons of transitional foragers, pastoralists, and agro-pastoralists in western Eurasia that were up to 6,500 years old. Despite the high genetic diversity of S. enterica all ancient bacterial genomes clustered in a single previously uncharacterized branch that contains S. enterica adapted to multiple mammalian species. All ancient bacterial genomes from prehistoric (agro-)pastoralists fall within a part of this branch that also includes the human-specific S. enterica Paratyphi C, illustrating the evolution of a human pathogen over a period of five thousand years. Bacterial genomic comparisons suggest that the earlier ancient strains were not host specific, differed in pathogenic potential, and experienced convergent pseudogenization that accompanied their downstream host adaptation. These observations support the concept that the emergence of human adapted S. enterica is linked to human cultural transformations.

Treatment options for pancreatic cancer (PC) are severely limited due to late diagnosis, early metastasis and the inadequacy of chemotherapy and radiotherapy to combat the aggressive biology of the disease. In recent years, plant-derived bioactive compounds have emerged as a source of novel, anti-cancer agents. Used in traditional medicine worldwide, Elaeocarpus species have reported anti-inflammatory, antioxidant and anti-cancer properties. This study aimed to isolate and identify potential anti-PC compounds in the fruit of Elaeocarpus reticulatus Sm. A 50% acetone crude extract significantly decreased the viability of four pancreatic cell lines (≥ 10 µg/mL for BxPC-3 cells) and induced apoptosis in BxPC-3 and HPDE cells. Analysis by HPLC identified the triterpenoid Cucurbitacin I as a likely component of the extract. Furthermore, treatment with Cucurbitacin I significantly reduced the viability of HPDE and BxPC-3 cells, with results comparable to the same concentration of gemcitabine. Interestingly, attempts to isolate bioactive compounds revealed that the crude extract was more effective at reducing PC-cell viability than the fractionated extracts. This study provides initial insight into the bioactive constituents of E. reticulatus fruits.

Across Europe, the genetics of the Chalcolithic/Bronze Age transition is increasingly characterized in terms of an influx of Steppe-related ancestry. The effect of this major shift on the genetic structure of populations in the Italian Peninsula remains underexplored. Here, genome-wide shotgun data for 22 individuals from commingled cave and single burials in Northeastern and Central Italy dated between 3200 and 1500 BCE provide the first genomic characterization of Bronze Age individuals (n = 8; 0.001-1.2× coverage) from the central Italian Peninsula, filling a gap in the literature between 1950 and 1500 BCE. Our study confirms a diversity of ancestry components during the Chalcolithic and the arrival of Steppe-related ancestry in the central Italian Peninsula as early as 1600 BCE, with this ancestry component increasing through time. We detect close patrilineal kinship in the burial patterns of Chalcolithic commingled cave burials and a shift away from this in the Bronze Age (2200-900 BCE) along with lowered runs of homozygosity, which may reflect larger changes in population structure. Finally, we find no evidence that the arrival of Steppe-related ancestry in Central Italy directly led to changes in frequency of 115 phenotypes present in the dataset, rather that the post-Roman Imperial period had a stronger influence, particularly on the frequency of variants associated with protection against Hansen's disease (leprosy). Our study provides a closer look at local dynamics of demography and phenotypic shifts as they occurred as part of a broader phenomenon of widespread admixture during the Chalcolithic/Bronze Age transition. ispartof: CURRENT BIOLOGY vol:31 issue:12 pages:2576-+ ispartof: location:England status: published

Helicobacter pylori colonization of the stomach is a strong risk factor for the development of stomach cancer and peptic ulcer disease. In this study, we tested the hypothesis that H. pylori infection triggers alterations in gastric lipid composition. Mongolian gerbils were experimentally infected with H. pylori for 3 months. Conventional histologic staining revealed mucosal inflammation in stomachs from the H. pylori-infected animals but not in stomachs from uninfected control animals. Atrophic gastritis (a premalignant condition characterized by loss of corpus-specific parietal and chief cells), gastric mucosal hyperplasia, dysplasia, and/or gastric cancer were detected in stomachs from several infected animals. We then used imaging mass spectrometry to analyze the relative abundance and spatial distribution of gastric lipids. We detected ions corresponding to 36 distinct lipids that were differentially abundant when comparing gastric tissues from H. pylori-infected animals with tissues from uninfected animals. Liquid chromatography-tandem mass spectrometry analysis of lipid extracts from homogenized gastric tissues provided additional supportive evidence for the identification of several differentially abundant lipids. Sixteen of the differentially abundant lipids were localized mainly to the gastric corpus in stomachs from uninfected animals and were markedly reduced in abundance in stomachs from H. pylori-infected animals with severe disease (atrophic gastritis and dysplasia or gastric cancer). These findings indicate that H. pylori infection can lead to alterations in gastric lipid composition and constitute a new approach for identifying biomarkers of gastric atrophy and premalignant changes. IMPORTANCE H. pylori colonization of the stomach triggers a cascade of gastric alterations that can potentially culminate in stomach cancer. The molecular alterations that occur in gastric tissue prior to development of stomach cancer are not well understood. We demonstrate here that H. pylori-induced premalignant changes in the stomach are accompanied by extensive alterations in gastric lipid composition. These alterations are predicted to have important functional consequences relevant to H. pylori-host interactions and the pathogenesis of gastric cancer.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were rising during early summer 2021 in many countries as a result of the Delta variant. We assessed reverse transcription polymerase chain reaction swab positivity in the Real-time Assessment of Community Transmission–1 (REACT-1) study in England. During June and July 2021, we observed sustained exponential growth with an average doubling time of 25 days, driven by complete replacement of the Alpha variant by Delta and by high prevalence at younger, less-vaccinated ages. Prevalence among unvaccinated people [1.21% (95% credible interval 1.03%, 1.41%)] was three times that among double-vaccinated people [0.40% (95% credible interval 0.34%, 0.48%)]. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.

Objective: Tau neurofibrillary tangles (T) are the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in Alzheimer's disease (AD). However, there is substantial variability in the T-N relationship – manifested in higher or lower atrophy than expected for level of tau in a given brain region. The goal of this study was to determine if region-based quantitation of this variability allows for identification of underlying modulatory factors, including polypathology. Methods: Cortical thickness (N) and 18F-Flortaucipir SUVR (T) were computed in 104 gray matter regions from a cohort of cognitively-impaired, amyloid-positive (A+) individuals. Region-specific residuals from a robust linear fit between SUVR and cortical thickness were computed as a surrogate for T-N mismatch. A summary T-N mismatch metric defined using residuals were correlated with demographic and imaging-based modulatory factors, and to partition the cohort into data-driven subgroups. Results: The summary T-N mismatch metric correlated with underlying factors such as age and burden of white matter hyperintensity lesions. Data-driven subgroups based on clustering of residuals appear to represent different biologically relevant phenotypes, with groups showing distinct spatial patterns of higher or lower atrophy than expected. Interpretation: These data support the notion that a measure of deviation from a normative relationship between tau burden and neurodegeneration across brain regions in individuals on the AD continuum captures variability due to multiple underlying factors, and can reveal phenotypes, which if validated, may help identify possible contributors to neurodegeneration in addition to tau, which may ultimately be useful for cohort selection in clinical trials. ANN NEUROL 2021;90:751–762.

We identify amino acid variants within dominant SARS-CoV-2 T-cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T-cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T-cell responsiveness was seen due to Q213K in the A*01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215, due to P13L, P13S and P13T in the B*27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17, and due to T362I and P365S in the A*03:01/A*11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T-cell lines unable to recognise variant epitopes have diverse T-cell receptor repertoires. These data demonstrate the potential for T-cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T-cell as well as humoral immunity., Graphical Abstract

Caloric restriction increases lifespan across species and has health benefits in humans. Because complying with a low-calorie diet is challenging, here we investigated pharmacological interventions mimicking the benefits of caloric restriction. Searching for compounds that elicit a similar gene expression signature to caloric restriction, we identified rilmenidine, an I1-imidazoline receptor agonist and prescription medication for the treatment of hypertension. We then show that treating C. elegans with rilmenidine at young and older ages increases lifespan. We also demonstrate that the stress-resilience, healthspan, and lifespan benefits upon rilmenidine treatment in worms are mediated by the I1-imidazoline receptor nish-1, implicating this receptor as a potential longevity target. Furthermore, we show that rilmenidine treatment increased ERK phosphorylation via NISH-1. Consistent with the shared caloric-restriction-mimicking gene signature, supplementing rilmenidine to caloric restricted C. elegans, genetic reduction of TORC1 function, or rapamycin treatment did not further increase lifespan. The rilmenidine-induced longevity required the transcription factors FOXO/DAF-16 and NRF1,2,3/SKN-1, both important for caloric restriction-mediated longevity. Furthermore, we find that autophagy, but not AMPK signaling, was needed for rilmenidine-induced longevity. Lastly, we find that treating mice with rilmenidine showed transcriptional changes in liver and kidney similar to caloric restriction. Overall, our findings reveal rilmenidine as a caloric restriction mimetic and as a novel geroprotective compound.

The ratio of concentrate to forage within diets is known to alter rumen microbial profiles, but comparatively less information is available on the effect of differing sources of individual nutrients on the microbiome. The objective of this study was to investigate rumen microbial responses to diets composed of protein and fiber sources expected to vary in nutrient degradability. The responses of interest included relative abundances of bacterial taxa as well as estimations of community richness and diversity. Ten ruminally cannulated wethers (Suffolk, Dorset, or Suffolk × Dorset) received four diet treatments consisting of either beet pulp or timothy hay and soybean meal (SBM) or heat-treated soybean meal (HSBM) in a partially replicated 4 × 4 Latin square experiment for 21 days. Timothy hay and beet pulp were expected to provide differing rumen degradabilities of neutral detergent fiber (NDF) while the soybean meals were expected to provide differing rumen degradabilities of crude protein (CP). Solid and liquid samples of rumen contents were collected for microbial DNA isolation and Next-Generation sequencing. Numerous rumen bacterial population shifts were observed due to change in fiber source, with increased abundances (P < 0.05) of fibrolytic populations associated with timothy hay diets compared with beet pulp diets. Conversely, populations of the pectin-degrading genera, Treponema and Lachnospira, increased on the beet pulp treatment (P = 0.015 and P = 0.0049, respectively). Limited impact on bacterial taxa was observed between diets differing in protein source. The Paraprevotellaceae genus YRC22 was observed to increase in abundance on HSBM diets (P = 0.023) and the phylum Spirochaetes tended to be more abundant on SBM than HSBM diets (P = 0.071). Beet pulp decreased rumen bacterial diversity (P = 0.0027) and tended to decrease bacterial species richness (P = 0.051) compared to timothy hay. Our results serve to further underscore the sensitivity of rumen microbes to changes in their preferred substrates, particularly of those associated with fiber degradation.

Integration host factor (IHF) is a heterodimeric nucleoid-associated protein that plays roles in bacterial nucleoid architecture and genome-wide gene regulation. The ihfA and ihfB genes encode the subunits and are located 350 kilobase pairs apart, in the Right replichore of the Salmonella chromosome. IHF is composed of one IhfA and one IhfB subunit. Despite this 1:1 stoichiometry, mass spectrometry revealed that IhfB is produced in 2-fold excess over IhfA. We re-engineered Salmonella to exchange reciprocally the protein-coding regions of ihfA and ihfB, such that each relocated protein-encoding region was driven by the expression signals of the other’s gene. Mass spectrometry showed that in this ‘rewired’ strain, IhfA is produced in excess over IhfB, correlating with enhanced stability of the hybrid ihfB-ihfA mRNA that was expressed from the ihfB promoter. Nevertheless, the rewired strain grew at a similar rate to the wild type, had identical cell morphology, and was similar in competitive fitness. However, compared to the wild type, it was less motile, had growth-phase-specific reductions in SPI-1 and SPI-2 gene expression and was engulfed at a higher rate by RAW macrophage. Our data show that while exchanging the physical locations of its ihf genes and the rewiring of their regulatory circuitry are well tolerated in Salmonella, genes involved in the production of type 3 secretion systems exhibit dysregulation accompanied by altered phenotypes.IMPACT STATEMENTIntegration Host Factor (IHF) is an abundant nucleoid-associated protein that organises DNA architecturally, influencing gene expression globally in Salmonella and other bacteria. IHF is composed of two related, non-identical, subunits, produced by genes that are 350 kilobase pairs apart. Each ihf gene has unique expression controls and is embedded in a complex genetic network that supports mRNA translation. Given that the subunits are thought to be required in a 1:1 ratio to form functional IHF, we were surprised by this physical and regulatory separation. We rewired the Salmonella genome so that each subunit was produced using the other’s regulatory signals and gene location. This revealed a high degree of tolerance to the effects of this rewiring. However, we discovered that bacterial motility was disrupted, as was the expression of virulence genes that have been acquired by horizontal gene transfer. Proteomic analysis using mass spectroscopy (MS) showed the extent of the alterations to cell composition. Our MS data also demonstrated that the subunits of IHF are not produced in a 1:1 ratio in either the wild type or the rewired strain. We discuss this finding in terms of the ability of each subunit to stabilise its partner.DATA SUMMARYWhole genome sequence data for strain OrfSwapihfA-ihfB are available from the European Nucleotide Archive with accession number ERS4653309.Data from mass spectrometry analyses are available via ProteomeXchange with identifier PXD027465 (login: reviewer_pxd027465@ebi.ac.uk and password: GVeNIUB2).All supporting data have been provided in the article or through supplementary data files.RepositoriesWhole genome sequence data for strain OrfSwapihfA-ihfB are available from the European Nucleotide Archive with accession number ERS4653309. Data from mass spectrometry analyses are available via ProteomeXchange with identifier PXD027465 (login: reviewer_pxd027465@ebi.ac.uk and password: GVeNIUB2).

Objective To test the "vitamin D-folate hypothesis for the evolution of human skin pigmentation." Methods Total ozone mapping spectrometer (TOMS) satellite data were used to examine surface UV-irradiance in a large (n = 649) Australian cross-sectional study population. Genetic analysis was used to score vitamin D- and folate-related gene polymorphisms (n = 22), along with two pigmentation gene variants (IRF4-rs12203592/HERC2-rs12913832). Red cell folate and vitamin D3 were measured by immunoassay and HPLC, respectively. Results Ultraviolet radiation (UVR) and pigmentation genes interact to modify blood vitamin levels; Light skin IRF4-TT genotype has greatest folate loss while light skin HERC2-GG genotype has greatest vitamin D3 synthesis (reflected in both TOMS and seasonal data). UV-wavelength exhibits a dose-response relationship in folate loss within light skin IRF4-TT genotype (305 > 310 > 324 > 380 nm). Significant vitamin D3 photosynthesis only occurs within light skin HERC2-GG genotype, and is maximal at 305 nm. Three dietary antioxidants (vitamins C, E, and β-carotene) interact with UVR and pigmentation genes preventing oxidative loss of labile reduced folate vitamers, with greatest benefit in light skin IRF4-TT subjects. The putative photosensitiser, riboflavin, did not sensitize red cell folate to UVR and actually afforded protection. Four genes (5xSNPs) influenced blood vitamin levels when stratified by pigmentation genotype; MTHFR-rs1801133/rs1801131, TS-rs34489327, CYP24A-rs17216707, and VDR-ApaI-rs7975232. Lightest IRF4-TT/darkest HERC2-AA genotype combination (greatest folate loss/lowest vitamin D3 synthesis) has 0% occurrence. The opposing, commonest (39%) compound genotype (darkest IRF4-CC/lightest HERC2-GG) permits least folate loss and greatest synthesis of vitamin D3 . Conclusion New biophysical evidence supports the vitamin D-folate hypothesis for evolution of skin pigmentation.

No abstract available.

Steroids are a class of organic molecule typified by a seventeen carbon skeleton consisting of four fused rings. These molecules have crucial roles in a number of biological processes across both plants and animals such as regulating membrane fluidity, signaling, and hormone biosynthesis. Cholesterol in particular is used by plants as a precursor to biosynthesise steroidal saponins, a group of natural products often found to be the active component of herbal medicines. However, plant extracts often contain a large number of impurities, and these molecules are difficult to chemically synthesise due to their complexity, rendering production of pure steroidal saponins challenging. By identifying the enzymes in this biosynthetic pathway, it may be possible to develop semi-synthetic methods towards these bioactive compounds, vastly cutting both the time and production costs. The Australian yam Dioscorea transversa presents an ideal model plant to study this biosynthetic pathway, as its roots contain only two steroidal saponins. These saponins are thought to be produced via three initial sequential cytochrome P450 mediated hydroxylations at key positions on cholesterol, producing an intermediate that is further cyclised and glycosylated to yield the observed saponins. Previous work has identified several P450 enzymes from D. transversa that may be implicated in this pathway, but in order to determine the substate preferences and products of these enzymes, a suite of 12 hydroxycholesterols were required. Chapters 1-2 detail the synthesis of hydroxycholesterols that may be present in the steroidal saponin biosynthetic pathway in D. transversa. These compounds possess each combination of hydroxylations that could be present in this pathway, and also explore different stereochemistry at two of these positions. By synthesising these compounds from only two starting materials -diosgenin and stigmasterol- the scattered literature synthesis were unified, allowing access to a variety of hydroxysterols from two commercially available materials. Collaborators then used the synthesised steroids as standards to identify enzyme turnover products, as well as substrates for enzyme turnover, allowing elucidation of one of the enzymes in the steroidal saponin biosynthetic pathway of D. transversa. Cholesterol is also used as a carbon and energy source by mycobacteria such as Mycobacterium tuberculosis. This unusual capability is made possible by a large suite of genes devoted to cholesterol catabolism, a process which is initiated by P450 mediated oxidation of the side chain. Previous studies have shown that cholesterol analogues with a degradation resistant side chain can effect micromolar inhibition of Mycobacterium tuberculosis in vitro. The key transformation that caused these compounds to become inhibitors was hydroxylation of the C16 position. Using techniques developed in Chapters 1-2, Chapters 3-4 discuss synthesis of a range of cholesterol derivatives with a variety of functionality at the terminal position of the side chain. In particular, the impact of the C3 and C16 hydroxyl group was explored by comparing compounds with this functionality to those in which it had been removed. A range of side chain moieties were installed, exploring both known P450 inhibitor functionality and groups with demonstrated anti-tubercular activity. The synthesised steroids were then tested by collaborators in the West group for in vitro inhibition against M. tuberculosis. This data confirmed the role of each hydroxyl group and several inhibitors showed significantly improved activity compared to the initial lead.

In women, the non-growing population of follicles that comprise the ovarian reserve is determined at birth and serves as the reservoir for future fertility. This reserve of dormant, primordial follicles and the mechanisms controlling their selective activation which constitute the committing step into folliculogenesis are essential for determining fertility outcomes in women. Much of the available data on the mechanisms responsible for primordial follicle activation focuses on a selection of key molecular pathways, studied primarily in animal models, with findings often not synonymous in humans. The excessive induction of primordial follicle activation may cause the development of premature ovarian insufficiency (POI), a condition characterised by menopause before age 40 years. POI affects 1–2% of all women and is accompanied by additional health risks. Therefore, it is critical to further our understanding of primordial follicle activation in order to diagnose, treat and prevent premature infertility. Research in primordial follicle activation has focused on connecting new molecules to already established key signalling pathways, such as phosphatidylinositol 3-Kinase (PI3K) and mammalian target of rapamycin (mTOR). Additionally, other aspects of the ovarian environment, such as the function of the extracellular matrix, in contributing to primordial follicle activation have gained traction. Clinical applications are examining replication of this extracellular environment through the construction of biological matrices mimicking the 3D ovary, to support follicular growth through to ovulation. This review outlines the importance of the events leading to the establishment of the ovarian reserve and highlights the fundamental factors known to influence primordial follicle activation in humans presenting new horizons for female infertility treatment.

Some lichenized ascomycetes synthesize melanic pigments in their upper cortices when exposed to ultraviolet light and high solar radiation. Our previous work showed that melanized chloro- and cyanolichens from both high light and more shaded habitats were less photoinhibited than pale ones during controlled exposure to high light. However, protection from high light might not necessarily be the consequence of just sun-screening by melanins in upper cortices. An inherent problem with earlier experiments was that the photobionts of melanized thalli might have received more light than those beneath pale cortices. The photobionts may therefore have possessed other light-induced tolerance mechanisms that gave protection from photoinhibition. Here, we aimed to test directly the inherent tolerance of lichen photobionts to photoinhibition. The method involved removing the lower cortices and medullas of three lichen species, Cetraria islandica, Crocodia aurata and Lobaria pulmonaria, and exposing the photobionts to light from below. Results confirmed that most of the improvement in tolerance to photoinhibition in melanized lichens derives from fungal melanization in the upper cortex. However, in C. islandica, the most heavily melanized species, algae from melanized thalli possessed a significantly higher tolerance to photoinhibition than those from pale thalli, suggesting that photobionts can also adapt themselves to high light.

Successful combinations of radiotherapy and immunotherapy depend on the presence of live T cells within the tumor; however, radiotherapy is believed to damage T cells. Here, based on longitudinal in vivo imaging and functional analysis, we report that a large proportion of T cells survive clinically relevant doses of radiation and show increased motility, and higher production of interferon gamma, compared with T cells from unirradiated tumors. Irradiated intratumoral T cells can mediate tumor control without newly-infiltrating T cells. Transcriptomic analysis suggests T cell reprogramming in the tumor microenvironment and similarities with tissue-resident memory T cells, which are more radio-resistant than circulating/lymphoid tissue T cells. TGFβ is a key upstream regulator of T cell reprogramming and contributes to intratumoral Tcell radio-resistance. These findings have implications for the design of radio-immunotherapy trials in that local irradiation is not inherently immunosuppressive, and irradiation of multiple tumors might optimize systemic effects of radiotherapy., Lymphocytes are considered one of the most radiosensitive cell types in the body. Here the authors show that unlike circulating lymphocytes, tumor-infiltrating T cells survive therapeutic doses of irradiation, remaining functional and contributing to radiotherapy induced anti-tumor immunity.

Maintenance of mitochondrial integrity is critical for normal cellular homoeostasis. Most cells respond to stress stimuli and undergo apoptosis by perturbing mitochondrial structure and function to release proteins, such as cytochrome c, which are essential for the execution of the intrinsic apoptotic cascade. Cancer cells evade these events by overexpressing the anti-apoptotic BCL-2 family of proteins on mitochondrial membranes. Inhibitors of the anti-apoptotic BCL-2 family proteins, also known as BH3 mimetics, antagonise the pro-survival functions of these proteins and result in rapid apoptosis. Although the precise mechanism by which BH3 mimetics induce apoptosis has been well characterised, not much is known in terms of the structural changes that occur in mitochondria during apoptosis. Using a panel of highly selective BH3 mimetics and a wide range of cell lines, we demonstrate that BH3 mimetics induce extensive mitochondrial fission, accompanied by swelling of the mitochondrial matrix and rupture of the outer mitochondrial membrane. These changes occur in a BAX/ BAK-dependent manner. Although a major mitochondrial fission GTPase, DRP-1, has been implicated in mitochondrial apoptosis, our data demonstrate that DRP-1 might function independently/downstream of BH3 mimetic-mediated mitochondrial fission to facilitate the release of cytochrome c and apoptosis. Moreover, downregulation of DRP-1 prevented cytochrome c release and apoptosis even when OPA1, a protein mediating mitochondrial fusion, was silenced. Although BH3 mimetic-mediated displacement of BAK and other BH3-only proteins from BCL-XL and MCL-1 was unaffected by DRP-1 downregulation, it prevented BAK activation significantly, thus placing DRP-1 as one of the most critical players, along with BAX and BAK, that governs BH3 mimetic-mediated cytochrome c release and apoptosis.

Many species of lichenized ascomycetes are capable of synthesizing darkly colored melanin pigments by polymerizing phenolic compounds. Available data suggest that different clades of lichens produce various kinds of melanins, with N2-fixing Peltigeralean lichens producing N-rich DOPA or “eumelanins” and lichens from other orders producing N-poor “allomelanins.” In general, melanic lichens seem to be more common in environments with high levels of abiotic stress such as polar and montane regions, but they are by no means restricted to these habitats. Here, we review the occurrence of melanins in lichens, their chemical structure, methods of quantification and biological roles. Good evidence exists that melanins in lichens protect the mycobiont from high UV, and the photobiont against high PAR. However, given their many unique properties, it seems likely that melanins help lichens to survive a range of biotic and abiotic stresses.

Maternal undernutrition during pregnancy is prevalent across the globe, and the origins of many chronic diseases can be traced back to in utero conditions. This systematic review considers the current evidence in animal models regarding the relationship between maternal global nutrient restriction during pregnancy and offspring kidney structure and function. CINAHL, Cochrane, EMBASE, MEDLINE, and Scopus were searched to November 2017. Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were followed, and articles were screened by two independent reviewers. Twenty-eight studies met the inclusion criteria: 16 studies were on rats, 9 on sheep, 2 on baboons, and 1 on goats. The majority of the rat studies had maternal global nutrient restriction during pregnancy at 50% of ad libitum while restriction for sheep and baboon studies ranged from 50% to 75%. Because of the heterogeneity of outcome measures and the large variation in the age of offspring at followup, no meta-analysis was possible. Common outcome measures included kidney weight, nephron number, glomerular size, glomerular filtration rate, and creatinine clearance. To date, there have been no studies assessing kidney function in large animal models. Most studies were rated as having a high or unknown risk of bias. The current body of evidence in animals suggests that exposure to maternal global nutrient restriction during pregnancy has detrimental effects on offspring kidney structure and function, such as lower kidney weight, lower nephron endowment, larger glomerular size, and lower glomerular filtration rate. Further long-term followup of studies in large animal models investigating kidney function through to adulthood are warranted.

Disease transmission by insect vectors will depend on integrated physiological responses to interacting environmental variables. We explored how interactions between temperature and sucrose concentration affected immunity and fecundity, two variables that contribute to vectorial capacity, in Culex pipiens Linnaeus, 1758 mosquitoes. We provided female C. pipiens with either 2% or 20% sucrose and exposed them to low (22 °C), moderate (25 °C), or high (30 °C) temperatures for 8 days. We then measured the strength of the melanization response in one subpopulation of females and the number of eggs laid as a measure of fecundity in another subpopulation. Temperature interacted with diet to weaken immunity under 2% sucrose at 22 and 25 °C. This effect disappeared at 30 °C, suggesting that high temperatures allowed mosquitoes to compensate for the effects of decreased sucrose. Conversely, increasing temperature increased egg production on a diet of 20% sucrose, but heat exposure on a diet of 2% sucrose decreased fecundity. Overall, we suggest that heat exposure requires investment in thermal protection, which may prompt reconfiguration of the immune system and (or) decreased investment in reproduction. Thus, our understanding of the effects of climate change rest on which physiological system we measure and under which combinations of stressors.

Tissue biopsy metabolic activity, assessed using the oxidation-reduction indicator resazurin, may serve as a proxy to assess energy expenditure associated with maintenance in nongrowing animals or growth rate in growing animals. Herein, we evaluate the repeatability, practicality, and sensitivity of a resazurin-based assay for ranking bovine skeletal muscle biopsies based on metabolic activity. Six yearling Holstein heifers (body weight = 330 ± 11.3 kg) were fed 4 dietary treatments consisting of high or low rumen-degradable starch and fiber arranged factorially in a partially replicated Latin square design. Periods were 18 d, consisting of 3 d for diet transition, 14 d for diet adaptation, and 1 d for sample collection. Semitendinosus biopsies were collected into ice-cold Dulbecco's modified Eagle medium (Fisher Scientific, Hampton, NH) from each heifer during each period. Analysis was initiated within an hour of sample collection. To assess tissue metabolic rate, biopsies were transferred to Dulbecco's modified Eagle medium with resazurin and incubated at 37°C. Fluorescence of each sample was read at time 0 and at 15-min intervals for 2 h. Change in fluorescence was representative of skeletal muscle reducing equivalent production. Fluorescent signal strength increased with time and relative rank of treatments did not change with time; accordingly, future studies may compare fluorescence at a single time point. Change in fluorescence at 120 min was used for analysis of the fixed effects of fiber, starch, and animal when accounting for a random effect of period. Samples collected when animals were on a high-ruminally degradable starch diet were more metabolically active than samples collected from animals on low-starch diets. Significant differences in metabolic activity among individual animals were also identified. Average relative fluorescence was correlated with dry matter intake, average daily gain, and feed-to-gain ratio. The relative fluorescence tended to correlate with average daily gain (r = 0.749) and feed-to-gain ratio (r = -0.783); change in fluorescence did not correlate with dry matter intake. Although evaluated on a small sample size, this technique shows promise as a potential means of ranking animals by growth or feed efficiency. Further work on a larger experimental population is needed to confirm the usefulness of this assay as a consistent and reliable predictor of these important phenotypic parameters.

Glial adaptations within the central nervous system are well known to modulate central sensitization and pain. Recently, it has been suggested that activity of glial-related proinflammatory cytokines may potentiate peripheral inflammation, via central neurogenic processes. However, a role for altered glial function has not yet been investigated in the context of endometriosis, a chronic inflammatory condition in women associated with peripheral lesions, often manifesting with persistent pelvic pain. Using a minimally invasive mouse model of endometriosis, we investigated associations between peripheral endometriosis-like lesions and adaptations in central glial reactivity. Spinal cords (T13-S1) from female C57BL/6 mice with endometriosis-like lesions (ENDO) were imaged via fluorescent immunohistochemistry for the expression of glial fibrillary acidic protein (GFAP; astrocytes) and CD11b (microglia) in the dorsal horn (n = 5). Heightened variability ( P = .02) as well as an overall increase ( P = .04) in the mean area of GFAP immunoreactivity was found in ENDO versus saline-injected control animals. Interestingly, spinal levels showing the greatest alterations in GFAP immunoreactivity appeared to correlate with the spatial location of lesions within the abdominopelvic cavity. A subtle but significant increase in the mean area of CD11b immunostaining was also observed in ENDO mice compared to controls ( P = .02). This is the first study to describe adaptations in nonneuronal, immune-like cells of the central nervous system attributed to the presence of endometriosis-like lesions.

Alzheimer’s disease (AD) is a complex and heterogeneous disease that can be affected by various genetic factors. Although the cause of AD is not yet known and there is no treatment to cure this disease, its progression can be delayed. AD has recently been recognized as a brain-specific type of diabetes called type 3 diabetes. Several studies have shown that people with type 2 diabetes (T2D) have a higher risk of developing AD. Therefore, it is important to identify subgroups of patients with AD that may be more likely to be associated with T2D. We here describe a new approach to identify the correlation between AD and T2D at the genetic level. Subgroups of AD and T2D were each generated using a non-negative matrix factorization (NMF) approach, which generated clusters containing subsets of genes and samples. In the gene cluster that was generated by conventional gene clustering method from NMF, we selected genes with significant differences in the corresponding sample cluster by Kruskal–Wallis and Dunn-test. Subsequently, we extracted differentially expressed gene (DEG) subgroups, and candidate genes with the same regulation direction can be extracted at the intersection of two disease DEG subgroups. Finally, we identified 241 candidate genes that represent common features related to both AD and T2D, and based on pathway analysis we propose that these genes play a role in the common pathological features of AD and T2D. Moreover, in the prediction of AD using logistic regression analysis with an independent AD dataset, the candidate genes obtained better prediction performance than DEGs. In conclusion, our study revealed a subgroup of patients with AD that are associated with T2D and candidate genes associated between AD and T2D, which can help in providing personalized and suitable treatments.

We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted., Graphical abstract, Meng et al. report that the SARS-CoV-2 spike ΔH69/V70 has arisen multiple times. The deletion increases entry efficiency associated with increased cleaved spike in virions and can compensate for loss of infectivity. The B.1.1.7 spike requires ΔH69/V70 for efficient cell entry and cell-cell fusion activity.

Marine ecosystem models often consider temporal dynamics on the order of months to years, and spatial dynamics over regional and global scales as a means to understand the ecology, evolution, and biogeochemical impacts of marine life. Large-scale dynamics are themselves driven over diel scales as a result of light-driven forcing, feedback, and interactions. Motivated by high-frequency measurements taken by Lagrangian sampling in the North Pacific Subtropical Gyre, we develop a hierarchical set of multitrophic community ecology models to investigate and understand daily ecological dynamics in the near-surface ocean including impacts of light-driven growth, infection, grazing, and phytoplankton size structure. Using these models, we investigate the relative impacts of viral-induced and grazing mortality for Prochlorococcus; and more broadly compare in silico dynamics with in situ observations. Via model-data fitting, we show that a multi-trophic model with size structure can jointly explain diel changes in cyanobacterial abundances, cyanobacterial size structure, viral abundance, viral infection rates, and grazer abundances. In doing so, we find that a significant component (between 5% to 55%) of estimated Prochlorococcus mortality is not attributed to either viral lysis (by T4- or T7-like cyanophage) or grazing by heterotrophic nanoflagellates. Instead, model-data integration suggests a heightened ecological relevance of other mortality mechanisms -- including grazing by other predators, particle aggregation, and stress-induced loss mechanisms. Altogether, linking mechanistic multitrophic models with high-resolution measurements provides a route for understanding of diel origins of large-scale marine microbial community and ecosystem dynamics.

Foliar water uptake (FWU) occurs in plants of diverse ecosystems; however, the diversity of pathways and their associated FWU kinetics remain poorly resolved. We characterized a novel FWU pathway in two mangrove species of the Sonneratia genus, S. alba and S. caseolaris. Further, we assessed the influence of leaf wetting duration, wet-dry seasonality and leaf dehydration on leaf conductance to surface water (Ksurf ). The symplastic tracer dye, disodium fluorescein, revealed living cells subtending and encircling leaf epidermal structures known as cork warts as a pathway of FWU entry into the leaf. Rehydration kinetics experiments revealed a novel mode of FWU, with slow and steady rates of water uptake persistent over a duration of 12 h. Ksurf increased with longer durations of leaf wetting and was greater in leaves with more negative water potentials at the initiation of leaf wetting. Ksurf declined by 68% between wet and dry seasons. Our results suggest that FWU via cork warts in Sonneratia sp. may be rate limited and under active regulation. We conclude that FWU pathways in halophytes may require ion exclusion to avoid uptake of salt when inundated, paralleling the capacity of halophyte roots for ion selectivity during water acquisition. This article is protected by copyright. All rights reserved.

The invasive spotted-wing drosophila,Drosophila suzukii, is a major pest of fruit crops world-wide. Management ofD. suzukiirelies heavily on chemical control in both organic and conventional systems, and there is a need to develop more sustainable management practices. We evaluated the efficacy of three colors of plastic mulches at reducing populations ofD. suzukiiin fall-bearing raspberry and assessed the mulches’ impacts on canopy microclimate factors relevant toD. suzukii. Black, white, and metallic plastic mulches reduced adultD. suzukiipopulations by 42-51% and larval populations by 52-72% compared to the grower standard. The mulches did not change canopy temperature or relative humidity, but metallic mulches increased canopy light intensity compared to the black mulch. Radiance in the visible spectrum (401-680 nm) was higher for the white and metallic mulch plots, but the black mulch plots did not differ from the control. In the UV spectrum (380-400 nm), all three plastic mulches had higher radiance than the control plots. Future studies will determine whether changes in radiance are associated with the observed reduction inD. suzukiipopulations. Plastic mulches are a promising cultural practice for managingD. suzukiisince they can reduce adult and larval populations and could be incorporated into an integrated pest management program in both organic and conventional systems.

Many modern techniques employed to uncover the molecular fundamentals underlying biological processes require dissociated cells as their starting point/substrate. Investigations into ovarian endocrinology or folliculogenesis, therefore, necessitate robust protocols for dissociating the ovary into its constituent cell populations. While in the mouse, methods to obtain individual, mature follicles are well-established, the separation and isolation of single cells of all types from early mouse follicles, including somatic cells, has been more challenging. Herein we present two methods for the isolation of somatic cells in the ovary. These methods are suitable for a range of applications relating to the study of folliculogenesis and mouse ovarian development. First, an enzymatic dissociation utilising collagenase and a temporary, primary cell culture step using neonatal mouse ovaries which yields large quantities of granulosa cells from primordial, activating, and primary follicles. Second, a rapid papain dissociation resulting in a high viability single cell suspension of ovarian somatic cells in less than an hour, which can be applied from embryonic to adult ovarian samples. Collectively these protocols can be applied to a broad array of investigations with unique advantages and benefits pertaining to both.

Alzheimer’s Disease Neuroimaging Initiative., Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging., J.W.V. acknowledges support from the government of Canada through a tri-council Vanier Canada Graduate Doctoral fellowship from the McGill Centre for Integrative Neuroscience and the Healthy Brains, Healthy Lives initiative, and from the National Institutes of Health (NIH) (no. T32MH019112). A.L.Y. is supported by a Medical Research Council Skills Development Fellowship (MR/T027800/1). N.P.O. is a UK Research and Innovation Future Leaders Fellow (no. MR/S03546X/1). N.P.O. and D.C.A. acknowledge support from the UK National Institute for Health Research University College London Hospitals Biomedical Research Centre, and D.C.A. acknowledges support from the Engineering and Physical Sciences Research Council grant no. EP/M020533/1. M.J.G. is supported by the Miguel Servet program (no. CP19/00031) and a research grant (no. PI20/00613) of the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional. R.L.J. acknowledges support from the NIH (no. K99AG065501). This project received funding from the European Union’s Horizon 2020 research and innovation programme under grant no. 666992. The BioFINDER studies are supported by the Swedish Research Council (no. 2016-00906), the Knut and Alice Wallenberg Foundation (no. 2017-0383), the Marianne and Marcus Wallenberg Foundation (no. 2015.0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer’s Foundation (no. AF-939932), the Swedish Brain Foundation (no. FO2019-0326), the Swedish Parkinson Foundation (no. 1280/20), the Skåne University Hospital Foundation (no. 2020-O000028), Regionalt Forskningsstöd (no. 2020-0314) and the Swedish Federal Government under the ALF agreement (no. 2018-Projekt0279). The Tau PET study in Gangnam Severance Hospital was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (nos. NRF2018R1D1A1B07049386 and NRF2020R1F1A1076154) and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health and Welfare, Republic of Korea (grant no. HI18C1159). We also thank B. L. Miller, H. J. Rosen, M. Gorno Tempini and W. Jagust for supporting the UCSF tau-PET studies, which were funded through the following sources: National Institute on Aging (NIA) no. R01 AG045611 (G.D.R.), no. P50 AG23501 (B.L.M., H.J.R., G.D.R.), no. P01 AG019724 (B.L.M., H.J.R., G.D.R.). The precursor of 18F-flortaucipir was provided by AVID Radiopharmaceuticals. The precursor of 18F-flutemetamol was sponsored by GE Healthcare. The precursor of 18F-RO948 was provided by Roche. Data collection and sharing for this project were funded by ADNI (NIH grant no. U01 AG024904) and Department of Defense ADNI (award no. W81XWH-12-2-0012). ADNI is funded by the NIA, the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; Bioclinica; Biogen; Bristol Myers Squibb; CereSpir; Cogstate; Eisai; Elan Pharmaceuticals; Eli Lilly and Company; EUROIMMUN; F. Hoffmann-La Roche and its affiliated company Genentech; Fujirebio; GE Healthcare; IXICO; Janssen Alzheimer Immunotherapy Research Development; Johnson & Johnson Pharmaceutical Research Development; Lumosity; Lundbeck; Merck; Meso Scale Diagnostics; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

The DNA in many organisms, including humans, is shown to be organised in topologically associating domains (TADs). InDrosophila, several architectural proteins are enriched at TAD borders, but it is still unclear whether these proteins play a functional role in the formation and maintenance of TADs. Here, we show that depletion of BEAF-32, Cp190, Chro and Dref leads to changes in TAD organisation and chromatin loops. Their depletion predominantly affects TAD borders located in heterochromatin, while TAD borders located in euchromatin are resilient to these mutants. Furthermore, transcriptomic data has revealed hundreds of genes displaying differential expression in these mutants and showed that the majority of differentially expressed genes are located within reorganised TADs. Our work identifies a novel and functional role for architectural proteins at TAD borders inDrosophilaand a link between TAD reorganisation and subsequent changes in gene expression.

All orthodox seeds eventually deteriorate during storage, a well-known problem in seed banking. Here we used a greenhouse study to test if priming deteriorated seeds with cathodic water can improve the emergence and subsequent seedling growth of three South African tree species, Bolusanthus speciosus, Combretum erythrophyllum and Erythrina caffra. Other priming solutions investigated were calcium magnesium (CaMg) solution and deionized water. In the present study, seeds were subjected to an artificial deterioration by increasing their water content to 14% and keeping them at 40 °C and 100% RH until they had lost 50% of their germination under laboratory conditions. Fresh and deteriorated seeds were primed with cathodic water, CaMg solution and deionized water, with non-primed fresh and deteriorated seeds as controls. Controlled deterioration significantly reduced total emergence and the biomass and photosynthetic parameters of the resulting seedlings. In one species (Bolusanthus speciosus), priming the deteriorated seeds with cathodic water significantly improved emergence parameters. However, in all species cathodic water significantly improved the total biomasses and other growth parameters of the seedlings derived from deteriorated seeds. Priming with CaMg solution and deionized water had little effect on emergence and while improving the growth of seedlings derived from deteriorated seeds, they were less effective than cathodic water. In fresh seeds, priming with all solutions resulted in small improvements in some parameters. Controlled deterioration of fresh seeds reduced the membrane stability index (MSI) in two of the three species and in all species increased the levels of the lipid oxidation products MDA and 4-HNE. Priming deteriorated seeds with cathodic water increased the MSI and reduced the MDA contents in all species and the 4-HNE content in one species. Other priming solutions were generally less effective in ameliorating oxidative stress. Results suggest that the strong antioxidative properties of cathodic water can explain its ability to ameliorate deterioration. In conclusion, the present study shows that priming with cathodic water is an effective way of invigorating deteriorated orthodox seeds and that it may have considerable potential in orthodox seed conservation.

Our previous work showed that many lichenized Ascomycetes can generate hydroxyl radicals using quinone-based extracellular redox cycling. During cycling, hydroquinones must be formed and subsequently regenerated from quinones using a quinone reductase (QR). However, we also showed that no simple correlation exists between QR activity and rates of hydroxyl radical formation. To further investigate the role of QR in hydroxyl radical formation, three model lichen species, Leptogium furfuraceum, Lasallia pustulata and Peltigera membranacea were selected for further investigation. All possessed QR activity and could metabolize quinones, and both Leptogium furfuraceum and Lasallia pustulata actively produced hydroxyl radicals. By contrast, P. membranacea produced almost no hydroxyl radicals, and although the lichen readily metabolized quinones, no hydroquinone production was detected. Peltigera had laccase (LAC) activity that was c. 50 times higher than in the other two species, suggesting that LAC rapidly oxidizes the hydroquinones, preventing radical formation deriving from auto-oxidation. It appears that in some lichens hydroxyl radical formation is blocked by the presence of high redox enzyme activity. QR from P. didactyla was studied further and found to display similar properties to the enzyme from free-living fungi, although it possessed an unusually high molecular mass (c. 62 kDa).