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[This corrects the article DOI: 10.1371/journal.pone.0296203.].

The post-medieval period in Europe saw a dramatic increase in metabolic bone disease related to vitamin D deficiency (VDD). Recent paleopathological work has utilized interglobular dentin (IGD) as a proxy for poor vitamin D status during development, while enamel peptide analysis allows the identification of chromosomal sex in non-adult remains. Here we explore the relationship between sex, the presence of IGD, and macroscopic markers of VDD in an industrial era assemblage from Northeast England. 25 individuals (9 females, 9 males, 9 unknown sex) from the cemetery site at Coach Lane, North Shields (1711-1857) were selected for paleopathological analysis, histological assessment of IGD, and enamel peptide determination of chromosomal sex. Ground tooth sections from 21 individuals were of suitable quality for detection of IGD, and enamel peptide analysis confirmed the chromosomal sex of ten individuals. Sixteen individuals (76.1%) exhibited ≥1 episode of IGD. Nine of these (42.8%) exhibited >1 episode and four (19%) exhibited ≥4 episodes in regular intervals. Male sex was significantly associated with the presence of IGD (p = 0.0351; 100% males vs. 54.5% females). Females were more likely to exhibit macroscopic evidence of VDD (45.5% females vs 30% males) but this was not statistically significant. Periods of poor mineral metabolism during childhood appear much more prevalent at Coach Lane than macroscopic evidence suggests. Evidence of seasonal IGD episodes indicates that northern latitude played a major role in poor VD status in the Northeast of England. The significant association of IGD with male sex may be due to sex-related differences in dentinal mineralization or a higher risk of poor VD status in males aged <5 years. More work is needed to establish an evidence-based threshold for pathological levels of IGD before the presence of this feature can confidently be used as a biomarker for poor VD status.

Child labour is the most common form of child abuse in the world today, with almost half of child workers employed in hazardous industries. The large-scale employment of children during the rapid industrialisation of the late 18 th and early 19 th centuries in England is well documented. During this period, the removal of pauper children from workhouses in cities to work as apprentices in rural mills in the North of England was commonplace. Whilst the experiences of some of these children have been recorded historically, this study provides the first direct evidence of their lives through bioarchaeological analysis. The excavation of a rural churchyard cemetery in the village of Fewston, North Yorkshire, yielded the skeletal remains of 154 individuals, including an unusually large proportion of children aged between 8 to 20 years. A multi-method approach was undertaken, including osteological and palaeopathological examination, stable isotope and amelogenin peptide analysis. The bioarchaeological results were integrated with historical data regarding a local textile mill in operation during the 18 th -19 th centuries. The results for the children were compared to those obtained from contemporaneous individuals of known identity (from coffin plates) of comparable date. Most of the children exhibited distinctive ‘non-local’ isotope signatures and a diet low in animal protein when compared to the named local individuals. These children also showed severe growth delays and pathological lesions indicative of early life adversity, as well as respiratory disease, which is a known occupational hazard of mill work. This study has provided unique insights into the harrowing lives of these children; born into poverty and forced to work long hours in dangerous conditions. This analysis provides a stark testimony of the impacts of industrial labour on the health, growth and mortality risk of children, with implications for the present as well as our understanding of the past.

Pharmaceuticals pose a major threat to the marine environment, and several studies have recently described their negative effects on marine organisms. Pharmaceutical compounds are constantly being released into aquatic ecosystems, and chronic exposure, even at low concentrations, may have a major impact on marine organisms. The purpose of the present study is to evaluate the biological changes induced by one of the most widely used pharmaceuticals—paracetamol—in the blue mussel Mytilus edulis , after a long-term exposure at environmentally relevant concentrations. We present our data alongside and in comparison with results from a previous short-term exposure, to demonstrate the significance of exposure period on the effects of paracetamol in adult blue mussels. After 24 days of laboratory exposure, seven potential target genes were selected to examine toxicological effects in mussels’ gonads and possible disruptive effects on reproductive processes. The results show the modulation of some important reproduction-related genes: estrogen receptor-2 ( ER2 ), vitelline envelope zona pellucida domain-9 ( V9 ), and vitellogenin ( VTG ). Variations in mRNA expression of four other genes involved in apoptosis ( HSP70 , CASP8 , BCL2 , and FAS ) are also highlighted. Histopathological alterations caused by paracetamol, together with neutral red retention time response in mussels’ hemocytes, are presented herein. Overall, this study highlights the exacerbated effects of low concentration of paracetamol after chronic exposure, similar to the damage induced by higher concentrations in a short exposure scenario, thus emphasizing the importance of length of exposure period when studying the effects of this substance. Additionally, this study also discusses the potential of paracetamol to inflict several major changes in the reproductive system of mussels and thus possibly affect the survival of populations.

Cells subjected to sustained high osmolarity almost universally respond by accumulating compatible organic osmolytes that, in contrast to inorganic ions, are not deleterious even at high intracellular concentrations. Their accumulation from the external environment by known organic osmolyte transporters, such as the four identified in mammals, occurs only slowly in response to sustained high osmolarity, by synthesis of new transporter proteins. Most cells, however, are not subject to high or varying osmolarity, and it is not clear whether organic osmolytes are generally required at normal osmolarities or how they are regulated. The fertilized egg of the mouse is protected in the oviduct from perturbations in osmolarity. However, deleterious effects of osmotic stress were evident in vitro even at normal oviductal osmolarity. Glycine was found to protect development, indicating that early mouse embryos may use glycine as an organic osmolyte at physiological osmolarity. We have now found that GLYT1, a glycine transporter of the neurotransmitter transporter gene family, functions as the organic osmolyte transporter that mediates the osmotically regulated accumulation of glycine and regulates cell volume in early embryos. Furthermore, osmotic stimulation of GLYT1 transport was immediate, without a requirement for protein synthesis, implying regulation different from known organic osmolyte transporters. Thus, GLYT1 appears to have a previously unidentified role as an organic osmolyte transporter that functions in acute organic osmolyte and volume homeostasis near normal osmolarity.

Child labour is the most common form of child abuse in the world today, with almost half of child workers employed in hazardous industries. The large-scale employment of children during the rapid industrialisation of the late 18.sup.th and early 19.sup.th centuries in England is well documented. During this period, the removal of pauper children from workhouses in cities to work as apprentices in rural mills in the North of England was commonplace. Whilst the experiences of some of these children have been recorded historically, this study provides the first direct evidence of their lives through bioarchaeological analysis. The excavation of a rural churchyard cemetery in the village of Fewston, North Yorkshire, yielded the skeletal remains of 154 individuals, including an unusually large proportion of children aged between 8 to 20 years. A multi-method approach was undertaken, including osteological and palaeopathological examination, stable isotope and amelogenin peptide analysis. The bioarchaeological results were integrated with historical data regarding a local textile mill in operation during the 18.sup.th -19.sup.th centuries. The results for the children were compared to those obtained from contemporaneous individuals of known identity (from coffin plates) of comparable date. Most of the children exhibited distinctive 'non-local' isotope signatures and a diet low in animal protein when compared to the named local individuals. These children also showed severe growth delays and pathological lesions indicative of early life adversity, as well as respiratory disease, which is a known occupational hazard of mill work. This study has provided unique insights into the harrowing lives of these children; born into poverty and forced to work long hours in dangerous conditions. This analysis provides a stark testimony of the impacts of industrial labour on the health, growth and mortality risk of children, with implications for the present as well as our understanding of the past.

In the summer of 1986 a mass grave was discovered along the bank of the river Tryggevælde Å where it empties into Køge Bugt, the bay south of modern Copenhagen, Denmark. The human remains, dating to the late Mesolithic Ertebølle culture, consisted of eight individuals of multiple ages, ranging c. 35–45 years old to newborn children. Four were arranged on one side of the grave, with four on the other, placed head to foot. How they were related and what befell them is a mystery. Herein, we present a bioarchaeological assessment of these individuals for the first time and apply an acid etch-based analysis of dimorphic sex chromosome-linked tooth enamel peptides to confirm their biological sex. Our results allow a direct connection between engendered grave treatment and biological sex in non-adult individuals as young as c. 4 years of age. We conclude with a discussion of the possible circumstances of their deaths and their possible relationships to one another.

Objective: The biology of high grade serous ovarian carcinoma (HGSOC) is poorly understood. Little has been reported on intratumoral homogeneity or heterogeneity of primary HGSOC tumors and their metastases. We evaluated the global protein expression profiles of paired primary and metastatic HGSOC from formalin-fixed, paraffin-embedded (FFPE) tissue samples. Methods: After IRB approval, six patients with advanced HGSOC were identified with tumor in both ovaries at initial surgery. Laser capture microdissection (LCM) was used to extract tumor for protein digestion. Peptides were extracted and analyzed by reversed-phase liquid chromatography coupled to a linear ion trap mass spectrometer. Tandem mass spectra were searched against the UniProt human protein database. Differences in protein abundance between samples were assessed and analyzed by Ingenuity Pathway Analysis software. Immunohistochemistry (IHC) for select proteins from the original and an additional validation set of five patients was performed. Results: Unsupervised clustering of the abundance profiles placed the paired specimens adjacent to each other. IHC H-score analysis of the validation set revealed a strong correlation between paired samples for all proteins. For the similarly expressed proteins, the estimated correlation coefficients in two of three experimental samples and all validation samples were statistically significant (p < 0.05). The estimated correlation coefficients in the experimental sample proteins classified as differentially expressed were not statistically significant. Conclusion: A global proteomic screen of primary HGSOC tumors and their metastatic lesions identifies tumoral homogeneity and heterogeneity and provides preliminary insight into these protein profiles and the cellular pathways they constitute.

Remdesivir (RDV), a broadly acting nucleoside analogue, is the only FDA approved small molecule antiviral for the treatment of COVID-19 patients. To date, there are no reports identifying SARS-CoV-2 RDV resistance in patients, animal models or in vitro . Here, we selected drug-resistant viral populations by serially passaging SARS-CoV-2 in vitro in the presence of RDV. Using high throughput sequencing, we identified a single mutation in RNA-dependent RNA polymerase (NSP12) at a residue conserved among all coronaviruses in two independently evolved populations displaying decreased RDV sensitivity. Introduction of the NSP12 E802D mutation into our SARS-CoV-2 reverse genetics backbone confirmed its role in decreasing RDV sensitivity in vitro . Substitution of E802 did not affect viral replication or activity of an alternate nucleoside analogue (EIDD2801) but did affect virus fitness in a competition assay. Analysis of the globally circulating SARS-CoV-2 variants (>800,000 sequences) showed no evidence of widespread transmission of RDV-resistant mutants. Surprisingly, we observed an excess of substitutions in spike at corresponding sites identified in the emerging SARS-CoV-2 variants of concern (i.e., H69, E484, N501, H655) indicating that they can arise in vitro in the absence of immune selection. The identification and characterisation of a drug resistant signature within the SARS-CoV-2 genome has implications for clinical management and virus surveillance.

The gut microbiota influences both local and systemic inflammation. Inflammation contributes to development, progression, and treatment of cancer, but it remains unclear whether commensal bacteria affect inflammation in the sterile tumor microenvironment. Here, we show that disruption of the microbiota impairs the response of subcutaneous tumors to CpG-oligonucleotide immunotherapy and platinum chemotherapy. In antibiotics-treated or germ-free mice, tumor-infiltrating myeloid-derived cells responded poorly to therapy, resulting in lower cytokine production and tumor necrosis after CpG-oligonucleotide treatment and deficient production of reactive oxygen species and cytotoxicity after chemotherapy. Thus, optimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment.