Independent age estimates resolve the controversy of ancient human footprints at White Sands.

Human footprints at White Sands National Park, New Mexico, USA, reportedly date to between ~23,000 and 21,000 years ago according to radiocarbon dating of seeds from the aquatic plant Ruppia cirrhosa. These ages remain controversial because of potential old carbon reservoir effects that could compromise their accuracy. We present new calibrated 14C ages of terrestrial pollen collected from the same stratigraphic horizons as those of the Ruppia seeds, along with optically stimulated luminescence ages of sediments from within the human footprint-bearing sequence, to evaluate the veracity of the seed ages. The results show that the chronologic framework originally established for the White Sands footprints is robust and reaffirm that humans were present in North America during the Last Glacial Maximum.

Anthropogenic climate change has altered lake state in the Sierra Nevada (California, USA).

Climatic changes threaten freshwater resources and aquatic ecosystem health in the Sierra Nevada (California, USA), which has important consequences for millions of people and the world's fifth largest economy. However, the timing and magnitude of ecological changes driven by hydroclimate oscillations remain poorly understood in California's headwater region. Here, we develop a precisely dated, annually to decadally resolved lake sediment record of ecological change from the eastern Sierra Nevada that spans the last three millennia. Diatom paleoecology reveals a detailed history of abrupt limnologic transitions, best explained by modifications in water column stratification, mixing, and nutrient status in response to changing seasonality. Seasonally stratified conditions were registered during the Late Holocene Dry Period and the Medieval Climate Anomaly, illustrating the sensitivity of fossil diatoms to well-known periods of drought. Yet the most striking feature of the record is the uniqueness of ~1840-2016 CE: a period of singularly strong water column stratification, increased algal diversity, and reduced diatom productivity consistent with unprecedented "hot droughts." The data demonstrate that hot-dry conditions of the Industrial Era altered lake state to conditions unseen in the past ~3180 years, and suggest that regional trends identified by historical monitoring began far earlier than previously recognized. Our record illustrates the profound influence of anthropogenic climate warming on high-elevation lakes and the ecosystem services they provide in the Sierra Nevada, which hold implications for water quality and availability in California.

Genomic instability and metabolism in cancer.

Genomic instability and metabolic reprogramming are among the key hallmarks discriminating cancer cells from normal cells. The two phenomena contribute to the robust and evasive nature of cancer, particularly when cancer cells are exposed to chemotherapeutic agents. Genomic instability is defined as the increased frequency of mutations within the genome, while metabolic reprogramming is the alteration of metabolic pathways that cancer cells undergo to adapt to increased bioenergetic demand. An underlying source of these mutations is the aggregate product of damage to the DNA, and a defective repair pathway, both resulting in the expansion of genomic lesions prior to uncontrolled proliferation and survival of cancer cells. Exploitation of DNA damage and the subsequent DNA damage response (DDR) have aided in defining therapeutic approaches in cancer. Studies have demonstrated that targeting metabolic reprograming yields increased sensitivity to chemo- and radiotherapies. In the past decade, it has been shown that these two key features are interrelated. Metabolism impacts DNA damage and DDR via regulation of metabolite pools. Conversely, DDR affects the response of metabolic pathways to therapeutic agents. Because of the interplay between genomic instability and metabolic reprogramming, we have compiled findings which more selectively highlight the dialog between metabolism and DDR, with a particular focus on glucose metabolism and double-strand break (DSB) repair pathways. Decoding this dialog will provide significant clues for developing combination cancer therapies.

Genomic instability and mitochondrial homeostasis in cancer: does chromatin have a say?

While genomic instability and mitochondrial homeostasis are integral for cancer progression, how these two hallmarks interact remains poorly understood. Here, we reflect on the dialogue between chromatin-based genomic instability and impairment of mitochondrial function and depict the importance of this interaction in cancer progression to metastasis.

High-latitude warming initiated the onset of the last deglaciation in the tropics.

Atmospheric greenhouse gas concentrations are thought to have synchronized global temperatures during Pleistocene glacial-interglacial cycles, yet their impact relative to changes in high-latitude insolation and ice-sheet extent remains poorly constrained. Here, we use tropical glacial fluctuations to assess the timing of low-latitude temperature changes relative to global climate forcings. We report 10Be ages of moraines in tropical East Africa and South America and show that glaciers reached their maxima at ~29 to 20 ka, during the global Last Glacial Maximum. Tropical glacial recession was underway by 20 ka, before the rapid CO2 rise at ~18.2 ka. This "early" tropical warming was influenced by rising high-latitude insolation and coincident ice-sheet recession in both polar regions, which lowered the meridional thermal gradient and reduced tropical heat export to the high latitudes.

The growth of a xenograft breast cancer tumor model with engineered hyaluronan-accumulating stroma is dependent on hyaluronan and independent of CD44.

Hyaluronan accumulation in the tumor microenvironment is associated with poor prognosis in several solid human cancers. To understand the role of stromal hyaluronan in tumor progression, we engineered 3T3HAS3, a hyaluronan-producing fibroblast cell line, by lentiviral transduction of Balb/c 3T3 cells with the human hyaluronan synthase 3 (HAS3) gene. 3T3HAS3 cells significantly enhanced tumor growth when co-grafted with MDA-MB-468 cells in nude mice. Immunohistochemical analysis of the xenograft tumors showed that MDA-MB-468 cells were surrounded by hyaluronan-accumulating stroma, closely resembling the morphology observed in human breast cancer specimens. Tumor growth of MDA-MB-468 + 3T3HAS3 co-grafts was greatly reduced upon hyaluronan degradation by lentiviral transduction of a human hyaluronidase gene in 3T3HAS3 cells, or by systemic administration of pegvorhyaluronidase alfa (PEGPH20). In contrast, the growth of the co-graft tumors was not inhibited when CD44 expression was reduced or ablated by small hairpin RNA-mediated CD44 knockdown in MDA-MB-468 cells, CD44 CRISPR knockout in 3T3HAS3 cells, or by grafting these cells in CD44 knockout nude mice. Collectively, these data demonstrate that tumor growth of an engineered xenograft breast cancer model with hyaluronan-accumulating stroma can be dependent on hyaluronan and independent of CD44.

Remodeling the Tumor Microenvironment Sensitizes Breast Tumors to Anti-Programmed Death-Ligand 1 Immunotherapy.

Immunotherapies targeting immune checkpoint inhibitors have changed the landscape of cancer treatment, however, many patients are resistant or refractory to immunotherapy. The sensitivity of tumor cells to immunotherapy may be influenced by hyaluronan (HA) accumulation in the tumor microenvironment (TME). Enzymatic degradation of HA by pegvorhyaluronidase alfa (PEGPH20; PVHA) remodels the TME. This leads to reduced tumor interstitial pressure and decompressed tumor blood vessels, which are both associated with increased exposure of tumor cells to chemotherapy drugs. Here, we demonstrate PVHA increased the uptake of anti-programmed death-ligand 1 (PD-L1) antibody in HA-accumulating animal models of breast cancer. The increased levels of anti-PD-L1 antibody were associated with increased accumulation of T cells and natural killer cells and decreased myeloid-derived suppressor cells. PD-L1 blockade significantly inhibited tumor growth when combined with PVHA, but not alone. Our results suggest that PVHA can sensitize HA-accumulating tumors to anti-PD-L1 immunotherapy. SIGNIFICANCE: These findings show removal of hyaluronan in the tumor microenvironment improves immune cells and checkpoint inhibitors access to tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4149/F1.large.jpg.

Minimal East Antarctic Ice Sheet retreat onto land during the past eight million years.

The East Antarctic Ice Sheet (EAIS) is the largest potential contributor to sea-level rise. However, efforts to predict the future evolution of the EAIS are hindered by uncertainty in how it responded to past warm periods, for example, during the Pliocene epoch (5.3 to 2.6 million years ago), when atmospheric carbon dioxide concentrations were last higher than 400 parts per million. Geological evidence indicates that some marine-based portions of the EAIS and the West Antarctic Ice Sheet retreated during parts of the Pliocene1,2, but it remains unclear whether ice grounded above sea level also experienced retreat. This uncertainty persists because global sea-level estimates for the Pliocene have large uncertainties and cannot be used to rule out substantial terrestrial ice loss 3 , and also because direct geological evidence bearing on past ice retreat on land is lacking. Here we show that land-based sectors of the EAIS that drain into the Ross Sea have been stable throughout the past eight million years. We base this conclusion on the extremely low concentrations of cosmogenic 10Be and 26Al isotopes found in quartz sand extracted from a land-proximal marine sediment core. This sediment had been eroded from the continent, and its low levels of cosmogenic nuclides indicate that it experienced only minimal exposure to cosmic radiation, suggesting that the sediment source regions were covered in ice. These findings indicate that atmospheric warming during the past eight million years was insufficient to cause widespread or long-lasting meltback of the EAIS margin onto land. We suggest that variations in Antarctic ice volume in response to the range of global temperatures experienced over this period-up to 2-3 degrees Celsius above preindustrial temperatures 4 , corresponding to future scenarios involving carbon dioxide concentrations of between 400 and 500 parts per million-were instead driven mostly by the retreat of marine ice margins, in agreement with the latest models5,6.

Nephronectin Regulates Mesangial Cell Adhesion and Behavior in Glomeruli.

A critical aspect of kidney function occurs at the glomerulus, the capillary network that filters the blood. The glomerular basement membrane (GBM) is a key component of filtration, yet our understanding of GBM interactions with mesangial cells, specialized pericytes that provide structural stability to glomeruli, is limited. We investigated the role of nephronectin (Npnt), a GBM component and known ligand of α8ß1 integrin. Immunolocalization and in situ hybridization studies in kidneys of adult mice revealed that nephronectin is produced by podocytes and deposited into the GBM. Conditional deletion of Npnt from nephron progenitors caused a pronounced increase in mesangial cell number and mesangial sclerosis. Nephronectin colocalized with α8ß1 integrin to novel, specialized adhesion structures that occurred at sites of mesangial cell protrusion at the base of the capillary loops. Absence of nephronectin disrupted these adhesion structures, leading to mislocalization of α8ß1. Podocyte-specific deletion of Npnt also led to mesangial sclerosis in mice. These results demonstrate a novel role for nephronectin and α8ß1 integrin in a newly described adhesion complex and begin to uncover the molecular interactions between the GBM and mesangial cells, which govern mesangial cell behavior and may have a role in pathologic states.

Future loss of Arctic sea-ice cover could drive a substantial decrease in California's rainfall.

From 2012 to 2016, California experienced one of the worst droughts since the start of observational records. As in previous dry periods, precipitation-inducing winter storms were steered away from California by a persistent atmospheric ridging system in the North Pacific. Here we identify a new link between Arctic sea-ice loss and the North Pacific geopotential ridge development. In a two-step teleconnection, sea-ice changes lead to reorganization of tropical convection that in turn triggers an anticyclonic response over the North Pacific, resulting in significant drying over California. These findings suggest that the ability of climate models to accurately estimate future precipitation changes over California is also linked to the fidelity with which future sea-ice changes are simulated. We conclude that sea-ice loss of the magnitude expected in the next decades could substantially impact California's precipitation, thus highlighting another mechanism by which human-caused climate change could exacerbate future California droughts.

Afadin orients cell division to position the tubule lumen in developing renal tubules.

In many types of tubules, continuity of the lumen is paramount to tubular function, yet how tubules generate lumen continuity in vivo is not known. We recently found that the F-actin-binding protein afadin is required for lumen continuity in developing renal tubules, though its mechanism of action remains unknown. Here, we demonstrate that afadin is required for lumen continuity by orienting the mitotic spindle during cell division. Using an in vitro 3D cyst model, we find that afadin localizes to the cell cortex adjacent to the spindle poles and orients the mitotic spindle. In tubules, cell division may be oriented relative to two axes: longitudinal and apical-basal. Unexpectedly, in vivo examination of early-stage developing nephron tubules reveals that cell division is not oriented in the longitudinal (or planar-polarized) axis. However, cell division is oriented perpendicular to the apical-basal axis. Absence of afadin in vivo leads to misorientation of apical-basal cell division in nephron tubules. Together, these results support a model whereby afadin determines lumen placement by directing apical-basal spindle orientation, resulting in a continuous lumen and normal tubule morphogenesis.

A persistent and dynamic East Greenland Ice Sheet over the past 7.5 million years.

Climate models show that ice-sheet melt will dominate sea-level rise over the coming centuries, but our understanding of ice-sheet variations before the last interglacial 125,000 years ago remains fragmentary. This is because terrestrial deposits of ancient glacial and interglacial periods are overrun and eroded by more recent glacial advances, and are therefore usually rare, isolated and poorly dated. In contrast, material shed almost continuously from continents is preserved as marine sediment that can be analysed to infer the time-varying state of major ice sheets. Here we show that the East Greenland Ice Sheet existed over the past 7.5 million years, as indicated by beryllium and aluminium isotopes (10Be and 26Al) in quartz sand removed by deep, ongoing glacial erosion on land and deposited offshore in the marine sedimentary record. During the early Pleistocene epoch, ice cover in East Greenland was dynamic; in contrast, East Greenland was mostly ice-covered during the mid-to-late Pleistocene. The isotope record we present is consistent with distinct signatures of changes in ice sheet behaviour coincident with major climate transitions. Although our data are continuous, they are from low-deposition-rate sites and sourced only from East Greenland. Consequently, the signal of extensive deglaciation during short, intense interglacials could be missed or blurred, and we cannot distinguish between a remnant ice sheet in the East Greenland highlands and a diminished continent-wide ice sheet. A clearer constraint on the behaviour of the ice sheet during past and, ultimately, future interglacial warmth could be produced by 10Be and 26Al records from a coring site with a higher deposition rate. Nonetheless, our analysis challenges the possibility of complete and extended deglaciation over the past several million years.

Presenting Symptoms and Dysphagia Screen Predict Outcome in Mild and Rapidly Improving Acute Ischemic Stroke Patients.

OBJECTIVE: There are limited data on which patients not treated with intravenous (IV) tissue-type plasminogen activator (tPA) due to mild and rapidly improving stroke symptoms (MaRISS) have unfavorable outcomes. MATERIALS AND METHODS: Acute ischemic stroke (AIS) patients not treated with IV tPA due to MaRISS from January 1, 2009 to December 31, 2013 were identified as part of the Georgia Coverdell Acute Stroke Registry. Multivariable regression analysis was used to identify factors associated with a lower likelihood of favorable outcome, defined as discharge to home. RESULTS: There were 1614 AIS patients who did not receive IV tPA due to MaRISS (median National Institutes of Health stroke scale [NIHSS] 1], of which 305 (19%) did not have a favorable outcome. Factors associated with lower likelihood of favorable outcome included Medicare insurance status (odds ratio [OR]: .53, 95% confidence interval [CI]: .34-.84), arrival by emergency medical services (OR: .46, 95% CI: .29-.73), increasing NIHSS score (per unit OR: .89, 95% CI: .84-.93), weakness as the presenting symptom (OR: .50, 95% CI: .30-.84), and a failed dysphagia screen (OR: .43, 95% CI: .23-.80). During the study period, <1% of patients presenting to participating hospitals with MaRISS within the eligible time window received IV tPA. CONCLUSIONS: Baseline characteristics, presenting symptoms, and response to dysphagia screen identify a subgroup of patients who are more likely to have an unfavorable outcome. Whether IV tPA treatment can improve the outcome in this subgroup of patients needs to be evaluated in a randomized placebo-controlled trial.

Role of CD34 family members in lumen formation in the developing kidney.

Previous studies have shown CD34 family member Podocalyxin is required for epithelial lumen formation in vitro. We demonstrate that Endoglycan, a CD34 family member with homology to Podocalyxin, is produced prior to lumen formation in developing nephrons. Endoglycan localizes to Rab11-containing vesicles in nephron progenitors, and then relocalizes to the apical surface as progenitors epithelialize. Once an apical/luminal surface is formed, Endoglycan (and the actin-binding protein Ezrin) localize to large, intraluminal structures that may be vesicles/exosomes. We generated mice lacking Endoglycan and found mutants had timely initiation of lumen formation and continuous lumens, similar to controls. Mice with conditional deletion of both Endoglycan and Podocalyxin in developing nephrons also had normal tubular lumens. Despite this, Endoglycan/Podocalyxin is required for apical recruitment of the adaptor protein NHERF1, but not Ezrin, in podocyte precursors, a subset of the epithelia. In summary, while CD34 family members appear dispensable for lumen formation, our data identify Endoglycan as a novel pre-luminal marker and suggest lumen formation occurs via vesicular trafficking of apical cargo that includes Endoglycan.

Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production.

Thrombotic microangiopathy (TMA) is a disorder characterized by microvascular occlusion that can lead to thrombocytopenia, hemolytic anemia, and glomerular damage. Complement activation is the central event in most cases of TMA. Primary forms of TMA are caused by mutations in genes encoding components of the complement or regulators of the complement cascade. Recently, we and others have described a genetic form of TMA caused by mutations in the gene diacylglycerol kinase-ε (DGKE) that encodes the lipid kinase DGKε (Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi MR, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji WZ, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Nat Genet 45: 531-536, 2013; Ozaltin F, Li BH, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, Ibsirlioglu T, Korkmaz E, Bilginer Y, Duzova A, Ozen S, Topaloglu R, Besbas N, Ashraf S, Du Y, Liang CY, Chen P, Lu DM, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M. J Am Soc Nephrol 24: 377-384, 2013). DGKε is unrelated to the complement pathway, which suggests that unidentified pathogenic mechanisms independent of complement dysregulation may result in TMA. Studying Dgke knockout mice may help to understand the pathogenesis of this disease, but no glomerular phenotype has been described in these animals so far. Here we report that Dgke null mice present subclinical microscopic anomalies of the glomerular endothelium and basal membrane that worsen with age and develop glomerular capillary occlusion when exposed to nephrotoxic serum. We found that induction of cyclooxygenase-2 and of the proangiogenic prostaglandin E2 are impaired in Dgke null kidneys and are associated with reduced expression of the antithrombotic cell adhesion molecule platelet endothelial cell adhesion molecule-1/CD31 in the glomerular endothelium. Notably, prostaglandin E2 supplementation was able to rescue motility defects of Dgke knockdown cells in vitro and to restore angiogenesis in a test in vivo. Our results unveil an unexpected role of Dgke in the induction of cyclooxygenase-2 and in the regulation of glomerular prostanoids synthesis under stress.

Cultural implications of late Holocene climate change in the Cuenca Oriental, Mexico.

There is currently no consensus on the importance of climate change in Mesoamerican prehistory. Some invoke drought as a causal factor in major cultural transitions, including the abandonment of many sites at 900 CE, while others conclude that cultural factors were more important. This lack of agreement reflects the fact that the history of climate change in many regions of Mesoamerica is poorly understood. We present paleolimnological evidence suggesting that climate change was important in the abandonment of Cantona between 900 CE and 1050 CE. At its peak, Cantona was one of the largest cities in pre-Columbian Mesoamerica, with a population of 90,000 inhabitants. The site is located in the Cuenca Oriental, a semiarid basin east of Mexico City. We developed a subcentennial reconstruction of regional climate from a nearby maar lake, Aljojuca. The modern climatology of the region suggests that sediments record changes in summer monsoonal precipitation. Elemental geochemistry (X-ray fluorescence) and δ(18)O from authigenic calcite indicate a centennial-scale arid interval between 500 CE and 1150 CE, overlaid on a long-term drying trend. Comparison of this record to Cantona's chronology suggests that both the city's peak population and its abandonment occurred during this arid period. The human response to climate change most likely resulted from the interplay of environmental and political factors. During earlier periods of Cantona's history, increasing aridity and political unrest may have actually increased the city's importance. However, by 1050 CE, this extended arid period, possibly combined with regional political change, contributed to the city's abandonment.

Accumulation of extracellular hyaluronan by hyaluronan synthase 3 promotes tumor growth and modulates the pancreatic cancer microenvironment.

Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic ß-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and ß-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth.

Promoting responsible conduct of research: a Canadian perspective.

This article compares the current Canadian and American approaches to governing the responsible conduct of research. The Canadian Secretariat on Responsible Conduct of Research acts on behalf of Canada's three federal research agencies to implement their Framework on Responsible Conduct of Research. It operates not on the basis of regulatory authority, like its U.S. counterpart, the Office of Research Integrity, but rather on the basis of making compliance a condition of eligibility for funding. Both offices are dedicated to promoting good research practices and to enforcing good standards of research practice.

De novo lumen formation and elongation in the developing nephron: a central role for afadin in apical polarity.

A fundamental process in biology is the de novo formation and morphogenesis of polarized tubules. Although these processes are essential for the formation of multiple metazoan organ systems, little is known about the molecular mechanisms that regulate them. In this study, we have characterized several steps in tubule formation and morphogenesis using the mouse kidney as a model system. We report that kidney mesenchymal cells contain discrete Par3-expressing membrane microdomains that become restricted to an apical domain, coinciding with lumen formation. Once lumen formation has been initiated, elongation occurs by simultaneous extension and additional de novo lumen generation. We demonstrate that lumen formation and elongation require afadin, a nectin adaptor protein implicated in adherens junction formation. Mice that lack afadin in nephron precursors show evidence of Par3-expressing membrane microdomains, but fail to develop normal apical-basal polarity and generate a continuous lumen. Absence of afadin led to delayed and diminished integration of nectin complexes and failure to recruit R-cadherin. Furthermore, we demonstrate that afadin is required for Par complex formation. Together, these results suggest that afadin acts upstream of the Par complex to regulate the integration and/or coalescence of membrane microdomains, thereby establishing apical-basal polarity and lumen formation/elongation during kidney tubulogenesis.

Stem cell research ethics: consensus statement on emerging issues.

This article is a consensus statement by an international interdisciplinary group of academic experts and Canadian policy-makers on emerging ethical, legal and social issues in human embryonic stem cells (hESC) research in Canada. The process of researching consensus included consultations with key stakeholders in hESC research (regulations, stem cell researchers, and research ethics experts), preparation and distribution of background papers, and an international workshop held in Montreal in February 2007 to discuss the papers and debate recommendations. The recommendations provided in the consensus statement focus on issues of immediate relevance to Canadian policy-makers, including informed consent to hESC research, the use of fresh embryos in research, management of conflicts of interest, and the relevance of public opinion research to policy-making.