Yin Yang 1 controls cerebellar astrocyte maturation.

Diverse subpopulations of astrocytes tile different brain regions to accommodate local requirements of neurons and associated neuronal circuits. Nevertheless, molecular mechanisms governing astrocyte diversity remain mostly unknown. We explored the role of a zinc finger transcription factor Yin Yang 1 (YY1) that is expressed in astrocytes. We found that specific deletion of YY1 from astrocytes causes severe motor deficits in mice, induces Bergmann gliosis, and results in simultaneous loss of GFAP expression in velate and fibrous cerebellar astrocytes. Single cell RNA-seq analysis showed that YY1 exerts specific effects on gene expression in subpopulations of cerebellar astrocytes. We found that although YY1 is dispensable for the initial stages of astrocyte development, it regulates subtype-specific gene expression during astrocyte maturation. Moreover, YY1 is continuously needed to maintain mature astrocytes in the adult cerebellum. Our findings suggest that YY1 plays critical roles regulating cerebellar astrocyte maturation during development and maintaining a mature phenotype of astrocytes in the adult cerebellum.

The Association of Radiation Dose With Overall Survival for Patients Treated With Prostate Stereotactic Body Radiation Therapy.

Introduction Stereotactic body radiation therapy (SBRT) for prostate adenocarcinoma (PCa) has demonstrated excellent biochemical recurrence-free survival, with studies showing improved BRFS with higher-dose SBRT. However, current studies have been underpowered to evaluate the relationship of SBRT dose to overall survival (OS). In this retrospective study using the National Cancer Database (NCDB), we hypothesize that, given the low alpha/beta ratio of PCa, a relatively small increase in the dose-per-fraction would be associated with improved survival outcomes for intermediate-risk PCa (IR-PCa) comparing 36.25 Gy/5 fx [biologically equivalent dose (BEDα/ß = 1.5 = 211.46 Gy vs. 35 Gy (BED1.5 = 198.33 Gy)]. Materials and methods We queried records from the NCDB from 2005 to 2015 for men receiving prostate SBRT for IR-PCa (n=2673). 82% were treated using either 35 Gy/5 fx or 36.25 Gy/5 fx. We compared OS in men receiving 35 Gy versus 36.25 Gy. Inverse probability of treatment weighting (IPTW) was used to adjust for covariable imbalances. Unweighted- and weighted-multivariable analysis (MVA) using Cox regression was used to compare OS hazard ratios, accounting for age, race, Charlson-Deyo comorbidity score, treatment facility type, prostate-specific antigen (PSA), clinical T-stage, Gleason Score, and use of androgen deprivation therapy (ADT). Kaplan-Meier analysis was performed. Results Seven hundred and eighty men (35%) were treated with 35 Gy/5 fx and 1434 men (65%) were treated with 36.25 Gy/5 fx (n=2214). Compared to 35 Gy, treatment with 36.25 Gy was associated with significantly improved OS (hazard ratio [HR]: 0.61 [95% CI: 0.43-0.89], P=0.009) on MVA. On Kaplan-Meier analysis, 36.25 Gy was associated with improved survival (p=0.034), with a five-year OS of 92% and 88%, respectively. Conclusions In a multi-institutional retrospective database of 2,214 IR patients treated with prostate SBRT, a prescription dose of 36.25 Gy/5 fx was associated with improved OS vs. 35 Gy/5 fx. Results are hypothesis-generating but do lend support to the current National Comprehensive Cancer Network (NCCN) guidelines that the minimum recommended dose for prostate SBRT is 36.25 Gy/5 fx.

Late Pleistocene exploration and settlement of the Americas by modern humans.

North and South America were the last continents to be explored and settled by modern humans at the end of the Pleistocene. Genetic data, derived from contemporary populations and ancient individuals, show that the first Americans originated from Asia and after several population splits moved south of the continental ice sheets that covered Canada sometime between ~17.5 and ~14.6 thousand years (ka) ago. Archaeological evidence shows that geographically dispersed populations lived successfully, using biface, blade, and osseous technologies, in multiple places in North and South America between ~15.5 and ~14 ka ago. Regional archaeological complexes emerged by at least ~13 ka ago in North America and ~12.9 ka ago in South America. Current genetic and archaeological data do not support an earlier (pre-17.5 ka ago) occupation of the Americas.

RelB acts as a molecular switch driving chronic inflammation in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a primary brain tumor characterized by extensive necrosis and immunosuppressive inflammation. The mechanisms by which this inflammation develops and persists in GBM remain elusive. We identified two cytokines interleukin-1ß (IL-1) and oncostatin M (OSM) that strongly negatively correlate with patient survival. We found that these cytokines activate RelB/p50 complexes by a canonical NF-κB pathway, which surprisingly drives expression of proinflammatory cytokines in GBM cells, but leads to their inhibition in non-transformed astrocytes. We discovered that one allele of the gene encoding deacetylase Sirtuin 1 (SIRT1), needed for repression of cytokine genes, is deleted in 80% of GBM tumors. Furthermore, RelB specifically interacts with a transcription factor Yin Yang 1 (YY1) in GBM cells and activates GBM-specific gene expression programs. As a result, GBM cells continuously secrete proinflammatory cytokines and factors attracting/activating glioma-associated microglia/macrophages and thus, promote a feedforward inflammatory loop.

Reassessing the chronology of the archaeological site of Anzick.

Found in 1968, the archaeological site of Anzick, Montana, contains the only known Clovis burial. Here, the partial remains of a male infant, Anzick-1, were found in association with a Clovis assemblage of over 100 lithic and osseous artifacts-all red-stained with ochre. The incomplete, unstained cranium of an unassociated, geologically younger individual, Anzick-2, was also recovered. Previous chronometric work has shown an age difference between Anzick-1 and the Clovis assemblage (represented by dates from two antler rod samples). This discrepancy has led to much speculation, with some discounting Anzick-1 as Clovis. To resolve this issue, we present the results of a comprehensive radiocarbon dating program that utilized different pretreatment methods on osseous material from the site. Through this comparative approach, we obtained a robust chronometric dataset that suggests that Anzick-1 is temporally coeval with the dated antler rods. This implies that the individual is indeed temporally associated with the Clovis assemblage.

The genome of a Late Pleistocene human from a Clovis burial site in western Montana.

Clovis, with its distinctive biface, blade and osseous technologies, is the oldest widespread archaeological complex defined in North America, dating from 11,100 to 10,700 (14)C years before present (bp) (13,000 to 12,600 calendar years bp). Nearly 50 years of archaeological research point to the Clovis complex as having developed south of the North American ice sheets from an ancestral technology. However, both the origins and the genetic legacy of the people who manufactured Clovis tools remain under debate. It is generally believed that these people ultimately derived from Asia and were directly related to contemporary Native Americans. An alternative, Solutrean, hypothesis posits that the Clovis predecessors emigrated from southwestern Europe during the Last Glacial Maximum. Here we report the genome sequence of a male infant (Anzick-1) recovered from the Anzick burial site in western Montana. The human bones date to 10,705 ± 35 (14)C years bp (approximately 12,707-12,556 calendar years bp) and were directly associated with Clovis tools. We sequenced the genome to an average depth of 14.4× and show that the gene flow from the Siberian Upper Palaeolithic Mal'ta population into Native American ancestors is also shared by the Anzick-1 individual and thus happened before 12,600 years bp. We also show that the Anzick-1 individual is more closely related to all indigenous American populations than to any other group. Our data are compatible with the hypothesis that Anzick-1 belonged to a population directly ancestral to many contemporary Native Americans. Finally, we find evidence of a deep divergence in Native American populations that predates the Anzick-1 individual.

The late Pleistocene dispersal of modern humans in the Americas.

When did humans colonize the Americas? From where did they come and what routes did they take? These questions have gripped scientists for decades, but until recently answers have proven difficult to find. Current genetic evidence implies dispersal from a single Siberian population toward the Bering Land Bridge no earlier than about 30,000 years ago (and possibly after 22,000 years ago), then migration from Beringia to the Americas sometime after 16,500 years ago. The archaeological records of Siberia and Beringia generally support these findings, as do archaeological sites in North and South America dating to as early as 15,000 years ago. If this is the time of colonization, geological data from western Canada suggest that humans dispersed along the recently deglaciated Pacific coastline.