The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE ...loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71–90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE ε3/ε4 controls carried a stop-gain affecting ε4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option.
•A large cohort was searched for carriers of APOE LoF variants•Seven APOE LoF variant carriers, including five controls, were identified•Two ε3/ε4 controls with LoF variants on ε4 had normal amyloid at ages 76 and 90 years•ε4 appears to act via the gain of function; ε4 loss may protect against Alzheimer’s disease
The apolipoprotein E (APOE) ε4 allele strongly increases the risk for Alzheimer’s disease. Chemparathy et al. identified seven carriers of APOE loss-of-function (LoF) variants, including two controls with LoF variants on ε4 and normal amyloid at ages 76 and 90 years. The knockdown of ε4 may protect against Alzheimer’s disease.
People with germline mutation in one of the DNA mismatch repair (MMR) genes have increased colorectal cancer risk. For these high-risk people, study findings of the relationship between alcohol ...consumption and colorectal cancer risk have been inconclusive.
1,925 MMR gene mutations carriers recruited into the Colon Cancer Family Registry who had completed a questionnaire on lifestyle factors were included. Weighted Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between alcohol consumption and colorectal cancer.
Colorectal cancer was diagnosed in 769 carriers (40%) at a mean (SD) age of 42.6 (10.3) years. Compared with abstention, ethanol consumption from any alcoholic beverage up to 14 g/day and >28 g/day was associated with increased colorectal cancer risk (HR, 1.50; 95% CI, 1.09-2.07 and 1.69; 95% CI, 1.07-2.65, respectively;
= 0.05), and colon cancer risk (HR, 1.78; 95% CI, 1.27-2.49 and 1.94; 95% CI, 1.19-3.18, respectively;
= 0.02). However, there was no clear evidence for an association with rectal cancer risk. Also, there was no evidence for associations between consumption of individual alcoholic beverage types (beer, wine, spirits) and colorectal, colon, or rectal cancer risk.
Our data suggest that alcohol consumption, particularly more than 28 g/day of ethanol (∼2 standard drinks of alcohol in the United States), is associated with increased colorectal cancer risk for MMR gene mutation carriers.
Although these data suggested that alcohol consumption in MMR carriers was associated with increased colorectal cancer risk, there was no evidence of a dose-response, and not all types of alcohol consumption were associated with increased risk.
.
Clouds and Snowball Earth deglaciation Abbot, Dorian S.; Voigt, Aiko; Branson, Mark ...
Geophysical research letters,
28 October 2012, Letnik:
39, Številka:
20
Journal Article
Recenzirano
Odprti dostop
Neoproterozoic, and possibly Paleoproterozoic, glaciations represent the most extreme climate events in post‐Hadean Earth, and may link closely with the evolution of the atmosphere and life. ...According to the Snowball Earth hypothesis, the entire ocean was covered with ice during these events for a few million years, during which time volcanic CO2 increased enough to cause deglaciation. Geochemical proxy data and model calculations suggest that the maximum CO2 was 0.01–0.1 by volume, but early climate modeling suggested that deglaciation was not possible at CO2 = 0.2. We use results from six different general circulation models (GCMs) to show that clouds could warm a Snowball enough to reduce the CO2required for deglaciation by a factor of 10–100. Although more work is required to rigorously validate cloud schemes in Snowball‐like conditions, our results suggest that Snowball deglaciation is consistent with observations.
Key Points
We run a suite of GCMs with Snowball Earth boundary conditions
We find that clouds can reduce the CO2 needed to deglaciate by 10‐100
Snowball deglaciation no longer seems a serious problem for the hypothesis
We studied 2332 individuals with monoallelic mutations in MUTYH among 9504 relatives of 264 colorectal cancer (CRC) cases with a MUTYH mutation. We estimated CRC risks through 70 years of age of 7.2% ...for male carriers of monoallelic mutations (95% confidence interval CI, 4.6%–11.3%) and 5.6% for female carriers of monoallelic mutations (95% CI, 3.6%–8.8%), irrespective of family history. For monoallelic MUTYH mutation carriers with a first-degree relative with CRC diagnosed by 50 years of age who does not have the MUTYH mutation, risks of CRC were 12.5% for men (95% CI, 8.6%–17.7%) and 10% for women (95% CI, 6.7%–14.4%). Risks of CRC for carriers of monoallelic mutations in MUTYH with a first-degree relative with CRC are sufficiently high to warrant more intensive screening than for the general population.
► Dark material on Vesta observed by Dawn is remnant carbonaceous chondrite impactor. ► Global abundance of carbonaceous chondrite material <6vol.% similar to howardites. ► Distribution of dark ...material suggests delivery during Veneneia basin formation event. ► Suggests extensive volatile delivery onto Vesta by carbonaceous impactors. ► First direct link between HED meteorites and surface of Vesta.
NASA’s Dawn spacecraft observations of Asteroid (4) Vesta reveal a surface with the highest albedo and color variation of any asteroid we have observed so far. Terrains rich in low albedo dark material (DM) have been identified using Dawn Framing Camera (FC) 0.75μm filter images in several geologic settings: associated with impact craters (in the ejecta blanket material and/or on the crater walls and rims); as flow-like deposits or rays commonly associated with topographic highs; and as dark spots (likely secondary impacts) nearby impact craters. This DM could be a relic of ancient volcanic activity or exogenic in origin. We report that the majority of the spectra of DM are similar to carbonaceous chondrite meteorites mixed with materials indigenous to Vesta. Using high-resolution seven color images we compared DM color properties (albedo, band depth) with laboratory measurements of possible analog materials. Band depth and albedo of DM are identical to those of carbonaceous chondrite xenolith-rich howardite Mt. Pratt (PRA) 04401. Laboratory mixtures of Murchison CM2 carbonaceous chondrite and basaltic eucrite Millbillillie also show band depth and albedo affinity to DM. Modeling of carbonaceous chondrite abundance in DM (1–6vol.%) is consistent with howardite meteorites. We find no evidence for large-scale volcanism (exposed dikes/pyroclastic falls) as the source of DM. Our modeling efforts using impact crater scaling laws and numerical models of ejecta reaccretion suggest the delivery and emplacement of this DM on Vesta during the formation of the ∼400km Veneneia basin by a low-velocity (<2km/s) carbonaceous impactor. This discovery is important because it strengthens the long-held idea that primitive bodies are the source of carbon and probably volatiles in the early Solar System.
Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation ...carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first‐ and 3,255 second‐degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals CIs) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7–97) and ovarian cancer 17 (2.4–115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7–13); hepatobiliary cancer 4.5 (2.7–7.5); endometrial cancer 2.1 (1.1–3.9) and breast cancer 1.4 (1.0–2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5–77%) for males and 8% (2–33%) for females and ovarian cancer 14% (2–65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4–7%) for males and 2.3% (1.7–3.3%) for females; hepatobiliary cancer 3% (2–5%) for males and 1.4% (0.8–2.3%) for females; endometrial cancer 3% (2%–6%) and breast cancer 11% (8–16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.
What's new?
People who have a mutation in the MUTYH gene have an increased risk of colorectal cancer. But are they also at higher risk for other types of cancer? In this study, the authors found that people with one mutated copy of MUTYH (monoallelic) have an increased risk of gastric, liver, breast and endometrial cancers, while people with two mutated copies (biallelic) have an increased risk of bladder and ovarian cancers. This information will be useful for risk assessment in patients and families who carry MUTYH mutations.
Background
Despite regular surveillance colonoscopy, the metachronous colorectal cancer risk for mismatch repair (MMR) gene mutation carriers after segmental resection for colon cancer is high and ...total or subtotal colectomy is the preferred option. However, if the index cancer is in the rectum, management decisions are complicated by considerations of impaired bowel function. We aimed to estimate the risk of metachronous colon cancer for MMR gene mutation carriers who underwent a proctectomy for index rectal cancer.
Methods
This retrospective cohort study comprised 79 carriers of germline mutation in a MMR gene (18
MLH1,
55
MSH2,
4
MSH6,
and 2
PMS2
) from the Colon Cancer Family Registry who had had a proctectomy for index rectal cancer. Cumulative risks of metachronous colon cancer were calculated using the Kaplan–Meier method.
Results
During median 9 years (range 1–32 years) of observation since the first diagnosis of rectal cancer, 21 carriers (27 %) were diagnosed with metachronous colon cancer (incidence 24.25, 95 % confidence interval CI 15.81–37.19 per 1,000 person-years). Cumulative risk of metachronous colon cancer was 19 % (95 % CI 9–31 %) at 10 years, 47 (95 % CI 31–68 %) at 20 years, and 69 % (95 % CI 45–89 %) at 30 years after surgical resection. The frequency of surveillance colonoscopy was 1 colonoscopy per 1.16 years (95 % CI 1.01–1.31 years). The AJCC stages of the metachronous cancers, where available, were 72 % stage I, 22 % stage II, and 6 % stage III.
Conclusions
Given the high metachronous colon cancer risk for MMR gene mutation carriers diagnosed with an index rectal cancer, proctocolectomy may need to be considered.
Urologists perform the majority of vasectomies in the United States; however, family medicine physicians (FMPs) perform up to 35%. We hypothesized that differences exist in practice patterns and ...outcomes between urologists and FMPs. Patients who underwent a vasectomy from 2010 to 2016 were identified. Postvasectomy semen analysis (PVSA) practices were compared between urologists and FMPs, before and after release of the 2012 AUA vasectomy guidelines. From 2010 to 2016, FMPs performed 1435 (35.1%) of all vasectomies. PVSA follow-up rates were similar between the two groups (63.4% vs 64.8%, P = 0.18). Of the patients with follow-up, the median number of PVSAs obtained was 1 (range 1-6) in both groups (P = 0.22). Following the release of guidelines, fewer urologists obtained multiple PVSAs (69.8% vs 28.9% pre- and post-2012, P < 0.01). FMPs had a significant but lesser change in the use of multiple PVSAs (47.5% vs 38.4%, P < 0.01). Both groups made appropriate changes in the timing of the first PVSA, but FMPs continued to obtain PVSAs before 8 weeks (15.0% vs 6.5%, P < 0.01). FMPs had a higher rate of positive results in PVSAs obtained after 8 weeks, the earliest recommended by the AUA guidelines (4.1% vs 1.3%, P < 0.01). Significant differences in PVSA utilization between FMPs and urologists were identified and were impacted by the release of AUA guidelines in 2012. In summary, FMPs obtained multiple PVSAs more frequently and continued to obtain PVSAs prior to the 8-week recommendation, suggesting less penetration of AUA guidelines to nonurology specialties. Furthermore, FMPs had more positive results on PVSAs obtained within the recommended window.
LATIS: The Lyα Tomography IMACS Survey Newman, Andrew B.; Rudie, Gwen C.; Blanc, Guillermo A. ...
The Astrophysical journal,
03/2020, Letnik:
891, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract
We introduce LATIS, the Ly
α
Tomography IMACS Survey, a spectroscopic survey at Magellan designed to map the
z
= 2.2–2.8 intergalactic medium (IGM) in three dimensions by observing the Ly
α
...forest in the spectra of galaxies and QSOs. Within an area of 1.7 deg
2
, we will observe approximately half of ≳
L
* galaxies at
z
= 2.2–3.2 for typically 12 hr, providing a dense network of sightlines piercing the IGM with an average transverse separation of 2.5
h
−1
comoving Mpc (1 physical Mpc). At these scales, the opacity of the IGM is expected to be closely related to the dark matter density, and LATIS will therefore map the density field in the
z
∼ 2.5 universe at ∼Mpc resolution over the largest volume to date. Ultimately, LATIS will produce approximately 3800 spectra of
z
= 2.2–3.2 galaxies that probe the IGM within a volume of 4 × 10
6
h
−3
Mpc
3
, large enough to contain a representative sample of structures from protoclusters to large voids. Observations are already complete over one-third of the survey area. In this paper, we describe the survey design and execution. We present the largest IGM tomographic maps at comparable resolution yet made. We show that the recovered matter overdensities are broadly consistent with cosmological expectations based on realistic mock surveys, that they correspond to galaxy overdensities, and that we can recover structures identified using other tracers. LATIS is conducted in Canada–France–Hawaii Telescope Legacy Survey fields, including COSMOS. Coupling the LATIS tomographic maps with the rich data sets collected in these fields will enable novel studies of environment-dependent galaxy evolution and the galaxy–IGM connection at cosmic noon.
We present ultraviolet, optical and near-infrared observations of the interacting transient SN 2009ip, covering the period from the start of the outburst in 2012 October until the end of the 2012 ...observing season. The transient reached a peak magnitude of M
V
= −17.7 mag, with a total integrated luminosity of 1.9 × 1049 erg over the period of 2012 August-December. The light curve fades rapidly, dropping by 4.5 mag from the V-band peak in 100 d. The optical and near-infrared spectra are dominated by narrow emission lines with broad electron scattering wings, signalling a dense circumstellar environment, together with multiple components of broad emission and absorption in H and He at velocities in the range 0.5-1.2 × 104 km s−1. We see no evidence for nucleosynthesized material in SN 2009ip, even in late-time pseudo-nebular spectra. We set a limit of <0.02 M on the mass of any possible synthesized 56Ni from the late-time light curve. A simple model for the narrow Balmer lines is presented and used to derive number densities for the circumstellar medium in the range ∼109-1010 cm−3. Our near-infrared data do not show any excess at longer wavelengths, and we see no other signs of dust formation. Our last data, taken in 2012 December, show that SN 2009ip has spectroscopically evolved to something quite similar to its appearance in late 2009, albeit with higher velocities. It is possible that neither of the eruptive and high-luminosity events of SN 2009ip were induced by a core collapse. We show that the peak and total integrated luminosity can be due to the efficient conversion of kinetic energy from colliding ejecta, and that around 0.05-0.1 M of material moving at 0.5-1 × 104 km s−1 could comfortably produce the observed luminosity. We discuss the possibility that these shells were ejected by the pulsational pair instability mechanism, in which case the progenitor star may still exist, and will be observed after the current outburst fades. The long-term monitoring of SN 2009ip, due to its proximity, has given the most extensive data set yet gathered of a high-luminosity interacting transient and its progenitor. It is possible that some purported Type IIn supernovae are in fact analogues of the 2012b event and that pre-explosion outbursts have gone undetected.
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