Using recently collected high‐resolution seismic data along a dense linear transect across Ohio, West Virginia, and Virginia (called Mid‐Atlantic Geophysical Integrative Collaboration (MAGIC) ...profile), we analyze P‐to‐S receiver functions to investigate the undulations of the mantle transition zone (MTZ) discontinuities (410‐ and 660‐km) beneath the central Appalachian region. Our results incorporating the effects of local crustal and mantle structures suggest shallowing of both the 410‐ and the 660‐km discontinuities from the northwest (inland) to the southeast (coast) along MAGIC profile. Hydro‐thermal upwelling beneath the eastern U.S. coastal plain due to a hydrated MTZ and hot upwelling return flow associated with the descending lower mantle Farallon slab is consistent with our observations of MTZ structure considering 3D velocity heterogeneity. The inferred hydrous hot upwelling rising into the upper mantle may trigger dehydration melting atop the 410‐km discontinuity, which may help to explain the presence of a low velocity upper mantle anomaly beneath the region today.
Plain Language Summary
The dynamic and tectonic processes of passive continental margins that do not lie on plate boundaries are poorly understood compared with active continental margins. The mantle flow patterns beneath the eastern North America, a long‐lived passive continental margin, are debated, due to limited local high‐resolution seismic studies. Using a dense seismic array through Ohio, West Virginia, and Virginia (called MAGIC profile) with unprecedented resolution, we investigate the undulations of 410‐ and 660‐km discontinuities (boundaries of the mantle transition zone) beneath the eastern U.S. by analyzing seismic waves that have been converted at these discontinuities. After correcting for local crustal and mantle structures, we identify positively correlated shallowing of the 410‐ and 660‐km discontinuities from the inland to the coast, which are hard to explain by thermal heterogeneity alone. Our findings suggest the existence of hot upwelling return flow associated with the neighboring descending Farallon slab in the lower mantle beneath the eastern U.S. When this passive hot return flow rises through the hydrated transition zone into the upper mantle, dehydration melting atop 410‐km discontinuity may be triggered. The buoyant melt may further rise through the upper mantle, providing a potential explanation for upper mantle velocity anomalies beneath the region.
Key Points
Seismic receiver functions image mantle transition zone discontinuities from a regional high‐resolution transect across the eastern U.S
The results are difficult to reconcile with either thermal or hydration variations alone in the transition zone
Local hydro‐thermal upwelling due to hydrated transition zone and hot return flow associated with the descending Farallon slab may exist
Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly ...delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD.
In this open-label, dose-escalation phase 1–2a study, we gave monthly intrathecal HPβCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPβCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24S-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range.
Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPβCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPβCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPβCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423).
Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPβCD.
National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson.
The synthesis of serine from glucose is a key metabolic pathway supporting cellular proliferation in healthy and malignant cells. Despite this, the role that this aspect of metabolism plays in ...germinal center biology and pathology is not known. Here, we performed a comprehensive characterization of the role of the serine synthesis pathway in germinal center B cells and lymphomas derived from these cells. We demonstrate that upregulation of a functional serine synthesis pathway is a metabolic hallmark of B cell activation and the germinal center reaction. Inhibition of phosphoglycerate dehydrogenase (PHGDH), the first and rate-limiting enzyme in this pathway, led to defective germinal formation and impaired high-affinity antibody production. In addition, overexpression of enzymes involved in serine synthesis was a characteristic of germinal center B cell-derived lymphomas, with high levels of expression being predictive of reduced overall survival in diffuse large B cell lymphoma. Inhibition of PHGDH induced apoptosis in lymphoma cells, reducing disease progression. These findings establish PHGDH as a critical player in humoral immunity and a clinically relevant target in lymphoma.
The mountainous subantarctic island of South Georgia lies within the belt of strong westerly winds that blow around the Southern Ocean. Interaction of the prevailing circumpolar westerly winds with ...the island's central mountain chain, which rises to nearly 3,000 m, generates warm, dry föhn winds on the downwind side of the island, which are a significant feature of the local climate. We make use of 10 years of automatic weather station observations from King Edward Point (KEP), on the northeastern (climatologically downwind) coast of South Georgia, to develop a climatology of the occurrence and properties of föhn winds in this region. Using objective criteria to identify the onset and cessation of föhn, we find that KEP experiences föhn conditions for around 30% of the time. Föhn events last for about 30 hr on average and are associated with significant increases in temperature and wind speed, and decreases in relative humidity. On average, a föhn event is observed every 4 days, with little seasonal variation seen in the frequency of occurrence. However, föhn events observed during the austral summer season are, on average, both longer and more intense (as measured by changes in temperature, relative humidity, and wind speed) than those occurring in other seasons. The fraction of the time for which föhn conditions are observed at KEP increases (decreases) during months when the prevailing westerlies are strengthened (weakened). Monthly mean temperatures at KEP are positively correlated with the föhn fraction but variations in the latter only explain 16% of the variance of monthly mean temperature. We conclude that, while föhn plays an important role in shaping the local climate of South Georgia, other processes may be of greater importance in controlling regional climate variability and change.
The mountainous island of South Georgia (seen in this MODIS satellite image from NASA Worldview, taken on 8 August 2012) provides a barrier to the prevailing westerly winds of the Southern Ocean. As a result, warm, dry föhn winds frequently develop on the northeast (downwind) coast of the island. In this article, we present the first climatology of the occurrence and characteristics of these winds, investigate the factors that control their occurrence, and quantify their role in controlling the local climate of the island.
The eastern side of the Antarctic Peninsula (AP) mountain range and the adjacent ice shelves are frequently affected by föhn winds originating from upwind of the mountains. Six automatic weather ...stations (AWSs) and archived model output from 5 km resolution Antarctic Mesoscale Prediction System (AMPS) forecasts have been combined to identify the occurrence of föhn conditions, and their spatial distribution over the Larsen C Ice Shelf (LCIS) from 2009 to 2012.
Algorithms for semi‐automatic detection of föhn conditions have been developed for both AWS and AMPS data. The frequency of föhn varies by location, being most frequent at the foot of the AP and in the north of the ice shelf. They are most common in spring, when they can prevail for 50% of the time. The results of this study have important implications for further research, investigating the impact of föhn on surface melting, and the surface energy budget of the ice shelf. This is of particular interest due to the collapse of Larsen A and B ice shelves in 1995 and 2002 respectively, and the potential instability issues following a large calving event on Larsen C in 2017.
The spatial and temporal distribution of f'́ohn winds over the Larsen C ice shelf is presented for 2009–2012. F'́ohn winds can occur more than 50% of the time during spring, and are observed year‐round. They can raise air temperatures above freezing up to 130 km from the source of origin.
Hepatobiliary adverse events (AEs) have been observed in a small proportion of patients with metastatic breast cancer (MBC) treated with lapatinib. This study sought to identify gene variants ...associated with lapatinib-induced ALT elevation and hepatobiliary AEs.
A two-stage pharmacogenetic investigation of ALT elevation was conducted in lapatinib-treated patients with MBC. Exploratory marker identification evaluated classical HLA alleles, candidate genes, and genome-wide screening in 37 cases with ALT greater than 3 times the upper limit of normal (ULN) and 286 controls with ALT ≤ 1× ULN, selected from 901 lapatinib-treated patients in 12 trials. Markers achieving prespecified association thresholds were progressed to an independent confirmatory data set of 24 ALT cases and 155 controls selected from a subsequent trial of 374 lapatinib-treated patients.
Of 58 variants associated with ALT elevation in the exploratory data set, four exceeded the prespecified significance threshold in the confirmatory analysis. These variants reside in the same MHC genomic locus and include HLA-DQA1*02:01. In the confirmatory study, DQA1*02:01 allele carriage was present in 71% of ALT cases and in 21% of controls (P < .001; odds ratio, 9.0; 95% CI, 3.2 to 27.4). As a predictor of liver safety risk in ALT cases versus noncases, DQA1*02:01 had negative and positive predictive values of 0.97 (95% CI, 0.95 to 0.99) and 0.17 (95% CI 0.10 to 0.26), respectively.
These results support a role for immune mechanisms in lapatinib-induced hepatotoxicity. Further work is required to determine whether testing for DQA1*02:01 allele carriage is clinically useful in managing liver safety risk during lapatinib treatment.
Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation
. Gene induction typically involves ...cis-regulatory elements that contact and activate genes on the same chromosome
. Here we show that ecDNA hubs-clusters of around 10-100 ecDNAs within the nucleus-enable intermolecular enhancer-gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the bromodomain and extraterminal domain (BET) protein BRD4 in a MYC-amplified colorectal cancer cell line. The BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-derived-oncogene transcription. The BRD4-bound PVT1 promoter is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1 promoter on an exogenous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic silencing of ecDNA enhancers by CRISPR interference reveals intermolecular enhancer-gene activation among multiple oncogene loci that are amplified on distinct ecDNAs. Thus, protein-tethered ecDNA hubs enable intermolecular transcriptional regulation and may serve as units of oncogene function and cooperative evolution and as potential targets for cancer therapy.
Malaria transmission-blocking vaccines (TBVs) aim to elicit human antibodies that inhibit sporogonic development of Plasmodium falciparum in mosquitoes, thereby preventing onward transmission. ...Pfs48/45 is a leading clinical TBV candidate antigen and is recognized by the most potent transmission-blocking monoclonal antibody (mAb) yet described; still, clinical development of Pfs48/45 antigens has been hindered, largely by its poor biochemical characteristics. Here, we used structure-based computational approaches to design Pfs48/45 antigens stabilized in the conformation recognized by the most potently inhibitory mAb, achieving >25°C higher thermostability compared with the wild-type protein. Antibodies elicited in mice immunized with these engineered antigens displayed on liposome-based or protein nanoparticle-based vaccine platforms exhibited 1-2 orders of magnitude superior transmission-reducing activity, compared with immunogens bearing the wild-type antigen, driven by improved antibody quality. Our data provide the founding principles for using molecular stabilization solely from antibody structure-function information to drive improved immune responses against a parasitic vaccine target.
A new regime index is constructed to capture the seasonal development of the stratospheric polar vortex in the northern winter, based on the standard deviation of Ertel’s potential vorticity in the ...upper stratosphere in November–December. The narrow-jet flow regime is characterized by a polar vortex that is more confined to high latitudes in the early winter upper stratosphere. This upper-level vortex configuration is more susceptible to the disturbances of upward propagating planetary-scale Rossby waves; the stratospheric polar vortex thus weakens earlier and is vertically shallower. The wide-jet flow regime is characterized by a broader-than-average polar vortex that extends further into the subtropics in the early winter upper stratosphere. The polar night jet then gradually strengthens, moves poleward, and penetrates deep into the lowermost stratosphere, with a sharply defined polar vortex edge due to more frequent Rossby wave breaking. Composite difference analyses show that the wide- and narrow-jet regimes, defined in the uppermost stratosphere in November–December, lead to different circulation anomalies of the lower stratosphere and the troposphere in January–February, offering the potential for improved predictability of subseasonal to seasonal forecasts up to two months ahead. The lower-tropospheric responses in January–February are zonally asymmetric. The narrow-jet regime projects most strongly over the North Atlantic, with an equatorward-shifted and/or broader midlatitude westerly jet. The wide-jet-regime response is characterized by a weakened midlatitude westerly jet over the North Pacific. The two flow regimes also differ in their impacts on the storm track over western Europe and the east coast of North America, which may have implications for extreme weather events in those regions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Since the mid-1960s, rapid regional summer warming has occurred on the east coast of the northern Antarctic Peninsula, with near-surface temperatures increasing by more than 2°C. This warming has ...contributed significantly to the collapse of the northern sections of the Larsen Ice Shelf. Coincident with this warming, the summer Southern Hemisphere Annular Mode (SAM) has exhibited a marked trend, suggested by modeling studies to be predominantly a response to anthropogenic forcing, resulting in increased westerlies across the northern peninsula.
Observations and reanalysis data are utilized to demonstrate that the changing SAM has played a key role in driving this local summer warming. It is proposed that the stronger summer westerly winds reduce the blocking effect of the Antarctic Peninsula and lead to a higher frequency of air masses being advected eastward over the orographic barrier of the northern Antarctic Peninsula. When this occurs, a combination of a climatological temperature gradient across the barrier and the formation of a föhn wind on the lee side typically results in a summer near-surface temperature sensitivity to the SAM that is 3 times greater on the eastern side of the peninsula than on the west. SAM variability is also shown to play a less important role in determining summer temperatures at stations west of the barrier in the northern peninsula (~62°S), both at the surface and throughout the troposphere. This is in contrast to a station farther south (~65°S) where the SAM exerts little influence.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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