bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurocognitive Outcome Following Recovery from Severe Acute Respiratory Syndrome – Coronavirus-1 (SARS-CoV-1)
Authors: Pinnock Farena S. , Rich Jill B. , Vasquez Brandon , Wiegand Melanie , Patcai John , Troyer Angela K. , Murphy Kelly J.
Published: September 2021

Objective:

Severe acute respiratory syndrome (SARS) is a highly contagious viral respiratory illness associated with hypoxia and dyspnea. Many of those who contracted and recovered from SARS during the 2002–2003 outbreak reported persistent physical, psychological, and cognitive difficulties. Here, we investigated the residual influences of SARS on cognition for a subset of healthcare professionals who recovered and were referred for neuropsychological evaluation through their workplace insurance.

Method:

Twenty-eight healthcare professionals were evaluated on neuropsychological and mood functioning approximately 1.5 years post-recovery from a severe respiratory illness. Test scores were compared with age-matched normative data, and correlations were examined between mood, self-report memory scales, subjective complaints (e.g., poor concentration, pain, fatigue), illness severity (i.e., length of hospitalization, oxygen use during hospital stay), and cognitive performance.

Results:

Participants performed within age expectations on the majority of cognitive measures including overall memory ability. Although processing speed was generally within normal limits, 43% showed significant speed–accuracy trade-offs favoring accuracy over maintaining speed. Deficits were observed on measures of complex attention, such as working memory and the ability to sustain attention under conditions of distraction. Participants endorsed poorer memory ability than same-age peers on a meta-memory measure and mild to moderate depression and anxiety symptoms. Objective test performance was largely uncorrelated with self-reports, mood, or illness severity, except for moderate correlations between complex attention and participants’ subjective ratings of Everyday Task-Oriented Memory.

Conclusions:

These findings demonstrate specific long-term cognitive deficits associated with SARS and provide further evidence of the cognitive effects of hypoxic illnesses.
Impact of Changing Concavity Indices on Channel Steepness and Divide Migration Metrics
Authors: Gailleton Boris , Mudd Simon M. , Clubb Fiona J. , Grieve Stuart W. D. , Hurst Martin D.
Published: September 2021

The concavity index, , describes how quickly river channel gradient declines downstream. It is used in calculations of normalized channel steepness index, , a metric for comparing the relative steepness of channels with different drainage area. It is also used in calculating a transformed longitudinal coordinate, , which has been employed to search for migrating drainage divides. A value of 0.45 is typically assumed in studies. Here we quantify the variability in across multiple landscapes distributed across the globe. We describe the degree to which both the spatial distribution and magnitude of and can be distorted if is assumed rather than constrained. Differences between constrained and assumed of 0.1 or less are unlikely to affect the spatial distribution and relative magnitude of values, but larger differences can change the spatial distribution of and in extreme cases invert differences in relative steepness: relatively steep reaches can appear relatively gentle as quantified by . These inversions are function of the range of drainage area in the considered watersheds. We also demonstrate that the coordinate, and therefore the detection of migrating drainage divides, is sensitive to varying values of . The median of most likely across a wide range of mountainous and upland environments is 0.425. This wide range of variability suggests workers should not assume any value for , but should instead calculate a representative for the landscape of interest, and exclude basins for which this value is a poor fit.
Exhumation of the Ronda Peridotite During Hyper‐Extension: New Structural and Thermal Constraints From the Nieves Unit (Western Betic Cordillera, Spain)
Authors: Bessière Eloïse , Augier Romain , Jolivet Laurent , Précigout Jacques , Romagny Adrien
Published: September 2021

The Ronda peridotite (Betic Cordillera, Southern Spain) is the largest alpine‐type peridotite massif worldwide. Yet, the emplacement mechanism of these mantle rocks is still a highly debated topic. In this study, we aim at better constraining their context of exhumation by focusing on the Nieves Unit, which is mostly composed of Mesozoic metasediments displaying HT metamorphism and deformation along the contact with peridotite. The topmost parts of the peridotites and the bottom parts of the Nieves Unit share the same planar/linear fabric parallel to the contact accompanied by component of sinistral kinematic indicators. Raman Spectroscopy on Carbonaceous Material geothermometry then shows a contraction of peak‐temperature conditions within metasediments of the Nieves Unit, as well as a north‐eastward decrease along strike, highlighting a strong thinning of the unit and a significant obliquity of the isograds to the contact with the peridotites. Local magnetite ores and ophicalcite bodies are finally observed nearby the contact, suggesting a hyper‐extension context for the mantle exhumation. Indeed, the Nieves Unit, the Ronda peridotite and the Jubrique Unit, where a strong thinning has also been documented, are all in contact at a triple junction between the western contact of the peridotite and the Nieves/Jubrique contact. Altogether, these features support the idea that the western shear zone limiting the peridotites from the Nieves and Jubrique units is a tilted large‐scale extensional detachment that has exhumed mantle rocks from beneath the continental basement (Jubrique Unit) and its Mesozoic cover (Nieves Unit) during an episode of hyper‐extension.
Longer Days Likely Boosted Earth’s Early Oxygen
Authors: Benningfield Damond
Published: September 2021

Microbial mats in a Lake Huron sinkhole, combined with modeling work, suggest that the changing length of Earth’s day could have played a key role in oxygenating the atmosphere.
Tibetan Plateau Lakes as Heat Flux Hot Spots
Authors: Wheeling Kate
Published: September 2021

Freshwater lakes on the highest plateau in the world act like lenses that accumulate heat from the intense solar radiation, accelerating ice cover melt and affecting land-atmosphere fluxes.
Heat Generation in Cratonic Mantle Roots—New Trace Element Constraints From Mantle Xenoliths and Implications for Cratonic Geotherms
Authors: McIntyre T. , Kublik K. , Currie C. , Pearson D. G.
Published: September 2021

Heat generation within the cratonic lithospheric mantle (CLM) is an important but poorly determined parameter for constructing cratonic geotherms. Direct measurement of heat producing element (HPE: K, U, and Th) concentrations in bulk‐rock samples of cratonic mantle roots—provided as xenoliths in volcanic rocks such as kimberlites—is mostly compromised by infiltration of host melt into the xenoliths, resulting in over‐estimates of heat production. Here we use in situ methods (laser ablation inductively coupled plasma mass spectrometry) on minerals from a variety of cratonic mantle peridotites to avoid host‐magma contamination enabling new, more accurate determinations of heat production for a wide spectrum of model mantle lithologies. The most melt‐depleted, least metasomatized peridotites indicate that heat generation in un‐metasomatized depleted cratonic lithospheric mantle is negligible, at ∼0.00004 µW/m3, 102 to 103 times less than models that use more enriched or metasomatized compositions. Refertilized cratonic peridotites, typical of many kimberlite hosted xenoliths, have more elevated, but still low heat generation, of 0.006 µW/m3. We propose that the heat generation of typical cratonic mantle peridotite lies between these two bounds, that is, between 0.00004 and 0.006 µW/m3. Both values produce lower estimates of lithospheric thickness, by ∼10 to up to 80 km, depending on model assumptions, than estimates using higher HPE concentrations measured on bulk‐rock xenolith material.
Thermohaline Suppression of Upper Circumpolar Deep Water Eddies in the Ross Gyre
Authors: Bebieva Yana , Speer Kevin
Published: September 2021

Temperature and salinity measurements of a warm‐core eddy at the northern flank of the Ross Gyre are analyzed for dominant mixing mechanisms. The eddy is centered at the depths of the Circumpolar Deep Water and carries heat towards the gyre. Vertical and horizontal heat fluxes out of the eddy associated with internal wave turbulent mixing and thermohaline intrusions are estimated. Upward internal wave turbulent heat flux is W, whereas, the lateral intrusive heat flux is of the order of W. The horizontal flux due to intrusions is suggested to be the dominant mechanism for eddy decay and yields an eddy lifetime of about 6 months. The thermohaline intrusion‐eddy suppression mechanism is proposed and shown to be effective in suppressing the eddy field at the northern flank of the Ross Gyre. This effect has important implications for setting the basin‐wide heat budget and regulating sea‐ice cover.
Changes in the Tropical Lapse Rate due to Entrainment and Their Impact on Climate Sensitivity
Authors: Bao Jiawei , Stevens Bjorn , Kluft Lukas , Jiménez‐de‐la‐Cuesta Diego
Published: September 2021

The tropical temperature in the free troposphere deviates from a theoretical moist‐adiabat. The overall deviations are attributed to the entrainment of dry surrounding air. The deviations gradually approach zero in the upper troposphere, which we explain with a buoyancy‐sorting mechanism: the height to which individual convective parcels rise depends on parcel buoyancy, which is closely tied to the impact of entrainment during ascent. In higher altitudes, the temperature is increasingly controlled by the convective parcels that are warmer and more buoyant because of weaker entrainment effects. We represent such temperature deviations from moist‐adiabats in a clear‐sky one‐dimensional radiative‐convective equilibrium model. Compared with a moist‐adiabatic adjustment, having the entrainment‐induced temperature deviations lead to higher clear‐sky climate sensitivity. As the impact of entrainment depends on the saturation deficit, which increases with warming, our model predicts even more amplified surface warming from entrainment in a warmer climate.
Further Evidence of High Intensity During the Levantine Iron Age Anomaly in Southwestern Europe: Full Vector Archeomagnetic Dating of an Early Iron Age Dwelling From Western Spain
Authors: García‐Redondo N. , Calvo‐Rathert M. , Carrancho Á. , Goguitchaichvili A. , Iriarte E. , Blanco‐González A. , Dekkers M. J. , Morales‐Contreras J. , Alario‐García C. , Macarro‐Alcalde C.
Published: September 2021

We report an archeomagnetic study from the Early Iron Age archeological site of Cerro de San Vicente (Salamanca, Spain). The studied materials were sampled from one roundhouse and its central fireplace, a surrounding burnt floor, and slags with a twofold objective. First, to archeomagnetically determine the last use of the central fireplace, because dating with other methods was imprecise. Second, to retrieve information about the Earth's magnetic field in Western Europe from a period when the Levantine Iron Age Anomaly (LIAA) has been occasionally reported. This study includes mineralogical, archeomagnetic directional analyses, and multimethod archeointensity determinations. Paleomagnetic analyses of the central fireplace yield a mean direction: declination D = 15.1°, inclination I = 52.5°; k = 477.1, and α95 = 5.6°. Archeointensity determinations yield a mean anisotropy‐corrected archeointensity of 72.4 ± 2.0 μT (74.7 ± 4.3 μT if a pTRM‐check correction is applied) on the central fireplace and 48.2 ± 2.0 μT on slags. A full‐vector archeomagnetic dating was performed with the SHA.DIF.4k geomagnetic field model which yielded an age interval of last use of the central fireplace between 644 and 575 BCE (654–575 BCE with the pTRM‐check corrected data) at 95% confidence level. This date agrees with the archeological context. Results allows to place the high paleointensity obtained near the maximum observed in Iberia at this age, confirming the existence of this peak related to the LIAA in Western Europe where records of this feature are still scarce.
Controls on Post‐Seismic Landslide Behavior in Brittle Rocks
Authors: Brain Matthew J. , Moya Sebastian , Kincey Mark E. , Tunstall Neil , Petley David N. , Sepúlveda Sergio A.
Published: September 2021

Earthquakes trigger widespread landsliding in tectonically active landscapes. The effects of strong ground shaking on hillslope stability persist into the post‐seismic stage; rates of landsliding remain elevated in the years following an earthquake. The mechanisms that control the spatial pattern and rate of ongoing landsliding are poorly constrained, hindering our ability to reliably forecast how landscapes and landslide hazard evolve. To address this, we undertook a detailed geotechnical investigation in which we subjected representative rock samples to dynamic loading, simulating the effects of earthquake ground shaking on hillslopes of different configuration. Our results indicate that post‐seismic hillslope strength is not an intrinsic rock property; rather, it responds to the amplitude of imposed dynamic loads and the degree of pre‐existing shear surface formation within the rock. This path‐dependent behavior results from differences in the character of fractures generated by dynamic loads of different amplitude, and the ways in which apertures are mobilized or degraded in subsequent (post‐seismic) shearing. Sensitivity to dynamic loading amplitude is greater in shallow landslides in which shear surfaces are yet to fully form; such hillslopes can be strengthened or weakened by earthquake events, depending on their characteristics. In contrast, deeper landslides on steeper hillslopes in which shear surfaces have largely developed are less likely to display differences in behavior in response to dynamic loading because strain accumulation along pre‐existing fractures is dominant. Our results demonstrate the need to consider path‐dependent hillslope stability in numerical models used to forecast how landscapes respond to earthquakes and how post‐seismic hazard evolves.
Evidence of a South Asian Proto‐Monsoon During the Oligocene‐Miocene Transition
Authors: Beasley C. , Kender S. , Giosan L. , Bolton C. T. , Anand P. , Leng M. J. , Nilsson‐Kerr K. , Ullmann C. V. , Hesselbo S. P. , Littler K.
Published: September 2021

The geological history of the South Asian monsoon (SAM) before the Pleistocene is not well‐constrained, primarily due to a lack of available continuous sediment archives. Previous studies have noted an intensification of SAM precipitation and atmospheric circulation during the middle Miocene (∼14 Ma), but no records are available to test how the monsoon changed prior to this. In order to improve our understanding of monsoonal evolution, geochemical and sedimentological data were generated for the Oligocene‐early Miocene (30–20 Ma) from Indian National Gas Hydrate Expedition 01 Site NGHP‐01‐01A in the eastern Arabian Sea, at 2,674 m water depth. We find the initial glaciation phase (23.7–23.0 Ma) of the Oligocene‐Miocene transition (OMT) to be associated with an increase in water column ventilation and water mass mixing, suggesting an increase in winter monsoon type atmospheric circulation, possibly driven by a relative southward shift of the intertropical convergence zone. During the latter part of the OMT, or “deglaciation” phase (23.0–22.7 Ma), a long‐term decrease in Mn (suggestive of deoxygenation), increase in Ti/Ca and dissolution of the biogenic carbonate fraction suggest an intensification of a proto‐summer SAM system, characterized by the formation of an oxygen minimum zone in the eastern Arabian Sea and a relative increase of terrigenous material delivered by runoff to the site. With no evidence at this site for an active SAM prior to the OMT we suggest that changes in orbital parameters, as well as possibly changing Tethyan/Himalayan tectonics, caused this step change in the proto‐monsoon system at this intermediate‐depth site.
Connection Between a Subcontinental Plume and the Mid‐Lithospheric Discontinuity Leads to Fast and Intense Craton Lithospheric Thinning
Authors: Shi Ya‐Nan , Li Zhong‐Hai , Chen Ling , Morgan Jason P.
Published: September 2021

Removal and thinning of cratonic lithosphere is believed to have occurred under different tectonic settings, for example, near subduction zones and above mantle plumes. Subduction‐induced cratonic modification has been widely discussed; however, the mechanisms and dynamic processes of plume‐induced lithospheric removal remain elusive and require further systematic investigation. In this study, we use a series of 2‐D thermo‐mechanical models to explore the dynamics of the removal and thinning of cratonic lithosphere due to the interaction between a mantle plume and a weak mid‐lithosphere discontinuity (MLD) layer. Our modeling results suggest that the interaction between a mantle plume and weak MLD layer can lead to a large‐scale removal of the cratonic lithosphere once a connection between the hot upwelling and weak MLD layer is established. The presence of a vertical lithospheric weak zone and its closeness to the plume center play critical roles in creating a connection between the weak MLD and hot plume/asthenosphere. Furthermore, delamination of cratonic lithosphere is favored by a larger plume radius/volume, a higher plume temperature anomaly, and a lower viscosity of the MLD layer. A systematic comparison between subduction‐induced and plume‐induced lithospheric thinning patterns was also conducted. We summarize their significant differences on the origin and migration of melt generation, the water content in melts, and topographic evolution. The combination of numerical models and geological/geophysical observations indicates that mantle plume‐MLD interactions may have played a crucial role in lithospheric removal beneath the South Indian, South American, and North Siberian Cratons.
Climate Uncertainty and Optimal Groundwater Augmentation
Authors: Tran Dat Q. , Kovacs Kent F.
Published: September 2021

Two approaches to augment irrigation water supply are managed aquifer recharge (MAR) and on‐farm reservoirs with tail‐water recovery (OFS‐TWR). We explore the joint use of MAR and OFS‐TWR to sustain groundwater and agricultural income with climate variability by farmer risk preference. We find that MAR use declines slightly with greater risk aversion and declines rapidly with MAR cost. The use of OFS‐TWR increases with risk aversion. The use of MAR increases income by a larger percentage for risk‐neutral than very risk‐averse producers. Across risk aversion degree, the use of MAR leads to a percentage increase in income that is double the percentage increase in the standard deviation of income (i.e., income risk). At a low cost of MAR, there is little difference in MAR use between a very risk‐averse and a risk‐neutral producer across scenarios of crop profit margin and the initial depth to water. Large differences in OFS‐TWR use between a very risk‐averse and a risk‐neutral producer occur when there are relatively high crop profit margin, low initial water depth, or a low discount rate.
Rare GATA6 variants associated with risk of congenital heart disease phenotypes in 200,000 UK Biobank exomes
Authors: Williams Simon G. , Byrne Dominic J. F. , Keavney Bernard D.
Published: September 2021

Congenital heart disease (CHD) has a complex and largely uncharacterised genetic etiology. Using 200,000 UK Biobank (UKB) exomes, we assess the burden of ultra-rare, potentially pathogenic variants in the largest case/control cohort of predominantly mild CHD to date. We find an association with GATA6, a member of the GATA family of transcription factors that play an important role during heart development and has been linked with several CHD phenotypes previously. Several identified GATA6 variants are previously unreported and their roles in conferring risk to CHD warrants further study. We demonstrate that despite limitations regarding detailed familial phenotype information in large-scale biobank projects, through careful consideration of case and control cohorts it is possible to derive important associations.
Loss of Sirt6 in adipocytes impairs the ability of adipose tissue to adapt to intermittent fasting
Authors: Wu Dandan , Bang In Hyuk , Park Byung-Hyun , Bae Eun Ju
Published: September 2021

Intermittent fasting (IF) is gaining popularity for its effectiveness in improving overall health, including its effectiveness in achieving weight loss and euglycemia. The molecular mechanisms of IF, however, are not well understood. This study investigated the relationship between adipocyte sirtuin 6 (Sirt6) and the metabolic benefits of IF. Adipocyte-specific Sirt6-knockout (aS6KO) mice and wild-type littermates were fed a high-fat diet (HFD) ad libitum for four weeks and then subjected to 12 weeks on a 2:1 IF regimen consisting of two days of feeding followed by one day of fasting. Compared with wild-type mice, aS6KO mice subjected to HFD + IF exhibited a diminished response, as reflected by their glucose and insulin intolerance, reduced energy expenditure and adipose tissue browning, and increased inflammation of white adipose tissue. Sirt6 deficiency in hepatocytes or in myeloid cells did not impair adaptation to IF. Finally, the results indicated that the impaired adipose tissue browning and reduced expression of UCP1 in aS6KO mice were accompanied by downregulation of p38 MAPK/ATF2 signaling. Our findings indicate that Sirt6 in adipocytes is critical to obtaining the improved glucose metabolism and metabolic profiles conferred by IF and that maintaining high levels of Sirt6 in adipocytes may mimic the health benefits of IF.
Ultrasensitive detection of endocrine disruptors via superfine plasmonic spectral combs
Authors: Liu Lanhua , Zhang Xuejun , Zhu Qian , Li Kaiwei , Lu Yun , Zhou Xiaohong , Guo Tuan
Published: September 2021

The apparent increase in hormone-induced cancers and disorders of the reproductive tract has led to a growing demand for new technologies capable of detecting endocrine disruptors. However, a long-lasting challenge unaddressed is how to achieve ultrahigh sensitive, continuous, and in situ measurement with a portable device for in-field and remote environmental monitoring. Here we demonstrate a simple-to-implement plasmonic optical fiber biosensing platform to achieve an improved light–matter interaction and advanced surface chemistry for ultrasensitive detection of endocrine disruptors. Our platform is based on a gold-coated highly tilted fiber Bragg grating that excites high-density narrow cladding mode spectral combs that overlap with the broad absorption of the surface plasmon for high accuracy interrogation, hence enabling the ultrasensitive monitoring of refractive index changes at the fiber surface. Through the use of estrogen receptors as the model, we design an estradiol–streptavidin conjugate with the assistance of molecular dynamics, converting the specific recognition of environmental estrogens (EEs) by estrogen receptor into surface-based affinity bioassay for protein. The ultrasensitive platform with conjugate-induced amplification biosensing approach enables the subsequent detection for EEs down to 1.5 × 10−3 ng ml−1 estradiol equivalent concentration level, which is one order lower than the defined maximal E2 level in drinking water set by the Japanese government. The capability to detect EEs down to nanogram per liter level is the lowest limit of detection for any estrogen receptor-based detection reported thus far. Its compact size, flexible shape, and remote operation capability open the way for detecting other endocrine disruptors with ultrahigh sensitivity and in various hard-to-reach spaces, thereby having the potential to revolutionize environment and health monitoring.
Instrumental aversion coding in the basolateral amygdala and its reversion by a benzodiazepine
Authors: Jean-Richard-dit-Bressel Philip , Tran Jenny , Didachos Angelos , McNally Gavan P.
Published: September 2021

Punishment involves learning the relationship between actions and their adverse consequences. Both the acquisition and expression of punishment learning depend on the basolateral amygdala (BLA), but how BLA supports punishment remains poorly understood. To address this, we measured calcium (Ca2+) transients in BLA principal neurons during punishment. Male rats were trained to press two individually presented levers for food; when one of these levers also yielded aversive footshock, responding on this punished lever decreased relative to the other, unpunished lever. In rats with the Ca2+indicator GCaMP6f targeted to BLA principal neurons, we observed excitatory activity transients to the footshock punisher and inhibitory transients to lever-presses earning a reward. Critically, as rats learned punishment, activity around the punished response transformed from inhibitory to excitatory and similarity analyses showed that these punished lever-press transients resembled BLA transients to the punisher itself. Systemically administered benzodiazepine (midazolam) selectively alleviated punishment. Moreover, the degree to which midazolam alleviated punishment was associated with how much punished response-related BLA transients reverted to their pre-punishment state. Together, these findings show that punishment learning is supported by aversion-coding of instrumental responses in the BLA and that the anti-punishment effects of benzodiazepines are associated with a reversion of this aversion coding.
Kynurenines increase MRS metabolites in basal ganglia and decrease resting-state connectivity in frontostriatal reward circuitry in depression
Authors: Chen Xiangchuan , Beltran Diana J. , Tsygankova Valeriya D. , Woolwine Bobbi J. , Patel Trusharth , Baer Wendy , Felger Jennifer C. , Miller Andrew H. , Haroon Ebrahim
Published: September 2021

Inflammation is associated with the development of anhedonia in major depression (MD), but the pathway by which inflammatory molecules gain access to the brain and lead to anhedonia is not clear. Molecules of the kynurenine pathway (KP), which is activated by inflammation, readily influx into the brain and generate end products that alter brain chemistry, disrupt circuit functioning, and result in the expression of inflammatory behaviors such as anhedonia. We examined the impact of plasma and CSF KP metabolites on brain chemistry and neural function using multimodal neuroimaging in 49 depressed subjects. We measured markers of glial dysfunction and distress including glutamate (Glu) and myo-inositol in the left basal ganglia using magnetic resonance spectroscopy (MRS); metrics of local activity coherence (regional homogeneity, ReHo) and functional connectivity from resting-state functional MRI measures; and anhedonia from the Inventory for Depressive Symptoms-Self Report Version (IDS-SR). Plasma kynurenine/tryptophan (KYN/TRP) ratio and cerebrospinal fluid (CSF) 3-hydroxykynurenine (3HK) were associated with increases in left basal ganglia myo-inositol. Plasma kynurenic acid (KYNA) and KYNA/QA were associated with decreases and quinolinic acid (QA) with increases in left basal ganglia Glu. Plasma and CSF KP were associated with decreases in ReHo in the basal ganglia and dorsomedial prefrontal regions (DMPFC) and impaired functional connectivity between these two regions. DMPFC-basal ganglia mediated the effect of plasma and CSF KP on anhedonia. These findings highlight the pathological impact of KP system dysregulation in mediating inflammatory behaviors such as anhedonia.
Molecular profiling of advanced solid tumours. The impact of experimental molecular-matched therapies on cancer patient outcomes in early-phase trials: the MAST study
Authors: Gambardella Valentina , Lombardi Pasquale , Carbonell-Asins Juan Antonio , Tarazona Noelia , Cejalvo Juan Miguel , González-Barrallo Inés , Martín-Arana Jorge , Tébar-Martínez Roberto , Viala Alba , Bruixola Gema , Hernando Cristina , Blasco Inma , Papaccio Federica , Martínez-Ciarpaglini Carolina , Alfaro-Cervelló Clara , Seda-García Enrique , Blesa Sebastián , Chirivella Isabel , Castillo Josefa , Montón-Bueno José Vicente , Roselló Susana , Huerta Marisol , Pérez-Fidalgo Alejandro , Martín-Martorell Paloma , Insa-Mollá Amelia , Fleitas Tania , Rentero-Garrido Pilar , Zúñiga-Trejos Sheila , Cervantes Andrés , Roda Desamparados
Published: September 2021

Introduction

Molecular-matched therapies have revolutionized cancer treatment. We evaluated the improvement in clinical outcomes of applying an in-house customized Next Generation Sequencing panel in a single institution.

Methods

Patients with advanced solid tumors were molecularly selected to receive a molecular-matched treatment into early phase clinical trials versus best investigators choice, according to the evaluation of a multidisciplinary molecular tumor board. The primary endpoint was progression-free survival (PFS) assessed by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1).

Results

Of a total of 231 molecularly screened patients, 87 were eligible for analysis. Patients who received matched therapy had a higher median PFS2 (6.47 months; 95% CI, 2.24–14.43) compared to those who received standard therapy (2.76 months; 95% CI, 2.14–3.91, Log-rank p = 0.022). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the experimental arm (0.33 vs 0.08; p = 0.008).

Discussion

We demonstrate the pivotal role of the institutional molecular tumor board in evaluating the results of a customized NGS panel. This process optimizes the selection of available therapies, improving disease control. Prospective randomized trials are needed to confirm this approach and open the door to expanded drug access.
Effect of endothelial progenitor cell-derived extracellular vesicles on endothelial cell ferroptosis and atherosclerotic vascular endothelial injury
Authors: Li Lin , Wang Haining , Zhang Jing , Chen Xiao , Zhang Zhongwang , Li Qiang
Published: September 2021

Atherosclerosis (AS) is a chronic inflammatory disorder characterized by endothelial dysfunction. Endothelial progenitor cells (EPCs) can overcome endothelial dysfunction and reduce AS risk. This study focused on the role of EPC-secreted extracellular vesicles (EPC-EVs) in AS. First, mouse EPCs and mouse aortic endothelial cells (MAECs) were isolated and identified. EVs were isolated from EPCs and identified. EPC-EVs were co-cultured with MAECs and the internalization of EVs was observed. Glutathione (GSH) consumption, reactive oxygen species (ROS) production, lipid peroxidation, and iron accumulation and cell death in endothelial cells were detected. The binding relationship between miR-199a-3p and specificity protein 1 (SP1) was confirmed using dual-luciferase and RIP assays. The mouse model of AS was established. The relationships between miR-199a-3p expression and aortic area plaque and serum pro-inflammatory factor were analyzed. The degree of atherosclerotic lesion was detected using oil red O staining and the serum inflammatory factors were detected using ELISA. Our results elicited that EPC-EVs inhibited cell death, GSH consumption, ROS production, lipid peroxidation, and iron accumulation in endothelial cells, thereby suppressing ferroptosis of endothelial cells. EPC-EVs transferred miR-199a-3p into endothelial cells. miR-199a-3p targeted SP1. Silencing miR-199a-3p or overexpression of SP1 in endothelial cells reversed the effect of EPC-EVs on ferroptosis of endothelial cells. In vivo experiments confirmed that EPC-EVs inhibited ferroptosis of endothelial cells and then alleviated the occurrence of AS via the miR-199a-3p/SP1 axis. To conclude, EPC-EVs transferred miR-199a-3p to inhibit SP1, thus repressing ferroptosis of endothelial cells and retarding the occurrence of AS.
Developmental genetics of color pattern establishment in cats
Authors: Kaelin Christopher B. , McGowan Kelly A. , Barsh Gregory S.
Published: September 2021

Intricate color patterns are a defining aspect of morphological diversity in the Felidae. We applied morphological and single-cell gene expression analysis to fetal skin of domestic cats to identify when, where, and how, during fetal development, felid color patterns are established. Early in development, we identify stripe-like alterations in epidermal thickness preceded by a gene expression pre-pattern. The secreted Wnt inhibitor encoded by Dickkopf 4 plays a central role in this process, and is mutated in cats with the Ticked pattern type. Our results bring molecular understanding to how the leopard got its spots, suggest that similar mechanisms underlie periodic color pattern and periodic hair follicle spacing, and identify targets for diverse pattern variation in other mammals.
Adoptive immunotherapy with transient anti-CD4 treatment enhances anti-tumor response by increasing IL-18Rαhi CD8+ T cells
Authors: Kim Seon-Hee , Cho Eunjung , Kim Yu I. , Han Chungyong , Choi Beom K. , Kwon Byoung S.
Published: September 2021

Adoptive T cell therapy (ACT) requires lymphodepletion preconditioning to eliminate immune-suppressive elements and enable efficient engraftment of adoptively transferred tumor-reactive T cells. As anti-CD4 monoclonal antibody depletes CD4+ immune-suppressive cells, the combination of anti-CD4 treatment and ACT has synergistic potential in cancer therapy. Here, we demonstrate a post-ACT conditioning regimen that involves transient anti-CD4 treatment (CD4post). Using murine melanoma, the combined effect of cyclophosphamide preconditioning (CTXpre), CD4post, and ex vivo primed tumor-reactive CD8+ T-cell infusion is presented. CTXpre/CD4post increases tumor suppression and host survival by accelerating the proliferation and differentiation of ex vivo primed CD8+ T cells and endogenous CD8+ T cells. Endogenous CD8+ T cells enhance effector profile and tumor-reactivity, indicating skewing of the TCR repertoire. Notably, enrichment of polyfunctional IL-18Rαhi CD8+ T cell subset is the key event in CTXpre/CD4post-induced tumor suppression. Mechanistically, the anti-tumor effect of IL-18Rαhi subset is mediated by IL-18 signaling and TCR–MHC I interaction. This study highlights the clinical relevance of CD4post in ACT and provides insights regarding the immunological nature of anti-CD4 treatment, which enhances anti-tumor response of CD8+ T cells.
In situ inorganic conductive network formation in high-voltage single-crystal Ni-rich cathodes
Authors: Fan Xinming , Ou Xing , Zhao Wengao , Liu Yun , Zhang Bao , Zhang Jiafeng , Zou Lianfeng , Seidl Lukas , Li Yangzhong , Hu Guorong , Battaglia Corsin , Yang Yong
Published: September 2021

High nickel content in LiNixCoyMnzO2 (NCM, x ≥ 0.8, x + y + z = 1) layered cathode material allows high specific energy density in lithium-ion batteries (LIBs). However, Ni-rich NCM cathodes suffer from performance degradation, mechanical and structural instability upon prolonged cell cycling. Although the use of single-crystal Ni-rich NCM can mitigate these drawbacks, the ion-diffusion in large single-crystal particles hamper its rate capability. Herein, we report a strategy to construct an in situ Li1.4Y0.4Ti1.6(PO4)3 (LYTP) ion/electron conductive network which interconnects single-crystal LiNi0.88Co0.09Mn0.03O2 (SC-NCM88) particles. The LYTP network facilitates the lithium-ion transport between SC-NCM88 particles, mitigates mechanical instability and prevents detrimental crystalline phase transformation. When used in combination with a Li metal anode, the LYTP-containing SC-NCM88-based cathode enables a coin cell capacity of 130 mAh g−1 after 500 cycles at 5 C rate in the 2.75-4.4 V range at 25 °C. Tests in Li-ion pouch cell configuration (i.e., graphite used as negative electrode active material) demonstrate capacity retention of 85% after 1000 cycles at 0.5 C in the 2.75-4.4 V range at 25 °C for the LYTP-containing SC-NCM88-based positive electrode.
Global relationships between crop diversity and nutritional stability
Authors: Nicholson Charlie C. , Emery Benjamin F. , Niles Meredith T.
Published: September 2021

Nutritional stability – a food system’s capacity to provide sufficient nutrients despite disturbance – is an important, yet challenging to measure outcome of diversified agriculture. Using 55 years of data across 184 countries, we assemble 22,000 bipartite crop-nutrient networks to quantify nutritional stability by simulating crop and nutrient loss in a country, and assess its relationship to crop diversity across regions, over time and between imports versus in country production. We find a positive, saturating relationship between crop diversity and nutritional stability across countries, but also show that over time nutritional stability remained stagnant or decreased in all regions except Asia. These results are attributable to diminishing returns on crop diversity, with recent gains in crop diversity among crops with fewer nutrients, or with nutrients already in a country’s food system. Finally, imports are positively associated with crop diversity and nutritional stability, indicating that many countries’ nutritional stability is market exposed.
Transcriptional network involving ERG and AR orchestrates Distal-less homeobox-1 mediated prostate cancer progression
Authors: Goel Sakshi , Bhatia Vipul , Kundu Sushmita , Biswas Tanay , Carskadon Shannon , Gupta Nilesh , Asim Mohammad , Morrissey Colm , Palanisamy Nallasivam , Ateeq Bushra
Published: September 2021

Distal-less homeobox-1 (DLX1) is a well-established non-invasive biomarker for prostate cancer (PCa) diagnosis, however, its mechanistic underpinnings in disease pathobiology are not known. Here, we reveal the oncogenic role of DLX1 and show that abrogating its function leads to reduced tumorigenesis and metastases. We observed that ~60% of advanced-stage and metastatic patients display higherDLX1levels. Moreover, ~96% ofTMPRSS2-ERGfusion-positive and ~70% of androgen receptor (AR)-positive patients show elevatedDLX1, associated with aggressive disease and poor survival. Mechanistically, ERG coordinates with enhancer-bound AR and FOXA1 to drive transcriptional upregulation ofDLX1in ERG-positive background. However, in ERG-negative context, AR/AR-V7 and FOXA1 suffice to upregulateDLX1. Notably, inhibiting ERG/AR-mediatedDLX1transcription using BET inhibitor (BETi) or/and anti-androgen drugs reduce its expression and downstream oncogenic effects. Conclusively, this study establishesDLX1as a direct-target of ERG/AR with an oncogenic role and demonstrates the clinical significance of BETi and anti-androgens for DLX1-positive patients.
Gene interfered-ferroptosis therapy for cancers
Authors: Gao Jinliang , Luo Tao , Wang Jinke
Published: September 2021

Although some effective therapies have been available for cancer, it still poses a great threat to human health and life due to its drug resistance and low response in patients. Here, we develop a ferroptosis-based therapy by combining iron nanoparticles and cancer-specific gene interference. The expression of two iron metabolic genes (FPNandLCN2) was selectively knocked down in cancer cells by Cas13a or microRNA controlled by a NF-κB-specific promoter. Cells were simultaneously treated by iron nanoparticles. As a result, a significant ferroptosis was induced in a wide variety of cancer cells. However, the same treatment had little effect on normal cells. By transferring genes with adeno-associated virus and iron nanoparticles, the significant tumor growth inhibition and durable cure were obtained in mice with the therapy. In this work, we thus show a cancer therapy based on gene interference-enhanced ferroptosis.
A compendium of uniformly processed human gene expression and splicing quantitative trait loci
Authors: Kerimov Nurlan , Hayhurst James D. , Peikova Kateryna , Manning Jonathan R. , Walter Peter , Kolberg Liis , Samoviča Marija , Sakthivel Manoj Pandian , Kuzmin Ivan , Trevanion Stephen J. , Burdett Tony , Jupp Simon , Parkinson Helen , Papatheodorou Irene , Yates Andrew D. , Zerbino Daniel R. , Alasoo Kaur
Published: September 2021

Many gene expression quantitative trait locus (eQTL) studies have published their summary statistics, which can be used to gain insight into complex human traits by downstream analyses, such as fine mapping and co-localization. However, technical differences between these datasets are a barrier to their widespread use. Consequently, target genes for most genome-wide association study (GWAS) signals have still not been identified. In the present study, we present the eQTL Catalogue (https://www.ebi.ac.uk/eqtl), a resource of quality-controlled, uniformly re-computed gene expression and splicing QTLs from 21 studies. We find that, for matching cell types and tissues, the eQTL effect sizes are highly reproducible between studies. Although most QTLs were shared between most bulk tissues, we identified a greater diversity of cell-type-specific QTLs from purified cell types, a subset of which also manifested as new disease co-localizations. Our summary statistics are freely available to enable the systematic interpretation of human GWAS associations across many cell types and tissues.
Lateral resolution limit of laser Doppler vibrometer microscopes for the measurement of surface acoustic waves
Authors: Kowarsch Robert , Rembe Christian
Published: September 2021

The lateral or transverse resolution of single-point interferometers for vibration measurement is especially critical for microelectromechanical systems (MEMS) vibrating up to the gigahertz range. In this regime, the acoustic wavelengths are typically in the range of the size of the laser focus. Thus, a successful vibration measurement requires distinct knowledge about the lateral resolution limit and its dependencies with instrumentation parameters. In this paper, we derive an analytic approximation formula, which allows for estimation of the systematic measurement deviation of the vibration amplitude and, thus, a definition of the lateral resolution limit of single-point interferometers for vibration measurement. Further, a compensation and an optimum numerical aperture are proposed the reduce the measurement deviation. For this, the model includes a laser-interferometer microscope of Mach-Zehnder type with Gaussian laser beams considering the Gouy effect and wavefront curvature. As a measurement scenario, an unidirectional surface acoustic wave (SAW) is regarded. The theoretic findings have been validated in the experiment with a representative vibration measurement on a SAW filter at $$433\,{\mathrm {MHz}}$$433MHzwith our heterodyne laser-Doppler interferometer with offset-locked semiconductor lasers. The provided formulas help instrument designers and users to choose suitable instrument parameters, especially the numerical aperture of the utilized microscope objective.
Multi-tissue transcriptome analysis of two Begonia species reveals dynamic patterns of evolution in the chalcone synthase gene family
Authors: Emelianova Katie , Martínez Martínez Andrea , Campos-Dominguez Lucia , Kidner Catherine
Published: September 2021

Begonia is an important horticultural plant group, as well as one of the most speciose Angiosperm genera, with over 2000 described species. Genus wide studies of genome size have shown that Begonia has a highly variable genome size, and analysis of paralog pairs has previously suggested that Begonia underwent a whole genome duplication. We address the contribution of gene duplication to the generation of diversity in Begonia using a multi-tissue RNA-seq approach. We chose to focus on chalcone synthase (CHS), a gene family having been shown to be involved in biotic and abiotic stress responses in other plant species, in particular its importance in maximising the use of variable light levels in tropical plants. We used RNA-seq to sample six tissues across two closely related but ecologically and morphologically divergent species, Begonia conchifolia and B. plebeja, yielding 17,012 and 19,969 annotated unigenes respectively. We identified the chalcone synthase gene family members in our Begonia study species, as well as in Hillebrandia sandwicensis, the monotypic sister genus to Begonia, Cucumis sativus, Arabidopsis thaliana, and Zea mays. Phylogenetic analysis suggested the CHS gene family has high duplicate turnover, all members of CHS identified in Begonia arising recently, after the divergence of Begonia and Cucumis. Expression profiles were similar within orthologous pairs, but we saw high inter-ortholog expression variation. Sequence analysis showed relaxed selective constraints on some ortholog pairs, with substitutions at conserved sites. Evidence of pseudogenisation and species specific duplication indicate that lineage specific differences are already beginning to accumulate since the divergence of our study species. We conclude that there is evidence for a role of gene duplication in generating diversity through sequence and expression divergence in Begonia.
Uric acid as a prognostic factor and critical marker of COVID-19
Authors: Li Gang , Wu Xia , Zhou Chen-liang , Wang Ye-ming , Song Bin , Cheng Xiao-bin , Dong Qiu-fen , Wang Liu-lin , You Sha-sha , Ba Yuan-ming
Published: September 2021

The purpose of this study is to explore whether uric acid (UA) can independently act as a prognostic factor and critical marker of the 2019 novel corona virus disease (COVID-19). A multicenter, retrospective, and observational study including 540 patients with confirmed COVID-19 was carried out at four designated hospitals in Wuhan. Demographic, clinical, laboratory data were collected and analyzed. The primary end point was in-hospital death of patients with COVID-19. The concentration of admission UA (adUA) and the lowest concentration of uric acid during hospitalization (lowUA) in the dead patients were significantly lower than those in the survivors. Multivariate logistic regression analysis showed the concentration of lowUA (OR 0.986, 95% CI 0.980–0.992, p < 0.001) was able to independently predict the risk of in-hospital death. The mean survival time in the low-level group of lowUA was significantly lower than other groups. When lowUA was ≤ 166 µmol/L, the sensitivity and specificity in predicting hospital short-term mortality were 76.9%, (95% CI 68.5–85.1%) and 74.9% (95% CI 70.3–78.9%). This retrospective study determined that the lowest concentration of UA during hospitalization can be used as a prognostic indicator and a marker of disease severity in severe patients with COVID-19.
Π-GISANS: probing lateral structures with a fan shaped beam
Authors: Vorobiev Alexei , Paracini Nicolò , Cárdenas Marité , Wolff Max
Published: September 2021

We have performed grazing incidence neutron small angle scattering using a fan shaped incident beam focused along one dimension. This allows significantly reduced counting times for measurements of lateral correlations parallel to an interface or in a thin film where limited depth resolution is required. We resolve the structure factor of iron inclusions in aluminium oxide and show that the ordering of silica particles deposited on a silicon substrate depends on their size. We report hexagonal packing for 50 nm but not for 200 nm silica spheres deposited by a modified Langmuir-Schaefer method on a silicon substrate. For the 200 nm particles we extract the particles shape from the form factor. Moreover, we report dense packing of the particles spread on a free water surface. We name this method π-GISANS to highlight that it differs from GISANS as it gives lateral information while averaging the in-depth structure.