bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-effective options for increasing consumption of under-consumed food groups and nutrients in the USA
Authors: Brauchla Mary , Fulgoni Victor L
Published: February 2021

Objective:

To identify the most cost-effective options/contributors of under-consumed food groups and nutrients in the USA.

Design:

Twenty-four-hour dietary recall data were used for the dietary sources of under-consumed food groups and nutrients. Costs were estimated using USDA National Food Price Database 2001–2004 after adjustments for inflation using Consumer Price Index.

Setting:

National Health and Nutrition Examination Survey, 2013–2016.

Participants:

A total of 10 112 adults aged 19+ years.

Results:

Top five cost-effective options for food groups were apple and citrus juice, bananas, apples, and melons for fruit; baked/boiled white potatoes, mixtures of mashed potatoes, lettuce, carrots and string beans for vegetables; oatmeal, popcorn, rice, yeast breads and pasta/noodles/cooked grains for whole grain; and reduced-fat, low-fat milk, flavoured milk and cheese for dairy. Top five cost-effective sources of under-consumed nutrients were rice, tortillas, pasta/noodles/cooked grains, rolls and buns, and peanut butter–jelly sandwiches for Mg; grits/cooked cereals, low- and high-sugar ready-to-eat (RTE) cereal, rolls and buns, and rice for Fe; low- and high-sugar RTE cereals, rice, protein and nutritional powders, and rolls and buns for Zn; carrots, margarine, other red and orange vegetables, liver and organ meats, butter and animal fats for vitamin A; and citrus juice, other fruit juice, vegetable juice, mustard and other condiments, and apple juice for vitamin C.

Conclusions:

Apple/citrus juice, white potatoes/carrots, oatmeal, RTE cereals and milk were the most cost-effective food sources of multiple under-consumed food groups and nutrients and can help promote healthy eating habits at minimal cost.
State Violence, Justice, And The Suffering Of Others
Authors: Sanos Sandrine
Published: February 2021

In 1955, Alain Resnais's now canonical documentary, Nuit et Brouillard (Night and Fog) ended with an ominous question, asking “who, among us, is keeping watch from this strange watchtower [of the ruins of Auschwitz] to warn of the arrival of our new executioners” who might bring about the return of the “concentrationary plague?” One man had already made it his mission to do so: the French writer and former political deportee David Rousset. Rousset had shaken the French world of letters and politics with the 1946 publication of L'univers concentrationnaire (The Concentrationary Universe), which warned of the civilizational and moral cesura that the Nazi camps had been. The term quickly became a widely used conceptual framework. Former deportee and Catholic writer Jean Cayrol borrowed from it to write his voice-over to Night and Fog. In 1949, Rousset published another text that created a scandal in Cold War France: an Appeal to “fellow deportees” calling upon them to “investigate the USSR's concentrationary universe” (Kuby, 46). This indictment fiercely divided the French left. In 1950, he brought a libel suit against another former deportee, communist writer Pierre Daix, who had accused him of amnesiac “apoliticism” (Kuby, 65–6; Dean, 61). Just before, in the wake of his Appeal, Rousset had founded an organization against concentrationary regimes with those, like him, who had been political deportees. In 1951, it put the Soviet Union on trial for crimes against humanity. Rousset and his organization were involved in many trials, eager to denounce the “new executioners” who had revived the “scourge of the camps” in the postwar world. For many today, he is an “exceptional” man because, as philosopher and critic Tzvetan Todorov argues, he was not paralyzed by the memory of “this painful experience”; instead, he harnessed it into action against dehumanizing state violence. For Todorov, Rousset had allowed morality to prevail over base political considerations.
ICESat‐2 Pointing Calibration and Geolocation Performance
Authors: Luthcke S. B. , Thomas T. C. , Pennington T. A. , Rebold T. W. , Nicholas J. B. , Rowlands D. D. , Gardner A. S. , Bae S.
Published: February 2021

ICESat‐2 science requirements are dependent on the accurate real‐time pointing control (i.e., geolocation control) and postprocessed geolocation knowledge of the laser altimeter surface returns. Prelaunch pointing alignment errors and postlaunch pointing alignment variation result in large geolocation errors that must be calibrated on orbit. In addition, the changing sun‐orbit geometry causes thermal‐mechanical forced laser frame alignment variations at the orbit period and trends from days, weeks, and months. Early mission analysis computed precise postlaunch laser beam alignment calibration. The alignment calibration was uploaded to the spacecraft and enabled the pointing control performance to achieve 4.4 ± 6.0 m, a significant improvement over the 45 m (1 σ) mission requirement. Laser frame alignment calibrations are used to reduce the alignment bias and time variation, as well as the orbital variation contributions to geolocation knowledge error from 6 to 1.7 m (1 σ). Relative beam alignment of the six beams is calibrated and shown to contribute between 0.5 ± 0.1 m and 2.4 ± 0.2 m of remaining geolocation knowledge error. Independent geolocation assessment based on comparison to high‐resolution digital elevation models agrees well with the calibration geolocation error estimates. The analysis demonstrates the ICESat‐2 mission is performing far better than its geolocation knowledge requirement of 6.5 m (1 σ) after the laser frame alignment bias variation and orbital variation calibrations have been applied. Remaining geolocation error is beam dependent and ranges from 2.5 m for beam 6 to 4.4 m for beam 2 (mean + 1 σ).
The Impact of the Disturbed Electric Field in the Sporadic E (Es) Layer Development Over Brazilian Region
Authors: Resende L. C. A. , Shi J. , Denardini C. M. , Batista I. S. , Picanço G. A. S. , Moro J. , Chagas R. A. J. , Barros D. , Chen S. S. , Nogueira P. A. B. , Andrioli V. F. , Silva R. P. , Carrasco A. J. , de Araujo R. C. , Wang C. , Liu Z.
Published: February 2021

During disturbed periods, E region electric fields can cause anomalous Es layer behavior, which is observed in the digital ionosonde data. To investigate the influence of these electric fields in the Es layer development, we analyzed a set of 20 magnetic storms from 2015 to 2018 over Boa Vista (BV, 2.8°N, 60.7°W, dip ∼18°), São Luís (SLZ, 2.3°S, 44.2°W, dip ∼8°), and Cachoeira Paulista (CXP, 22.41°S, 45°W, dip ∼35°). The electric field zonal components during the main and recovery phases of each magnetic storm are computed to study the corresponding characteristics of these Es seen in ionograms. Additionally, a numerical model (MIRE, Portuguese acronym for E Region Ionospheric Model) is used to analyze the Es layer dynamics modification around disturbed times. Using observation data and simulations, we were able to establish a threshold value for the electric field intensity for each region that can affect the Es layer formation. The results sustain that the strong Es layer in BV can be an indicator of the disturbed dynamo event. At SLZ, on the other hand, the Es layers are affected by the competition mechanisms of their formation, as equatorial electrojet irregularities and winds, during the main phase of the magnetic storm. Over CXP, the Es layer dynamics are dominated by the wind shear mechanism. Finally, this study provides new insights into the real impact of the electric field in the Es layer development over the Brazilian sector. Thus, our results lead to a better understanding of the underlying mechanisms related to the Es layer formation and dynamics.
On the Association Between Electron Flux Oscillations and Local Phase Space Density Gradients
Authors: Sarris Theodore E. , Li Xinlin , Zhao Hong , Khoo Leng Ying , Liu Wenlong , Temerin Michael A.
Published: February 2021

Electron flux oscillations are often observed in electron energy channels in the range of 10 keV to 100 keV. They are observed in the form of flux fluctuations with periods corresponding to the drift periods of electrons around the Earth and can be produced in the magnetosphere as a result of drift resonant interactions in association with broadband ultra‐low frequency (ULF) waves. They are observed in particular during quiet times and are indicators of ongoing drift‐resonant processes and resulting radial transport caused by ULF waves. In this study we investigate the association of the appearance of such flux oscillations with the local phase space density. In particular, it is shown that flux oscillations appear when nonzero phase space density gradients are present and furthermore that the observed amplitude of flux oscillations is dependent on radial phase space density gradients, with steeper gradients enabling the observation of flux oscillations with higher‐amplitude. Via statistical observations from the Van Allen probes twin‐spacecraft mission while at apogee at L* ∼5 to ∼5.6 it is found that, during quiet times, electron flux oscillations are more likely to diminish for electron energy of ∼400 keV, and associated phase space density is more likely to be zero for the corresponding first adiabatic invariant values of ∼300 MeV/G. It is also concluded that flux oscillations could be used as indicators of phase space density gradients.
Convergence of Daily GRACE Solutions and Models of Submonthly Ocean Bottom Pressure Variability
Authors: Schindelegger Michael , Harker Alexander A. , Ponte Rui M. , Dobslaw Henryk , Salstein David A.
Published: February 2021

Knowledge of submonthly variability in ocean bottom pressure (pb) is an essential element in space‐geodetic analyses and global gravity field research. Estimates of these mass changes are typically drawn from numerical ocean models and, more recently, GRACE (Gravity Recovery and Climate Experiment) series at daily sampling. However, the quality of pb fields from either source has been difficult to assess and reservations persist as to the dependence of regularized GRACE solutions on their oceanographic priors. Here, we make headway on the subject by comparing two daily satellite gravimetry products (years 2007–2009) both with each other and with pb output from a diverse mix of ocean models, complemented by insights from bottom pressure gauges. Emphasis is given to large spatial scales and periods <60 days. Satellite‐based mass changes are in good agreement over basin interiors and point to excess pb signals (∼2 cm root‐mean‐square error) over Southern Ocean abyssal plains in the present GRACE de‐aliasing model. These and other imperfections in baroclinic models are especially apparent at periods <10 days, although none of the GRACE series presents a realistic ground truth on time scales of a few days. A barotropic model simulation with parameterized topographic wave drag is most commensurate with the GRACE fields over the entire submonthly band, allowing for first‐order inferences about error and noise in the gravimetric mass changes. Estimated pb errors vary with signal magnitude and location but are generally low enough (0.5–1.5 cm) to judge model skill in dynamically active regions.
Climatology of Interhemispheric Mesopause Temperatures Using the High‐Latitude and Middle‐Latitude Meteor Radars
Authors: Yi Wen , Xue Xianghui , Reid Iain M. , Murphy Damian J. , Hall Chris M. , Tsutsumi Masaki , Ning Baiqi , Li Guozhu , Yang Guotao , Li Na , Chen Tingdi , Dou Xiankang
Published: February 2021

We present the climatology of mesopause temperatures using high‐latitude and middle‐latitude meteor radars. The daily mesopause temperatures are estimated using ambipolar diffusion coefficient data from the meteor radars at Davis Station (68.6°S, 77.9°E), in Antarctica, Svalbard (78.3°N, 16°E), Tromsø (69.6°N, 19.2°E) in the Arctic, and Mohe (53.5°N, 122.3°E) and Beijing (40.3°N, 116.2°E) in the northern middle latitudes. The seasonal variations in the meteor radar‐derived temperatures are in good agreement with the temperatures from the Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) instrument onboard the TIMED satellite. Interhemispheric observations indicate that the mesopause temperatures over the southern and northern polar regions show a clear seasonal asymmetry. The seasonal variations in the Davis Station meteor radar temperatures in the southern polar mesopause are dominated by an annual oscillation (AO) with a relatively weak semiannual oscillation (SAO), which show a clear minimum during summer and a maximum during winter. The mesopause temperatures in the northern high and middle latitudes observed by the Svalbard, Tromsø, Mohe, and Beijing meteor radars mainly show an AO, with a maximum during winter and a minimum during summer. The AO in the northern polar regions is stronger than that in the southern polar regions, while the SAO in the southern polar regions is relatively strong compared to that in the northern polar regions.
Winter Oxygen Regimes in Clear and Turbid Shallow Lakes
Authors: Rabaey Joseph S. , Domine Leah M. , Zimmer Kyle D. , Cotner James B.
Published: February 2021

Dissolved oxygen controls important processes in lakes, from chemical reactions to organism community structure and metabolism. In shallow lakes, small volumes allow for large fluctuations in dissolved oxygen concentrations, and the oxygen regime can greatly affect ecosystem‐scale processes. We used high frequency dissolved oxygen measurements to examine differences in oxygen regimes between two alternative stable states that occur in shallow lakes. We compared annual oxygen regimes in four macrophyte‐dominated, clear state lakes to four phytoplankton‐dominated, turbid state lakes by quantifying oxygen concentrations, anoxia frequency, and measures of whole‐lake metabolism. Oxygen regimes were not significantly different between lake states throughout the year except for during the winter under‐ice period. During winter, clear lakes had less oxygen, higher frequency of anoxic periods, and higher oxygen depletion rates. Winter oxygen depletion rates correlated positively with peak summer macrophyte biomass. Due to lower levels of oxygen, clear shallow lakes may experience anoxia more often and for longer duration during the winter, increasing the likelihood of fish winterkills. These observations have important implications for shallow lake management, which typically focuses efforts on maintaining the clearwater state.
Plio‐Pleistocene Continental Hydroclimate and Indian Ocean Sea Surface Temperatures at the Southeast African Margin
Authors: Taylor Audrey K. , Berke Melissa A. , Castañeda Isla S. , Koutsodendris Andreas , Campos Hernan , Hall Ian R. , Hemming Sidney R. , LeVay Leah J. , Sierra Alejandra Cartagena , O'Connor Keith ,   Expedition 361 Scientists
Published: February 2021

Efforts to understand long‐term Indian Ocean dynamics and land‐sea linkages in southeast Africa during periods of significant global and regional climate change have been inhibited by a lack of high‐resolution climate records, particularly during the Plio‐Pleistocene. Here we present new biomarker and pollen records from International Ocean Discovery Program (IODP) Site U1478, located at the Upper Agulhas Confluence near the Limpopo River mouth, to establish environmental conditions at the southeast African margin between 4 and 1.8 Ma and address this spatiotemporal gap. Compound‐specific hydrogen isotopes of terrestrial leaf waxes (δDwax) and TEX86, using marine archaeal lipids, document hydroclimate variability and sea surface temperature (SST), respectively, permitting an onshore‐offshore climate comparison. The U1478 records establish the Limpopo catchment response to the switch in Indonesian Throughflow source waters, the mid‐Pliocene Warm Period, and intensification of Northern Hemisphere glaciations at ∼2.7 Ma. Broad coherence between the δDwax and SST records supports a linkage between Indian Ocean temperatures and southeast African hydroclimate. We hypothesize that additional mechanisms including Indian Ocean cross‐basin SST gradients (ΔSST) and high latitude glaciation acted as hydroclimate controls during the Plio‐Pleistocene. We use ΔSST to evaluate ocean‐atmosphere patterns similar to the Indian Ocean Dipole (IOD) and establish generally wetter conditions in the region associated with positive IOD‐like phases. Additionally, an obliquity signal evident in the δDwax record indicates that glacial‐interglacial variability likely influenced the tropical rain belt position and also controlled rainfall. Hydroclimate and environmental conditions across the Plio‐Pleistocene in southeast Africa may have important implications for regional hominin evolution.
Strain and Velocity Across the Great Basin Derived From 15‐ka Fault Slip Rates: Implications for Continuous Deformation and Seismic Hazard in the Walker Lane, California‐Nevada, USA
Authors: Reitman Nadine G. , Molnar Peter
Published: February 2021

Average strain across the Great Basin over the past 15 Kyr derived from slip rates on individual faults shows a concentration of both right‐lateral shear and extension in the western Great Basin (Walker Lane). Straining is modest across the central Great Basin, with a zone of higher strain in the eastern Great Basin including the Wasatch Front. The horizontal velocity field derived from 15‐ka fault slip rates is similar to the pattern of GPS velocities, suggesting that regional strain release patterns have been constant over the past 15 Kyr. The magnitudes of velocities inferred from fault slip rates, relative to North America, are lower than those from GPS in the Walker Lane, suggesting that the geologic record is missing evidence of strike slip on faults, and seismic hazard may be higher than suggested by fault slip rates alone. The observed strain concentration in the western Great Basin is consistent with a Sierra Nevada block that is more rigid than the surrounding lithosphere of nonlinear rheology, which concentrates strain east of and adjacent to the rigid block. Treating the western U.S. as a thin viscous sheet with the Sierra Nevada block as a rigid boundary provides a consistent history of continuous deformation in the Walker Lane over decadal, millennial, and Neogene timescales.
Macronutrient intake during pregnancy in women with a history of obesity or gestational diabetes and offspring adiposity at 5 years of age
Authors: Meinilä Jelena , Klemetti Miira M. , Huvinen Emilia , Engberg Elina , Andersson Sture , Stach-Lempinen Beata , Koivusalo Saila
Published: February 2021

Background/objectives

The impact of maternal macronutrient intake during pregnancy on offspring childhood adiposity is unclear. We assessed the associations between maternal macronutrient intake during and after pregnancy with offspring adiposity at 5 years of age. Additionally, we investigated whether gestational diabetes (GDM), BMI, or breastfeeding modified these associations.

Subjects/methods

Altogether, 301 mother–child dyads with maternal prepregnancy BMI ≥ 30 and/or previous GDM participated in the Finnish Gestational Diabetes Prevention Study (RADIEL) and its 5 years follow-up. Macronutrient intakes (E%) were calculated from 3-day food records collected at 5–18 weeks’ gestation, in the third trimester, and at 12 months and 5 years after pregnancy. Offspring body fat mass (BFM) and fat percentage (BF%) at 5 years were measured by bioimpedance. Statistical analyses were multivariate linear regression.

Results

Mean (SD) prepregnancy BMI was 33(4) kg/m2. GDM was diagnosed in 47%. In normoglycemic women, higher first half of pregnancy n-3 PUFA intake was associated with lower offspring BFM (g) (ß−0.90; 95% CI −1.62, −0.18) and BF% (ß−3.45; 95% CI −6.17, −0.72). In women with GDM, higher first half of pregnancy n-3 PUFA intake was associated with higher offspring BFM (ß0.94; 95% CI 0.14, 1.75) and BF% (ß3.21; 95% CI 0.43, 5.99). Higher SFA intake in the third trimester and cumulative intake across pregnancy (mean of the first half and late pregnancy) was associated with higher BFM and BF% (across pregnancy:ß0.12; 95% CI 0.03, 0.20 andß0.44; 95% CI 0.15, 0.73, respectively). Higher carbohydrate intake across pregnancy was associated with lower BFM (ß−0.044; 95% CI −0.086, −0.003), and borderline associated with BF% (ß−0.15; 95% CI −0.31, 0.00).

Conclusions

The macronutrient composition of maternal diet during pregnancy is associated with offspring BFM and BF% at 5 years. GDM modifies the association between prenatal n-3 PUFA intake and offspring anthropometrics.
ECT2 overexpression promotes the polarization of tumor-associated macrophages in hepatocellular carcinoma via the ECT2/PLK1/PTEN pathway
Authors: Xu Dafeng , Wang Yu , Wu Jincai , Zhang Zhensheng , Chen Jiacheng , Xie Mingwei , Tang Rong , Chen Cheng , Chen Liang , Lin Shixun , Luo Xiangxiang , Zheng Jinfang
Published: February 2021

Hepatocellular carcinoma (HCC) is a common high-mortality cancer, mainly due to diagnostic difficulties during its early clinical stages. In this study, we aimed to identify genes that are important for HCC diagnosis and treatment, and we investigated the underlying mechanism of prognostic differences. Differentially expressed genes (DEGs) were identified by using the limma package, and receiver operating characteristic curve analysis was performed to identify diagnostic markers for HCC. Bioinformatics and clinical specimens were used to assess epithelial cell transforming 2 (ECT2) in terms of expression, prognostic value, pathways, and immune correlations. In vitro experiments were used to investigate the underlying mechanism and function of ECT2, and the results were confirmed through in vivo experiments. The integrated analysis revealed 53 upregulated DEGs, and one candidate biomarker for diagnosis (ECT2) was detected. High expression of ECT2 was found to be an independent prognostic risk factor for HCC. ECT2 expression showed a strong correlation with tumor-associated macrophages. We found that ECT2 overexpression increased the migration and proliferation of HCC cells. It also promoted the expression of PLK1, which subsequently interacted with PTEN and interfered with its nuclear translocation, ultimately enhancing aerobic glycolysis and promoting M2 macrophage polarization. M2 macrophages suppress the functions of NK cells and T cells, and this was confirmed in the in vivo experiments. Overall, ECT2 may promote the polarization of M2 macrophages by enhancing aerobic glycolysis and suppressing the functions of immune cells. ECT2 could serve as a candidate diagnostic and prognostic biomarker for HCC.
Ubiquitous quantum scarring does not prevent ergodicity
Authors: Pilatowsky-Cameo Saúl , Villaseñor David , Bastarrachea-Magnani Miguel A. , Lerma-Hernández Sergio , Santos Lea F. , Hirsch Jorge G.
Published: February 2021

In a classically chaotic system that is ergodic, any trajectory will be arbitrarily close to any point of the available phase space after a long time, filling it uniformly. Using Born’s rules to connect quantum states with probabilities, one might then expect that all quantum states in the chaotic regime should be uniformly distributed in phase space. This simplified picture was shaken by the discovery of quantum scarring, where some eigenstates are concentrated along unstable periodic orbits. Despite that, it is widely accepted that most eigenstates of chaotic models are indeed ergodic. Our results show instead that all eigenstates of the chaotic Dicke model are actually scarred. They also show that even the most random states of this interacting atom-photon system never occupy more than half of the available phase space. Quantum ergodicity is achievable only as an ensemble property, after temporal averages are performed.
Winner-takes-all resource competition redirects cascading cell fate transitions
Authors: Zhang Rong , Goetz Hanah , Melendez-Alvarez Juan , Li Jiao , Ding Tian , Wang Xiao , Tian Xiao-Jun
Published: February 2021

Failure of modularity remains a significant challenge for assembling synthetic gene circuits with tested modules as they often do not function as expected. Competition over shared limited gene expression resources is a crucial underlying reason. It was reported that resource competition makes two seemingly separate genes connect in a graded linear manner. Here we unveil nonlinear resource competition within synthetic gene circuits. We first build a synthetic cascading bistable switches (Syn-CBS) circuit in a single strain with two coupled self-activation modules to achieve two successive cell fate transitions. Interestingly, we find that the in vivo transition path was redirected as the activation of one switch always prevails against the other, contrary to the theoretically expected coactivation. This qualitatively different type of resource competition between the two modules follows a ‘winner-takes-all’ rule, where the winner is determined by the relative connection strength between the modules. To decouple the resource competition, we construct a two-strain circuit, which achieves successive activation and stable coactivation of the two switches. These results illustrate that a highly nonlinear hidden interaction between the circuit modules due to resource competition may cause counterintuitive consequences on circuit functions, which can be controlled with a division of labor strategy.
Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis
Authors: Radamaker Lynn , Baur Julian , Huhn Stefanie , Haupt Christian , Hegenbart Ute , Schönland Stefan , Bansal Akanksha , Schmidt Matthias , Fändrich Marcus
Published: February 2021

Systemic AL amyloidosis is a debilitating and potentially fatal disease that arises from the misfolding and fibrillation of immunoglobulin light chains (LCs). The disease is patient-specific with essentially each patient possessing a unique LC sequence. In this study, we present two ex vivo fibril structures of a λ3 LC. The fibrils were extracted from the explanted heart of a patient (FOR005) and consist of 115-residue fibril proteins, mainly from the LC variable domain. The fibril structures imply that a 180° rotation around the disulfide bond and a major unfolding step are necessary for fibrils to form. The two fibril structures show highly similar fibril protein folds, differing in only a 12-residue segment. Remarkably, the two structures do not represent separate fibril morphologies, as they can co-exist at different z-axial positions within the same fibril. Our data imply the presence of structural breaks at the interface of the two structural forms.
Single-cell profiling identifies pre-existing CD19-negative subclones in a B-ALL patient with CD19-negative relapse after CAR-T therapy
Authors: Rabilloud Tracy , Potier Delphine , Pankaew Saran , Nozais Mathis , Loosveld Marie , Payet-Bornet Dominique
Published: February 2021

Chimeric antigen receptor T cell (CAR-T) targeting the CD19 antigen represents an innovative therapeutic approach to improve the outcome of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Yet, despite a high initial remission rate, CAR-T therapy ultimately fails for some patients. Notably, around half of relapsing patients develop CD19 negative (CD19neg) B-ALL allowing leukemic cells to evade CD19-targeted therapy. Herein, we investigate leukemic cells of a relapsing B-ALL patient, at two-time points: before (T1) and after (T2) anti-CD19 CAR-T treatment. We show that at T2, the B-ALL relapse is CD19 negative due to the expression of a non-functional CD19 transcript retaining intron 2. Then, using single-cell RNA sequencing (scRNAseq) approach, we demonstrate that CD19neg leukemic cells were present before CAR-T cell therapy and thus that the relapse results from the selection of these rare CD19neg B-ALL clones. In conclusion, our study shows that scRNAseq profiling can reveal pre-existing CD19neg subclones, raising the possibility to assess the risk of targeted therapy failure.
Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide
Authors: Li Fei , Han Ming , Dai Pengfei , Xu Wei , He Juan , Tao Xiaoting , Wu Yang , Tong Xinyuan , Xia Xinyi , Guo Wangxin , Zhou Yunjiao , Li Yunguang , Zhu Yiqin , Zhang Xiaoyu , Liu Zhuang , Aji Rebiguli , Cai Xia , Li Yutang , Qu Di , Chen Yu , Jiang Shibo , Wang Qiao , Ji Hongbin , Xie Youhua , Sun Yihua , Lu Lu , Gao Dong
Published: February 2021

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.
General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins
Authors: Laps Shay , Atamleh Fatima , Kamnesky Guy , Sun Hao , Brik Ashraf
Published: February 2021

Despite six decades of efforts to synthesize peptides and proteins bearing multiple disulfide bonds, this synthetic challenge remains an unsolved problem in most targets (e.g., knotted mini proteins). Here we show a de novo general synthetic strategy for the ultrafast, high-yielding formation of two and three disulfide bonds in peptides and proteins. We develop an approach based on the combination of a small molecule, ultraviolet-light, and palladium for chemo- and regio-selective activation of cysteine, which enables the one-pot formation of multiple disulfide bonds in various peptides and proteins. We prepare bioactive targets of high therapeutic potential, including conotoxin, RANTES, EETI-II, and plectasin peptides and the linaclotide drug. We anticipate that this strategy will be a game-changer in preparing millions of inaccessible targets for drug discovery.
Long-term warming in a Mediterranean-type grassland affects soil bacterial functional potential but not bacterial taxonomic composition
Authors: Gao Ying , Ding Junjun , Yuan Mengting , Chiariello Nona , Docherty Kathryn , Field Chris , Gao Qun , Gu Baohua , Gutknecht Jessica , Hungate Bruce A. , Le Roux Xavier , Niboyet Audrey , Qi Qi , Shi Zhou , Zhou Jizhong , Yang Yunfeng
Published: February 2021

Climate warming is known to impact ecosystem composition and functioning. However, it remains largely unclear how soil microbial communities respond to long-term, moderate warming. In this study, we used Illumina sequencing and microarrays (GeoChip 5.0) to analyze taxonomic and functional gene compositions of the soil microbial community after 14 years of warming (at 0.8–1.0 °C for 10 years and then 1.5–2.0 °C for 4 years) in a Californian grassland. Long-term warming had no detectable effect on the taxonomic composition of soil bacterial community, nor on any plant or abiotic soil variables. In contrast, functional gene compositions differed between warming and control for bacterial, archaeal, and fungal communities. Functional genes associated with labile carbon (C) degradation increased in relative abundance in the warming treatment, whereas those associated with recalcitrant C degradation decreased. A number of functional genes associated with nitrogen (N) cycling (e.g., denitrifying genes encoding nitrate-, nitrite-, and nitrous oxidereductases) decreased, whereasnifHgene encoding nitrogenase increased in the warming treatment. These results suggest that microbial functional potentials are more sensitive to long-term moderate warming than the taxonomic composition of microbial community.
Biofilm-isolated Listeria monocytogenes exhibits reduced systemic dissemination at the early (12–24 h) stage of infection in a mouse model
Authors: Bai Xingjian , Liu Dongqi , Xu Luping , Tenguria Shivendra , Drolia Rishi , Gallina Nicholas L. F. , Cox Abigail D. , Koo Ok-Kyung , Bhunia Arun K.
Published: February 2021

Environmental cues promote microbial biofilm formation and physiological and genetic heterogeneity. In food production facilities, biofilms produced by pathogens are a major source for food contamination; however, the pathogenesis of biofilm-isolated sessile cells is not well understood. We investigated the pathogenesis of sessile Listeria monocytogenes (Lm) using cell culture and mouse models. Lm sessile cells express reduced levels of the lap, inlA, hly, prfA, and sigB and show reduced adhesion, invasion, translocation, and cytotoxicity in the cell culture model than the planktonic cells. Oral challenge of C57BL/6 mice with food, clinical, or murinized-InlA (InlAm) strains reveals that at 12 and 24 h post-infection (hpi), Lm burdens are lower in tissues of mice infected with sessile cells than those infected with planktonic cells. However, these differences are negligible at 48 hpi. Besides, the expressions of inlA and lap mRNA in sessile Lm from intestinal content are about 6.0- and 280-fold higher than the sessle inoculum, respectively, suggesting sessile Lm can still upregulate virulence genes shortly after ingestion (12 h). Similarly, exposure to simulated gastric fluid (SGF, pH 3) and intestinal fluid (SIF, pH 7) for 13 h shows equal reduction in sessile and planktonic cell counts, but induces LAP and InlA expression and pathogenic phenotypes. Our data show that the virulence of biofilm-isolated Lm is temporarily attenuated and can be upregulated in mice during the early stage (12–24 hpi) but fully restored at a later stage (48 hpi) of infection. Our study further demonstrates that in vitro cell culture assay is unreliable; therefore, an animal model is essential for studying the pathogenesis of biofilm-isolated bacteria.
Ab initio molecular dynamics and materials design for embedded phase-change memory
Authors: Sun Liang , Zhou Yu-Xing , Wang Xu-Dong , Chen Yu-Han , Deringer Volker L. , Mazzarello Riccardo , Zhang Wei
Published: February 2021

The Ge2Sb2Te5 alloy has served as the core material in phase-change memories with high switching speed and persistent storage capability at room temperature. However widely used, this composition is not suitable for embedded memories—for example, for automotive applications, which require very high working temperatures above 300 °C. Ge–Sb–Te alloys with higher Ge content, most prominently Ge2Sb1Te2 (‘212’), have been studied as suitable alternatives, but their atomic structures and structure–property relationships have remained widely unexplored. Here, we report comprehensive first-principles simulations that give insight into those emerging materials, located on the compositional tie-line between Ge2Sb1Te2 and elemental Ge, allowing for a direct comparison with the established Ge2Sb2Te5 material. Electronic-structure computations and smooth overlap of atomic positions (SOAP) similarity analyses explain the role of excess Ge content in the amorphous phases. Together with energetic analyses, a compositional threshold is identified for the viability of a homogeneous amorphous phase (‘zero bit’), which is required for memory applications. Based on the acquired knowledge at the atomic scale, we provide a materials design strategy for high-performance embedded phase-change memories with balanced speed and stability, as well as potentially good cycling capability.
Inference of phenotype-relevant transcriptional regulatory networks elucidates cancer type-specific regulatory mechanisms in a pan-cancer study
Authors: Emad Amin , Sinha Saurabh
Published: February 2021

Reconstruction of transcriptional regulatory networks (TRNs) is a powerful approach to unravel the gene expression programs involved in healthy and disease states of a cell. However, these networks are usually reconstructed independent of the phenotypic (or clinical) properties of the samples. Therefore, they may confound regulatory mechanisms that are specifically related to a phenotypic property with more general mechanisms underlying the full complement of the analyzed samples. In this study, we develop a method called InPheRNo to identify “phenotype-relevant” TRNs. This method is based on a probabilistic graphical model that models the simultaneous effects of multiple transcription factors (TFs) on their target genes and the statistical relationship between the target genes’ expression and the phenotype. Extensive comparison of InPheRNo with related approaches using primary tumor samples of 18 cancer types from The Cancer Genome Atlas reveals that InPheRNo can accurately reconstruct cancer type-relevant TRNs and identify cancer driver TFs. In addition, survival analysis reveals that the activity level of TFs with many target genes could distinguish patients with poor prognosis from those with better prognosis.
A single dose investigational subunit vaccine for human use against Nipah virus and Hendra virus
Authors: Geisbert Thomas W. , Bobb Kathryn , Borisevich Viktoriya , Geisbert Joan B. , Agans Krystle N. , Cross Robert W. , Prasad Abhishek N. , Fenton Karla A. , Yu Hao , Fouts Timothy R. , Broder Christopher C. , Dimitrov Antony S.
Published: February 2021

Nipah and Hendra viruses are highly pathogenic bat-borne paramyxoviruses recently included in the WHO Blueprint priority diseases list. A fully registered horse anti-Hendra virus subunit vaccine has been in use in Australia since 2012. Based on the same immunogen, the Hendra virus attachment glycoprotein ectodomain, a subunit vaccine formulation for use in people is now in a Phase I clinical trial. We report that a single dose vaccination regimen of this human vaccine formulation protects against otherwise lethal challenges of either Hendra or Nipah virus in a nonhuman primate model. The protection against the Nipah Bangladesh strain begins as soon as 7 days post immunization with low dose of 0.1 mg protein subunit. Our data suggest this human vaccine could be utilized as efficient emergency vaccine to disrupt potential spreading of Nipah disease in an outbreak setting.
Poromechanical controls on spontaneous imbibition in earth materials
Authors: Haghi Amir H. , Chalaturnyk Richard , Blunt Martin J. , Hodder Kevin , Geiger Sebastian
Published: February 2021

Over the last century, the state of stress in the earth’s upper crust has undergone rapid changes because of human activities associated with fluid withdrawal and injection in subsurface formations. The stress dependency of multiphase flow mechanisms in earth materials is a substantial challenge to understand, quantify, and model for many applications in groundwater hydrology, applied geophysics, CO2 subsurface storage, and the wider geoenergy field (e.g., geothermal energy, hydrogen storage, hydrocarbon recovery). Here, we conduct core-scale experiments using N2/water phases to study primary drainage followed by spontaneous imbibition in a carbonate specimen under increasing isotropic effective stress and isothermal conditions. Using X-ray computed micro-tomography images of the unconfined specimen, we introduce a novel coupling approach to reconstruct pore-deformation and simulate multiphase flow inside the deformed pore-space followed by a semi-analytical calculation of spontaneous imbibition. We show that the irreducible water saturation increases while the normalized volume of spontaneously imbibed water into the specimen decreases (46–25%) in response to an increase in effective stress (0–30 MPa), leading to higher residual gas saturations. Furthermore, the imbibition rate decreases with effective stress, which is also predicted by a numerical model, due to a decrease in water relative permeability as the pore-space becomes more confined and tortuous. This fundamental study provides new insights into the physics of multiphase fluid transport, CO2 storage capacity, and recovery of subsurface resources incorporating the impact of poromechanics.
Correlation of cochlear aperture stenosis with cochlear nerve deficiency in congenital unilateral hearing loss and prognostic relevance for cochlear implantation
Authors: Orzan Eva , Pizzamiglio Giulia , Gregori Massimo , Marchi Raffaella , Torelli Lucio , Muzzi Enrico
Published: February 2021

The use of neonatal hearing screening has enabled the identification of congenital unilateral sensorineural hearing loss (USNHL) immediately after birth, and today there are several intervention options available to minimize potential adverse effects of this disease, including cochlear implantation. This study aims to analyze the characteristics of the inner ear of a homogeneous group of congenital non-syndromic USNHL to highlight the features of the inner ear, which can help in clinical, surgical, and rehabilitative decision-making. A retrospective chart review was carried out at a tertiary referral center. Systematic diagnostic work-up and rigorous inclusion–exclusion criteria were applied to 126 children with unilateral hearing impairment, leading to a selection of 39 strictly congenital and non-syndromic USNHL cases, undergoing computed tomography (CT) and magnetic resonance (MR) imaging studies. The frequency and type of malformations of the inner ear in USNHL and unaffected contralateral ears were assessed, with an in-depth analysis of the deficiency of the cochlear nerve (CND), the internal auditory canal (IAC) and the cochlear aperture (CA). Inner ear anomalies were found in 18 out of 39 (46%) of the USNHL patients. In 1 subject, the anomalies were bilateral, and the CND resulted in the predominant identified defect (78% of our abnormal case series), frequently associated with CA stenosis. Only 3 out of 14 children with CND presented stenosis of the IAC. CND and CA stenosis (and to a much lesser extent IAC stenosis) are a frequent association within congenital and non-syndromic USNHL that could represent a distinct pathological entity affecting otherwise healthy infants. In the context of a diagnostic work-up, the evaluation with CT and MRI measurements should take place in a shared decision-making setting with thorough counseling. Both imaging techniques have proven useful in differentiating the cases that will most likely benefit from the cochlear implant, from those with potentially poor implant performance.
A case–control study of clinical characteristics and risk factors of symptomatic postpartum pubic symphysis diastasis
Authors: Sung Ji-Hee , Kang Mina , Lim Seung-Jae , Choi Suk-Joo , Oh Soo-young , Roh Cheong-Rae
Published: February 2021

Postpartum pubic symphysis diastasis (PPSD) refers to the separation of pubic symphysis after delivery. It is typically diagnosed based on clinical symptoms and radiologic findings. This study tried to assess clinical characteristics and risk factors of PPSD. This was a nested case–control study matched for year of delivery and gestational age at delivery using a retrospective cohort of women who delivered vaginally at a single institution. The incidence of PPSD was 0.156% (33/21,131). The incidence rate increased from 0.08% (7/9328) in 2000–2004 to 0.13% (9/7138) in 2005–2009 and to 0.36% (17/4665) in 2010–2016, simultaneously with an increase of maternal age (30.7 ± 3.5 years in 2000–2004 to 31.8 ± 3.8 years in 2005–2009 and 32.8 ± 3.8 years in 2010–2016). Nulliparity was associated with a higher incidence of PPSD (81.8% in cases vs. 57.6% in controls, p = 0.01). Other factors including pre-pregnancy body mass index, weight gain during pregnancy, gestational diabetes, induction of labor, duration of labor, epidural anesthesia, vacuum-assisted delivery, episiotomy, neonatal sex and birth weight failed to show difference between the two groups. In short, the incidence of PPSD increased with time along with an increase of maternal age. Nulliparity was the only significant risk factor for PPSD.
Automatic ganglion cell detection for improving the efficiency and accuracy of hirschprung disease diagnosis
Authors: Greenberg Ariel , Aizic Asaf , Zubkov Asia , Borsekofsky Sarah , Hagege Rami R. , Hershkovitz Dov
Published: February 2021

Histopathologic diagnosis of Hirschsprung's disease (HSCR) is time consuming and requires expertise. The use of artificial intelligence (AI) in digital pathology is actively researched and may improve the diagnosis of HSCR. The purpose of this research was to develop an algorithm capable of identifying ganglion cells in digital pathology slides and implement it as an assisting tool for the pathologist in the diagnosis of HSCR. Ninety five digital pathology slides were used for the construction and training of the algorithm. Fifty cases suspected for HSCR (727 slides) were used as a validation cohort. Image sets suspected to contain ganglion cells were chosen by the algorithm and then reviewed and scored by five pathologists, one HSCR expert and 4 non-experts. The algorithm was able to identify ganglion cells with 96% sensitivity and 99% specificity (in normal colon) as well as to correctly identify a case previously misdiagnosed as non-HSCR. The expert was able to achieve perfectly accurate diagnoses based solely on the images suggested by the algorithm, with over 95% time saved. Non-experts would require expert consultation in 20–58% of the cases to achieve similar results. The use of AI in the diagnosis of HSCR can greatly reduce the time and effort required for diagnosis and improve accuracy.
Three-dimensional ultrastructure of giant mitochondria in human non-alcoholic fatty liver disease
Authors: Shami Gerald J. , Cheng Delfine , Verhaegh Pauline , Koek Ger , Wisse Eddie , Braet Filip
Published: February 2021

Giant mitochondria are peculiarly shaped, extremely large mitochondria in hepatic parenchymal cells, the internal structure of which is characterised by atypically arranged cristae, enlarged matrix granules and crystalline inclusions. The presence of giant mitochondria in human tissue biopsies is often linked with cellular adversity, caused by toxins such as alcohol, xenobiotics, anti-cancer drugs, free-radicals, nutritional deficiencies or as a consequence of high fat Western diets. To date, non-alcoholic fatty liver disease is the most prevalent liver disease in lipid dysmetabolism, in which mitochondrial dysfunction plays a crucial role. It is not well understood whether the morphologic characteristics of giant mitochondria are an adaption or caused by such dysfunction. In the present study, we employ a complementary multimodal imaging approach involving array tomography and transmission electron tomography in order to comparatively analyse the structure and morphometric parameters of thousands of normal- and giant mitochondria in four patients diagnosed with non-alcoholic fatty liver disease. In so doing, we reveal functional alterations associated with mitochondrial gigantism and propose a mechanism for their formation based on our ultrastructural findings.