bluuebunny/crossref_metadata_2025 huggingface dataset:
Sub‐Annual to Interannual Arabian Sea Upwelling, Sea Surface Temperature, and Indian Monsoon Rainfall Reconstructed Using Congruent Micrometer‐Scale Climate Proxies
Authors: Napier Tiffany J. , Wörmer Lars , Wendt Jenny , Lückge Andreas , Rohlfs Nina , Hinrichs Kai‐Uwe
Published: March 2022

The Indian monsoon system impacts over 1 billion people, and rainfall from its southwest monsoon is critical for agriculture. Cool sea surface temperatures (SSTs) in the Arabian Sea have been associated with reduced monsoon rainfall and vice versa, although this relationship is difficult to examine due to scarce and short instrumental records. We utilize laminated Pakistan Margin sediments to reconstruct southwest monsoon rainfall and Arabian Sea SSTs at sub‐annual to multi‐annual resolution for the twentieth century. We applied paired sub‐mm mapping techniques to intact sediment core surfaces to measure elemental abundances and lipid biomarkers. The first principal component of the elemental results (PC1) explains 47% of the elemental variance and is driven by detrital lithogenic elements K, Ti, and Fe. PC1 is positively correlated with homogeneous India June‐September rainfall departures from 1903 to 1928 and 1949–1970 on a multi‐annual scale. Correlations in the remaining timespans are either negative or absent, likely driven by a combination of dam and barrage construction on the Hub and Indus Rivers and negative rainfall departures. We propose PC1 as a proxy for southwest monsoon rainfall on multi‐annual timescales prior to ∼1930. A dampened annual SST cycle is resolved with the alkenone paleothermometer, which also captures the interannual‐decadal trends of twentieth century Arabian Sea SSTs. We propose the crenarchaeol‐caldarchaeol tetraether index, sourced from planktonic Thaumarchaeota, as a delayed upwelling proxy for the western Arabian Sea. Our reconstructions corroborate the established relationship of reduced Arabian Sea upwelling leading to warmer SSTs and increased monsoon rainfall, and vice versa.
An Exploration of Bayesian Identification of Dominant Hydrological Mechanisms in Ungauged Catchments
Authors: Prieto Cristina , Le Vine Nataliya , Kavetski Dmitri , Fenicia Fabrizio , Scheidegger Andreas , Vitolo Claudia
Published: March 2022

Hydrological modeling of ungauged catchments, which lack observed streamflow data, is an important practical goal in hydrological sciences. A major challenge is to identify a model structure that reflects the hydrological processes relevant to the catchment of interest. This study contributes a Bayesian framework for identifying individual model mechanisms (process representations) from flow indices regionalized to the catchment of interest. We extend a method previously introduced for mechanism identification in gauged basins, by formulating the inference equations in the space of (regionalized) flow indices and by accounting for posterior parameter uncertainty. A flexible hydrological model is used to generate candidate mechanisms and model structures, followed by statistical hypothesis testing to identify “dominant” (more a posterior probable) model mechanisms. The proposed method is illustrated using real data and synthetic experiments based on 92 catchments from northern Spain, from which 16 catchments are treated as ungauged. 624 hydrological model structures from the flexible framework FUSE are employed. In real data experiments, the method identifies a dominant mechanism in 27% of 112 trials (processes and catchments). The most identifiable process is routing, whereas the least identifiable processes are percolation and unsaturated zone processes. In synthetic experiments, where “true” mechanisms are known, the reliability of method varies from 60% to 95% depending on the combined regionalization and hydrological error; the probability of making an identification remains stable at around 25%. More broadly, the study contributes perspectives on hydrological mechanism identification under data‐scarce conditions; limitations and opportunities for improvement are outlined.
Probabilistic Flood Hazard Mapping Considering Multiple Levee Breaches
Authors: Maranzoni A. , D’Oria M. , Mazzoleni M.
Published: March 2022

Probabilistic methods are widely adopted for residual flood hazard assessment in flood‐prone areas protected by levees. Such methods can consider various sources of uncertainty, including breach location and flood event characteristics, and allow for the quantification of the result confidence. However, the possible occurrence of multiple levee breaches during the same flood event is usually disregarded. This paper presents a probabilistic method based on levee fragility functions and basic probability rules to estimate the probability of selected breach scenarios, including multiple breaching events. The flood hazard classification is based on inundation variables calculated for flood events of different return periods. A combined 1D‐2D hydrodynamic model is used for flood simulations. Probabilistic inundation extent maps and probabilistic flood hazard level maps are then created. Finally, probabilistic flood hazard estimates are summarized in a map of a suitable central tendency of the hazard level, coupled with a map of the Shannon entropy as an uncertainty indicator. This pair of statistical maps provides concise and effective information on a reference flood hazard along with the associated uncertainty. The method was applied to a region located along the middle reach of the Po River (northern Italy). Comparable central flood hazard estimates are obtained for the two sets of breaching events including or not including multiple breaches, with higher uncertainty if multiple breaches are considered. This result highlights the importance of considering multiple breaching events in flood risk management.
Estimating Heat Wave Frequency and Strength: A Chicago Case Study
Authors: Sidik Saima
Published: March 2022

Numerical modeling shows widespread impacts of the 2012 Chicago heat wave, shedding light on heat wave and urban heat island impacts on the city’s temperature.
Microenvironmental stiffness mediates cytoskeleton re-organization in chondrocytes through laminin-FAK mechanotransduction
Authors: Zhou Chenchen , Duan Mengmeng , Guo Daimo , Du Xinmei , Zhang Demao , Xie Jing
Published: March 2022

Microenvironmental biophysical factors play a fundamental role in controlling cell behaviors including cell morphology, proliferation, adhesion and differentiation, and even determining the cell fate. Cells are able to actively sense the surrounding mechanical microenvironment and change their cellular morphology to adapt to it. Although cell morphological changes have been considered to be the first and most important step in the interaction between cells and their mechanical microenvironment, their regulatory network is not completely clear. In the current study, we generated silicon-based elastomer polydimethylsiloxane (PDMS) substrates with stiff (15:1, PDMS elastomer vs. curing agent) and soft (45:1) stiffnesses, which showed the Young’s moduli of ~450 kPa and 46 kPa, respectively, and elucidated a new path in cytoskeleton re-organization in chondrocytes in response to changed substrate stiffnesses by characterizing the axis shift from the secreted extracellular protein laminin β1, focal adhesion complex protein FAK to microfilament bundling. We first showed the cellular cytoskeleton changes in chondrocytes by characterizing the cell spreading area and cellular synapses. We then found the changes of secreted extracellular linkage protein, laminin β1, and focal adhesion complex protein, FAK, in chondrocytes in response to different substrate stiffnesses. These two proteins were shown to be directly interacted by Co-IP and colocalization. We next showed that impact of FAK on the cytoskeleton organization by showing the changes of microfilament bundles and found the potential intermediate regulators. Taking together, this modulation axis of laminin β1-FAK-microfilament could enlarge our understanding about the interdependence among mechanosensing, mechanotransduction, and cytoskeleton re-organization.
Intrauterine inflammation exacerbates maladaptive remodeling of the immature myocardium after preterm birth in lambs
Authors: Vrselja Amanda , Pillow J. Jane , Bensley Jonathan G. , Ellery Stacey J. , Ahmadi-Noorbakhsh Siavash , Moss Timothy J. , Black M. Jane
Published: March 2022

Background

Antenatal conditions that are linked with preterm birth, such as intrauterine inflammation, can influence fetal cardiac development thereby rendering the heart more vulnerable to the effects of prematurity. We aimed to investigate the effect of intrauterine inflammation, consequent to lipopolysaccharide exposure, on postnatal cardiac growth and maturation in preterm lambs.

Methods

Preterm lambs (~129 days gestational age) exposed antenatally to lipopolysaccharide or saline were managed according to contemporary neonatal care and studied at postnatal day 7. Age-matched fetal controls were studied at ~136 days gestational age. Cardiac tissue was sampled for molecular analyses and assessment of cardiac structure and cardiomyocyte maturation.

Results

Lambs delivered preterm showed distinct ventricular differences in cardiomyocyte growth and maturation trajectories as well as remodeling of the left ventricular myocardium compared to fetal controls. Antenatal exposure to lipopolysaccharide resulted in further collagen deposition in the left ventricle and a greater presence of immune cells in the preterm heart.

Conclusions

Adverse impacts of preterm birth on cardiac structure and cardiomyocyte growth kinetics within the first week of postnatal life are exacerbated by intrauterine inflammation. The maladaptive remodeling of the cardiac structure and perturbed cardiomyocyte growth likely contribute to the increased vulnerability to cardiac dysfunction following preterm birth.

Impact

Preterm birth induces maladaptive cardiac remodeling and adversely impacts cardiomyocyte growth kinetics within the first week of life in sheep.

These effects of prematurity on the heart are exacerbated when preterm birth is preceded by exposure to intrauterine inflammation, a common antecedent of preterm birth.

Inflammatory injury to the fetal heart coupled with preterm birth consequently alters neonatal cardiac growth and maturation and thus, may potentially influence long-term cardiac function and health.
Efficacy of transcutaneous electrical nerve stimulation in people with pain after spinal cord injury: a meta-analysis
Authors: Yang Ye , Tang Yun , Qin Huiqing , Xu Jianwen
Published: March 2022

Study Design

Meta-analysis.

Objectives

This study aimed to evaluate the effect of transcutaneous electrical nerve stimulation in people with pain after spinal cord injury by meta-analysis.

Methods

Reviewed PubMed, Embase, Cochrane library, as well as China National Knowledge Infrastructure (CNKI), Wanfang, and Vip databases to search the randomized controlled trials of pain after spinal cord injury through transcutaneous electrical nerve stimulation from the beginning of the library to March 2021, and analyze the literature with RevMan 5.3 software and the bias in the literature with STATA 12.0 software.

Results

There are six randomized controlled trials in the study with 165 cases. 83 cases in the test group were given transcutaneous electrical nerve stimulation, and 82 cases in the control group used sham stimulation or other treatments. Meta-analysis results showed the experimental group’s visual analog scale (MD = −1.52, 95%CI, −2.44 to −0.60,P = 0.001) and short-form McGill pain questionnaire scores (MD = −0.70, 95% CI, −1.03 to −0.25,P = 0.002) were lower than those of the control group.

Conclusions

Transcutaneous electrical nerve stimulation has some clinical therapeutic effects on persons with pain after spinal cord injury, but due to the lack of literature, the sample size is not large, and clinical trials need to be further improved later.
Morpholino-driven blockade of Dkk-1 in osteosarcoma inhibits bone damage and tumour expansion by multiple mechanisms
Authors: Pan Simin , Cesarek Michael , Godoy Carla , Co Cynthia M. , Schindler Catherine , Padilla Kelbi , Haskell Andrew , Barreda Heather , Story Christopher , Poole Roy , Dabney Alan , Gregory Carl A.
Published: March 2022

Background

Osteosarcoma (OS) is the most common primary bone malignancy. Chemotherapy plays an essential role in OS treatment, potentially doubling 5-year event-free survival if tumour necrosis can be stimulated. The canonical Wnt inhibitor Dickkopf-1 (Dkk-1) enhances OS survival in part through upregulation of aldehyde-dehydrogenase-1A1 which neutralises reactive oxygen species originating from nutritional stress and chemotherapeutic challenge.

Methods

A vivo morpholino (DkkMo) was employed to block the expression of Dkk-1 in OS cells. Cell mitosis, gene expression and bone destruction were measured in vitro and in vivo in the presence and absence of doxorubicin (DRB).

Results

DkkMo reduced the expression of Dkk-1 and Aldh1a1, reduced expansion of OS tumours, preserved bone volume and architecture and stimulated tumour necrosis. This was observed in the presence or absence of DRB.

Conclusion

These results indicate that administration of DkkMo with or without chemotherapeutics can substantially improve OS outcome with respect to tumour expansion and osteolytic corruption of bone in experimental OS model.
GSDMD enhances cisplatin-induced apoptosis by promoting the phosphorylation of eIF2α and activating the ER-stress response
Authors: Zhang Qianyu , Huang Zixian , Rui Xi , Wang Yan , Wang Yongqiang , Zhou Yuwei , Chen Rui , Chen Yongju , Wang Yuepeng , Li Shihao , Li Haigang , Shen Ximing , Liang Yancan , Zhang Yin , Huang Zhiquan
Published: March 2022

GSDMD is the key effector of pyroptosis, but its non-pyroptosis-related functions have seldom been reported. Here, we report that GSDMD is overexpressed in different types of tumours, including head and neck squamous-cell carcinoma, and it promotes the sensitivity of tumour cells to cisplatin. Unexpectedly, the enhanced cisplatin sensitivity is mediated by apoptosis but not pyroptosis, the well-known function of GSDMD. Furthermore, we found that GSDMD can activate the unfolded protein response by promoting the phosphorylation of eIF2α. Mechanistically, we demonstrated that GSDMD can directly bind to eIF2α and enhance the interaction between eIF2α and its upstream kinase PERK, leading to eIF2α phosphorylation. Consequently, the protein levels of ATF-4 were upregulated, downstream apoptosis-related proteins such as CHOP were activated, and apoptosis was induced. Remarkably, activation of endoplasmic-reticulum (ER) stress induced by GSDMD promotes cell apoptosis during cisplatin chemotherapy, thereby increasing the treatment sensitivity of tumours. Therefore, for the first time, our work reveals an unreported nonpyroptotic function of the classic pyroptosis protein GSDMD: it promotes cell apoptosis during cisplatin chemotherapy by inducing eIF2α phosphorylation and ER stress, which are related to the drug sensitivity of tumours. Our study also indicated that GSDMD might serve as a biomarker for cisplatin sensitivity.
Preferences for return of germline genome sequencing results for cancer patients and their genetic relatives in a research setting
Authors: Best Megan C. , Butow Phyllis , Savard Jacqueline , Jacobs Chris , Bartley Nicole , Davies Grace , Napier Christine E. , Ballinger Mandy L. , Thomas David M. , Biesecker Barbara , Tucker Katherine M. , Juraskova Ilona , Meiser Bettina , Schlub Timothy , Newson Ainsley J.
Published: March 2022

Germline genome sequencing (GS) holds great promise for cancer prevention by identifying cancer risk and guiding prevention strategies, however research evidence is mixed regarding patient preferences for receiving GS results. The aim of this study was to discern preferences for return of results by cancer patients who have actually undergone GS. We conducted a mixed methods study with a cohort of cancer probands (n = 335) and their genetic relatives (n = 199) undergoing GS in a research setting. Both groups completed surveys when giving consent. A subset of participants (n = 40) completed semi-structured interviews. A significantly higher percentage of probands thought people would like to be informed about genetic conditions for which there is prevention or treatment that can change cancer risk compared to conditions for which there is no prevention or treatment (93% [311] versus 65% [216]; p < 0.001). Similar results were obtained for relatives (91% [180] versus 61% [121]; p < 0.001). Themes identified in the analysis of interviews were: (1) Recognised benefits of GS, (2) Balancing benefits with risks, (3) Uncertain results are perceived as unhelpful and (4) Competing obligations. While utility was an important discriminator in what was seen as valuable for this cohort, there was a variety of responses. In view of varied participant preferences regarding return of results, it is important to ensure patient understanding of test validity and identify individual choices at the time of consent to GS. The nature and value of the information, and a contextual understanding of researcher obligations should guide result return.
Population genetic differentiation and genomic signatures of adaptation to climate in an abundant lizard
Authors: Ruiz Miñano Maravillas , While Geoffrey M. , Yang Weizhao , Burridge Christopher P. , Salvi Daniele , Uller Tobias
Published: March 2022

Species distributed across climatic gradients will typically experience spatial variation in selection, but gene flow can prevent such selection from causing population genetic differentiation and local adaptation. Here, we studied genomic variation of 415 individuals across 34 populations of the common wall lizard (Podarcis muralis) in central Italy. This species is highly abundant throughout this region and populations belong to a single genetic lineage, yet there is extensive phenotypic variation across climatic regimes. We used redundancy analysis to, first, quantify the effect of climate and geography on population genomic variation in this region and, second, to test if climate consistently sorts specific alleles across the landscape. Climate explained 5% of the population genomic variation across the landscape, about half of which was collinear with geography. Linear models and redundancy analyses identified loci that were significantly differentiated across climatic regimes. These loci were distributed across the genome and physically associated with genes putatively involved in thermal tolerance, regulation of temperature-dependent metabolism and reproductive activity, and body colouration. Together, these findings suggest that climate can exercise sufficient selection in lizards to promote genetic differentiation across the landscape in spite of high gene flow.
Recurring adaptive introgression of a supergene variant that determines social organization
Authors: Stolle Eckart , Pracana Rodrigo , López-Osorio Federico , Priebe Marian K. , Hernández Gabriel Luis , Castillo-Carrillo Claudia , Arias Maria Cristina , Paris Carolina Ivon , Bollazzi Martin , Priyam Anurag , Wurm Yannick
Published: March 2022

Introgression has been proposed as an essential source of adaptive genetic variation. However, a key barrier to adaptive introgression is that recombination can break down combinations of alleles that underpin many traits. This barrier might be overcome in supergene regions, where suppressed recombination leads to joint inheritance across many loci. Here, we study the evolution of a large supergene region that determines a major social and ecological trait in Solenopsis fire ants: whether colonies have one queen or multiple queens. Using coalescent-based phylogenies built from the genomes of 365 haploid fire ant males, we show that the supergene variant responsible for multiple-queen colonies evolved in one species and repeatedly spread to other species through introgressive hybridization. This finding highlights how supergene architecture can enable a complex adaptive phenotype to recurrently permeate species boundaries.
Past terrestrial hydroclimate sensitivity controlled by Earth system feedbacks
Authors: Feng Ran , Bhattacharya Tripti , Otto-Bliesner Bette L. , Brady Esther C. , Haywood Alan M. , Tindall Julia C. , Hunter Stephen J. , Abe-Ouchi Ayako , Chan Wing-Le , Kageyama Masa , Contoux Camille , Guo Chuncheng , Li Xiangyu , Lohmann Gerrit , Stepanek Christian , Tan Ning , Zhang Qiong , Zhang Zhongshi , Han Zixuan , Williams Charles J. R. , Lunt Daniel J. , Dowsett Harry J. , Chandan Deepak , Peltier W. Richard
Published: March 2022

Despite tectonic conditions and atmospheric CO2 levels (pCO2) similar to those of present-day, geological reconstructions from the mid-Pliocene (3.3-3.0 Ma) document high lake levels in the Sahel and mesic conditions in subtropical Eurasia, suggesting drastic reorganizations of subtropical terrestrial hydroclimate during this interval. Here, using a compilation of proxy data and multi-model paleoclimate simulations, we show that the mid-Pliocene hydroclimate state is not driven by direct CO2 radiative forcing but by a loss of northern high-latitude ice sheets and continental greening. These ice sheet and vegetation changes are long-term Earth system feedbacks to elevated pCO2. Further, the moist conditions in the Sahel and subtropical Eurasia during the mid-Pliocene are a product of enhanced tropospheric humidity and a stationary wave response to the surface warming pattern, which varies strongly with land cover changes. These findings highlight the potential for amplified terrestrial hydroclimate responses over long timescales to a sustained CO2 forcing.
Malfunction of airway basal stem cells plays a crucial role in pathophysiology of tracheobronchopathia osteoplastica
Authors: Hong Yue , Shan Shan , Gu Ye , Huang Haidong , Zhang Quncheng , Han Yang , Dong Yongpin , Liu Zeyu , Huang Moli , Ren Tao
Published: March 2022

Understanding disease-associated stem cell abnormality has major clinical implications for prevention and treatment of human disorders, as well as for regenerative medicine. Here we report a multifaceted study on airway epithelial stem cells in Tracheobronchopathia Osteochondroplastica (TO), an under-detected tracheobronchial disorder of unknown etiology and lack of specific treatment. Epithelial squamous metaplasia and heterotopic bone formation with abnormal cartilage proliferation and calcium deposits are key pathological hallmarks of this disorder, but it is unknown whether they are coincident or share certain pathogenic mechanisms in common. By functional evaluation and genome-wide profiling at both transcriptional and epigenetic levels, we reveal a role of airway basal cells in TO progression by acting as a repository of inflammatory and TGFβ-BMP signals, which contributes to both epithelial metaplasia and mesenchymal osteo-chondrogenesis via extracellular signaling and matrix remodeling. Restoration of microenvironment by cell correction or local pathway intervention may provide therapeutic benefits.
Enhanced jet stream waviness induced by suppressed tropical Pacific convection during boreal summer
Authors: Sun Xiaoting , Ding Qinghua , Wang Shih-Yu Simon , Topál Dániel , Li Qingquan , Castro Christopher , Teng Haiyan , Luo Rui , Ding Yihui
Published: March 2022

Consensus on the cause of recent midlatitude circulation changes toward a wavier manner in the Northern Hemisphere has not been reached, albeit a number of studies collectively suggest that this phenomenon is driven by global warming and associated Arctic amplification. Here, through a fingerprint analysis of various global simulations and a tropical heating-imposed experiment, we suggest that the suppression of tropical convection along the Inter Tropical Convergence Zone induced by sea surface temperature (SST) cooling trends over the tropical Eastern Pacific contributed to the increased summertime midlatitude waviness in the past 40 years through the generation of a Rossby-wave-train propagating within the jet waveguide and the reduced north-south temperature gradient. This perspective indicates less of an influence from the Arctic amplification on the observed mid-latitude wave amplification than what was previously estimated. This study also emphasizes the need to better predict the tropical Pacific SST variability in order to project the summer jet waviness and consequent weather extremes.
Structure-based design of prefusion-stabilized human metapneumovirus fusion proteins
Authors: Hsieh Ching-Lin , Rush Scott A. , Palomo Concepcion , Chou Chia-Wei , Pickens Whitney , Más Vicente , McLellan Jason S.
Published: March 2022

The human metapneumovirus (hMPV) fusion (F) protein is essential for viral entry and is a key target of neutralizing antibodies and vaccine development. The prefusion conformation is thought to be the optimal vaccine antigen, but previously described prefusion F proteins expressed poorly and were not well stabilized. Here, we use structures of hMPV F to guide the design of 42 variants containing stabilizing substitutions. Through combinatorial addition of disulfide bonds, cavity-filling substitutions, and improved electrostatic interactions, we describe a prefusion-stabilized F protein (DS-CavEs2) that expresses at 15 mg/L and has a melting temperature of 71.9 °C. Crystal structures of two prefusion-stabilized hMPV F variants reveal that antigenic surfaces are largely unperturbed. Importantly, immunization of mice with DS-CavEs2 elicits significantly higher neutralizing antibody titers against hMPV A1 and B1 viruses than postfusion F. The improved properties of DS-CavEs2 will advance the development of hMPV vaccines and the isolation of therapeutic antibodies.
Little-Parks like oscillations in lightly doped cuprate superconductors
Authors: Liao Menghan , Zhu Yuying , Hu Shuxu , Zhong Ruidan , Schneeloch John , Gu Genda , Zhang Ding , Xue Qi-Kun
Published: March 2022

Understanding the rich and competing electronic orders in cuprate superconductors may provide important insight into the mechanism of high-temperature superconductivity. Here, by measuring Bi2Sr2CaCu2O8+x in the extremely underdoped regime, we obtain evidence for a distinct type of ordering, which manifests itself as resistance oscillations at low magnetic fields (≤10 T) and at temperatures around the superconducting transition. By tuning the doping level p continuously, we reveal that these low-field oscillations occur only when p < 0.1. The oscillation amplitude increases with decreasing p but the oscillation period stays almost constant. We show that these low-field oscillations can be well described by assuming a periodic superconducting structure with a mesh size of about 50 nm. Such a charge order, which is distinctly different from the well-established charge density wave and pair density wave, seems to be an unexpected piece of the puzzle on the correlated physics in cuprates.
Functional genomics of RAP proteins and their role in mitoribosome regulation in Plasmodium falciparum
Authors: Hollin Thomas , Abel Steven , Falla Alejandra , Pasaje Charisse Flerida A. , Bhatia Anil , Hur Manhoi , Kirkwood Jay S. , Saraf Anita , Prudhomme Jacques , De Souza Amancio , Florens Laurence , Niles Jacquin C. , Le Roch Karine G.
Published: March 2022

The RAP (RNA-binding domain abundant in Apicomplexans) protein family has been identified in various organisms. Despite expansion of this protein family in apicomplexan parasites, their main biological functions remain unknown. In this study, we use inducible knockdown studies in the human malaria parasite, Plasmodium falciparum, to show that two RAP proteins, PF3D7_0105200 (PfRAP01) and PF3D7_1470600 (PfRAP21), are essential for parasite survival and localize to the mitochondrion. Using transcriptomics, metabolomics, and proteomics profiling experiments, we further demonstrate that these RAP proteins are involved in mitochondrial RNA metabolism. Using high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (eCLIP-seq), we validate that PfRAP01 and PfRAP21 are true RNA-binding proteins and interact specifically with mitochondrial rRNAs. Finally, mitochondrial enrichment experiments followed by deep sequencing of small RNAs demonstrate that PfRAP21 controls mitochondrial rRNA expression. Collectively, our results establish the role of these RAP proteins in mitoribosome activity and contribute to further understanding this protein family in malaria parasites.
Loss of the Bardet-Biedl protein Bbs1 alters photoreceptor outer segment protein and lipid composition
Authors: Masek Markus , Etard Christelle , Hofmann Claudia , Hülsmeier Andreas J. , Zang Jingjing , Takamiya Masanari , Gesemann Matthias , Neuhauss Stephan C. F. , Hornemann Thorsten , Strähle Uwe , Bachmann-Gagescu Ruxandra
Published: March 2022

Primary cilia are key sensory organelles whose dysfunction leads to ciliopathy disorders such as Bardet-Biedl syndrome (BBS). Retinal degeneration is common in ciliopathies, since the outer segments (OSs) of photoreceptors are highly specialized primary cilia. BBS1, encoded by the most commonly mutated BBS-associated gene, is part of the BBSome protein complex. Using a bbs1 zebrafish mutant, we show that retinal development and photoreceptor differentiation are unaffected by Bbs1-loss, supported by an initially unaffected transcriptome. Quantitative proteomics and lipidomics on samples enriched for isolated OSs show that Bbs1 is required for BBSome-complex stability and that Bbs1-loss leads to accumulation of membrane-associated proteins in OSs, with enrichment in proteins involved in lipid homeostasis. Disruption of the tightly regulated OS lipid composition with increased OS cholesterol content are paralleled by early functional visual deficits, which precede progressive OS morphological anomalies. Our findings identify a role for Bbs1/BBSome in OS lipid homeostasis, suggesting a pathomechanism underlying retinal degeneration in BBS.
Long-range transport of 2D excitons with acoustic waves
Authors: Peng Ruoming , Ripin Adina , Ye Yusen , Zhu Jiayi , Wu Changming , Lee Seokhyeong , Li Huan , Taniguchi Takashi , Watanabe Kenji , Cao Ting , Xu Xiaodong , Li Mo
Published: March 2022

Excitons are elementary optical excitation in semiconductors. The ability to manipulate and transport these quasiparticles would enable excitonic circuits and devices for quantum photonic technologies. Recently, interlayer excitons in 2D semiconductors have emerged as a promising candidate for engineering excitonic devices due to their long lifetime, large exciton binding energy, and gate tunability. However, the charge-neutral nature of the excitons leads to weak response to the in-plane electric field and thus inhibits transport beyond the diffusion length. Here, we demonstrate the directional transport of interlayer excitons in bilayer WSe2 driven by the propagating potential traps induced by surface acoustic waves (SAW). We show that at 100 K, the SAW-driven excitonic transport is activated above a threshold acoustic power and reaches 20 μm, a distance at least ten times longer than the diffusion length and only limited by the device size. Temperature-dependent measurement reveals the transition from the diffusion-limited regime at low temperature to the acoustic field-driven regime at elevated temperature. Our work shows that acoustic waves are an effective, contact-free means to control exciton dynamics and transport, promising for realizing 2D materials-based excitonic devices such as exciton transistors, switches, and transducers up to room temperature.
Alternative trastuzumab dosing strategies in HER2-positive early breast cancer are associated with patient out-of-pocket savings
Authors: Hsieh Po-Hung , Kacew Alec J. , Dreyer Marie , Serritella Anthony V. , Knoebel Randall W. , Strohbehn Garth W. , Ratain Mark J.
Published: March 2022

Patients with breast cancer frequently experience financial hardship, often due to the high costs of anti-cancer drugs. We sought to develop alternative trastuzumab dosing strategies, compare their pharmacokinetic effectiveness to standard dosing, and assess the expected financial implications of transitioning to them. We extracted clinical data from the records of 135 retrospectively identified patients with HER2-positive early breast cancer at a single, urban comprehensive cancer center who were treated with trastuzumab between 2017 and 2019. We performed pharmacokinetic simulations on a range of trastuzumab dose levels and frequencies, assessing efficacy by trough trastuzumab concentration (Ctrough) and population and individual likelihoods of Ctrough exceeding trastuzumab minimum effective concentration (MEC). We performed deterministic financial modeling to estimate the treatment-associated financial savings from alternative dosing strategies. Trastuzumab maintenance doses of 4 mg/kg every 3 weeks (Q3W) and 6 mg/kg every 4 weeks (Q4W) had nearly identical probabilities of Ctrough being above MEC as standard of care 6 mg/kg every 3 weeks. In the primary financial analysis, both trastuzumab 4 mg/kg Q3W and 6 mg/kg Q4W were associated with significant drug- and administration-related out-of-pocket cost savings over the duration of therapy, ranging from $765 (neoadjuvant, Q4W) to $2791 (adjuvant, Q4W). In particular, Q4W trastuzumab increased savings related to lost wages and travel cost avoidance. Low-dose and reduced frequency trastuzumab in appropriately selected patients may significantly reduce total drug utilization and meaningfully reduce patient financial toxicity. Prospective clinical trials evaluating low-dose or reduced-frequency administration of therapeutic monoclonal antibodies are warranted and needed.
A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution
Authors: Zhu Tianyu , Liu Jacklyn , Beck Stephan , Pan Sun , Capper David , Lechner Matt , Thirlwell Chrissie , Breeze Charles E. , Teschendorff Andrew E.
Published: March 2022

Bulk-tissue DNA methylomes represent an average over many different cell types, hampering our understanding of cell-type-specific contributions to disease development. As single-cell methylomics is not scalable to large cohorts of individuals, cost-effective computational solutions are needed, yet current methods are limited to tissues such as blood. Here we leverage the high-resolution nature of tissue-specific single-cell RNA-sequencing datasets to construct a DNA methylation atlas defined for 13 solid tissue types and 40 cell types. We comprehensively validate this atlas in independent bulk and single-nucleus DNA methylation datasets. We demonstrate that it correctly predicts the cell of origin of diverse cancer types and discovers new prognostic associations in olfactory neuroblastoma and stage 2 melanoma. In brain, the atlas predicts a neuronal origin for schizophrenia, with neuron-specific differential DNA methylation enriched for corresponding genome-wide association study risk loci. In summary, the DNA methylation atlas enables the decomposition of 13 different human tissue types at a high cellular resolution, paving the way for an improved interpretation of epigenetic data.
A long-term dataset of topography and nearshore bathymetry at the macrotidal pocket beach of Porsmilin, France
Authors: Bertin Stéphane , Floc’h France , Le Dantec Nicolas , Jaud Marion , Cancouët Romain , Franzetti Marcaurélio , Cuq Véronique , Prunier Christophe , Ammann Jérôme , Augereau Emmanuel , Lamarche Stevenn , Belleney Déborah , Rouan Mathias , David Laurence , Deschamps Anne , Delacourt Christophe , Suanez Serge
Published: March 2022

Long-term datasets documenting the evolution of coastal forms and processes, through the provision of recurring beach as well as shoreface morphological observations and accompanying time-series of environmental controls, remain difficult to collect and are rarely made available. However, they are increasingly needed to further our understanding of coastal change and to improve the models that will help planning what our future coast will be. This data descriptor presents the results of topographic and bathymetric surveys at Porsmilin, a macrotidal embayed beach situated in Brittany, northwest France. The Porsmilin beach survey program was launched in January 2003 by the Institut Universitaire Européen de la Mer (IUEM/Univ. Brest) and is continuing today in the framework of the French coastal observation service SNO-DYNALIT. The dataset contains over 16 years of monthly beach profile surveys and a large collection of repeated high-resolution subtidal and subaerial digital elevation models (DEMs). The dataset is accompanied by time-series of inshore waves and water levels, and enriched metadata, that will facilitate its future reuse in coastal research.
Housing unit and urbanization estimates for the continental U.S. in consistent tract boundaries, 1940–2019
Authors: Markley Scott N. , Holloway Steven R. , Hafley Taylor J. , Hauer Mathew E.
Published: March 2022

Subcounty housing unit counts are important for studying geo-historical patterns of (sub)urbanization, land-use change, and residential loss and gain. The most commonly used subcounty geographical unit for social research in the United States is the census tract. However, the changing geometries and historically incomplete coverage of tracts present significant obstacles for longitudinal analysis that existing datasets do not sufficiently address. Overcoming these barriers, we provide housing unit estimates in consistent 2010 tract boundaries for every census year from 1940 to 2010 plus 2019 for the entire continental US. Moreover, we develop an “urbanization year” indicator that denotes if and when tracts became “urbanized” during this timeframe. We produce these data by blending existing interpolation techniques with a novel procedure we call “maximum reabsorption.” Conducting out-of-sample validation, we find that our hybrid approach generally produces more reliable estimates than existing alternatives. The final dataset, Historical Housing Unit and Urbanization Database 2010 (HHUUD10), has myriad potential uses for research involving housing, population, and land-use change, as well as (sub)urbanization.
Global seasonal Sentinel-1 interferometric coherence and backscatter data set
Authors: Kellndorfer Josef , Cartus Oliver , Lavalle Marco , Magnard Christophe , Milillo Pietro , Oveisgharan Shadi , Osmanoglu Batu , Rosen Paul A. , Wegmüller Urs
Published: March 2022

This data set is the first-of-its-kind spatial representation of multi-seasonal, global C-band Synthetic Aperture Radar (SAR) interferometric repeat-pass coherence and backscatter signatures. Coverage comprises land masses and ice sheets from 82° Northern to 79° Southern latitudes. The data set is derived from multi-temporal repeat-pass interferometric processing of about 205,000 Sentinel-1 C-band SAR images acquired in Interferometric Wide-Swath Mode from 1-Dec-2019 to 30-Nov-2020. The data set encompasses three sets of seasonal (December-February, March-May, June-August, September-November) metrics produced with a pixel spacing of three arcseconds: 1) Median 6-, 12-, 18-, 24-, 36-, and 48-days repeat-pass coherence at VV or HH polarizations, 2) Mean radiometrically terrain corrected backscatter (γ0) at VV and VH, or HH and HV polarizations, and 3) Estimated parameters of an exponential coherence decay model. The data set has been produced to obtain global, spatially detailed information on how decorrelation affects interferometric measurements of surface displacement and is rich in spatial and temporal information for a variety of mapping applications.
A comprehensive catalogue of plant-pollinator interactions for Chile
Authors: Muschett Giselle , Fontúrbel Francisco E.
Published: March 2022

Pollinators and pollination services provide invaluable ecosystem services to agriculture and contribute to the maintenance of biodiversity. In Chile, pollination contributes greatly to the diversity of native ecosystems and provides ecosystem services to crops, but local pollinator abundance and diversity, as well as plant-animal interactions, remain poorly understood. We compiled all available information from the published scientific literature on pollinators, flower visitors, and plant-pollinator interactions in Chile and found 120 publications from which we extracted 2619 records. Those records contain locality, habit type, and establishment means of 357 plant species from 83 families. Thus, we built a database compiling information on their pollinators and flower visitors, including information on 492 pollinator species from 97 families and 13 orders. Our database provides the first systematisation of information about pollinators and pollination in Chile. This country relies heavily on pollinators both for its agricultural industry and its unique and highly endemic biodiversity. This information can be reused in future studies and would contribute significantly to pollinator conservation strategies.
A hybrid machine learning/deep learning COVID-19 severity predictive model from CT images and clinical data
Authors: Chieregato Matteo , Frangiamore Fabio , Morassi Mauro , Baresi Claudia , Nici Stefania , Bassetti Chiara , Bnà Claudio , Galelli Marco
Published: March 2022

COVID-19 clinical presentation and prognosis are highly variable, ranging from asymptomatic and paucisymptomatic cases to acute respiratory distress syndrome and multi-organ involvement. We developed a hybrid machine learning/deep learning model to classify patients in two outcome categories, non-ICU and ICU (intensive care admission or death), using 558 patients admitted in a northern Italy hospital in February/May of 2020. A fully 3D patient-level CNN classifier on baseline CT images is used as feature extractor. Features extracted, alongside with laboratory and clinical data, are fed for selection in a Boruta algorithm with SHAP game theoretical values. A classifier is built on the reduced feature space using CatBoost gradient boosting algorithm and reaching a probabilistic AUC of 0.949 on holdout test set. The model aims to provide clinical decision support to medical doctors, with the probability score of belonging to an outcome class and with case-based SHAP interpretation of features importance.
DNA- and RNA-based bacterial communities and geochemical zonation under changing sediment porewater dynamics on the Aldabra Atoll
Authors: von Hoyningen-Huene Avril Jean Elisabeth , Schneider Dominik , Fussmann Dario , Reimer Andreas , Arp Gernot , Daniel Rolf
Published: March 2022

The remote Aldabra Atoll, Seychelles, provides the rare opportunity to study bacterial communities in pristine carbonate sediments across an entire biome. The four sampled sites cover sand with high porewater exchange, bioturbated silt and mud with intermediate exchange, as well as a seasonally and episodically desiccated landlocked pool. As sediments harbour dead cells and environmental DNA alongside live cells, we used bacterial 16S rRNA gene and transcript analysis to distinguish between past and present inhabitants. Previously described laminated sediments mirroring past conditions in the Cerin, France could not be retrieved. Thus, the aim was adjusted to determine whether bacterial community composition and diversity follow typical geochemical zonation patterns at different locations of the atoll. Our data confirm previous observations that diversity decreases with depth. In the lagoon, the bacterial community composition changed from Pseudomonas dominating in the sand to diverse mixed surface and sulphate reduction zones in the anaerobic mud with strongly negative Eh. The latter correlated with high total alkalinity, ammonia, and total sulphide, alongside a decrease in SO42−/Cl− and high relative abundances of sulphate reducing (Halo-) Desulfovibrio, sulphur oxidizing Arcobacteraceae, photo(hetero)troph Cyanobacteria, Alphaproteobacteria, and fermenting Propionigenium. In contrast to expectations, deeper mud and pool sediments harboured high abundances of Halomonas or Alphaproteobacteria alongside high C/N and increased salinity. We believe that this atypical community shift may be driven by a change in the complexity of available organic matter.
Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1
Authors: Chasman Daniel I. , Hyde Craig L. , Giulianini Franco , Danning Rebecca D. , Wang Ellen Q. , Hickling Timothy , Ridker Paul M , Loomis A. Katrina
Published: March 2022

In this largest to-date genetic analysis of anti-drug antibody (ADA) response to a therapeutic monoclonal antibody (MAb), genome-wide association was performed for five measures of ADA status among 8844 individuals randomized to bococizumab, which targets PCSK9 for LDL-C lowering and cardiovascular protection. Index associations prioritized specific amino acid substitutions at theDRB1andDQB1MHC class II genes rather than canonical haplotypes. Two clusters of missense variants atDRB1were associated with general ADA measures (residues 9, 11, 13; and 96, 112, 120, 180) and a third cluster of missense variants inDQB1was associated with ADA measures including neutralizing antibody (NAb) titers (residues 66, 67, 71, 74, 75). The structural disposition of the missense substitutions implicates peptide antigen binding and CD4 effector function, mechanisms that are potentially generalizable to other therapeutic mAbs.

Clinicaltrials.gov: NCT01968954, NCT01968967, NCT01968980, NCT01975376, NCT01975389, NCT02100514.
Quantitative interocular comparison of total corneal surface area and corneal diameter in patients with highly asymmetric keratoconus
Authors: Crahay François-Xavier , Debellemanière Guillaume , Tobalem Stephan , Ghazal Wassim , Moran Sarah , Gatinel Damien
Published: March 2022

Keratoconus is a progressive corneal disorder which is frequently asymmetric. The aetiology of keratoconus remains unclear, and the concept of keratoconus as an ectatic disorder has been challenged recently. We carried out a retrospective study in 160 eyes of 80 patients, to evaluate and compare interocular differences in corneal diameter and surface area in patients with unilateral or highly asymmetric keratoconus (UHAKC). Calculations were performed using raw topographic elevation data derived from topographic measurements using Orbscan II, and we extrapolated surface areas up to measured corneal diameter. We also evaluated inter-eye correlation, and correlation between corneal surface area, corneal diameter and keratoconus severity. Our results showed a statistically significant but not clinically important greater corneal diameter (12.14 mm and 12.17 mm; p = 0.04), and corneal surface area (paired t-test, p < 0.0001; p = 0.0009 respectively) in more affected eyes. Inter-eye comparison revealed corneal diameter, anterior chamber depth, and corneal surface area were strongly correlated between eyes. Corneal surface area remained strongly correlated, and Bland–Altman analysis also showed strong inter-ocular agreement. Our results show that in patients with UHAKC the interocular difference in corneal diameter and corneal surface area is clinically insignificant, and are consistent with a redistribution, rather than increase, of corneal surface area with keratoconus progression.