bluuebunny/crossref_metadata_2025 huggingface dataset:
CRIME AND PUNISHMENT: ADAM SMITH’S THEORY OF SENTIMENTAL LAW AND ECONOMICS
Authors: Paganelli Maria Pia , Simon Fabrizio
Published: April 2022

For Adam Smith, a crime is not the result of a rational calculation of loss and gain but the consequence of envy and a vain desire to parade wealth to attract the approbation of others, combined with a natural systematic bias in overestimating the probability of success. Similarly, Smith does not conceive of legal sanctions as a rational deterrent but as deriving from the feeling of resentment. While the prevailing approach of the eighteenth century is a rational explanation of crime and a utilitarian use of punishment, Adam Smith instead builds his theory of criminal behavior and legal prosecution consistently on the sentiments. A well-functioning legal system is thus an unintended consequence of our desire to bring justice to the individual person, not the result of a rational calculation to promote the public good, just like a well-functioning economic system is the unintended consequence of our desire to better our own condition, not the result of a rational calculation to promote public good.
Are all children treated equally? Psychiatric care and treatment receipt among migrant, descendant and majority Swedish children: a register-based study
Authors: Gubi Ester , Sjöqvist Hugo , Dalman Christina , Bäärnhielm Sofie , Hollander Anna-Clara
Published: April 2022

Aims

Underutilisation of mental health services among migrant youth has been demonstrated repeatedly, but little is known about potential discrepancies in terms of treatment receipt for those who do reach services. This study examines the type and level of care received among migrant children and descendants of migrants, particularly investigating disparities in treatment receipt given a specific diagnosis.

Methods

We used register data of the total population aged 6–17 years in Stockholm, followed from 2006 to 2015, comprising 444 196 individuals, categorised as refugees, non-refugee migrants, descendants of migrants and Swedish-born. To identify recommended treatments for specific diagnoses we used official clinical guidelines. We report logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) of diagnosis receipt, treatment provision and level of care where a diagnosis was first registered.

Results

Migrant children had a lower likelihood of receiving a wide range of psychiatric diagnoses, including mood disorder (OR 0.58; 95% CI 0.52–0.64), anxiety disorder (OR 0.62; 95% CI 0.57–69) and neurodevelopmental disorder (OR 0.59; 95% CI 0.55–0.63). Moreover, when these diagnoses were set, migrant children had a lower likelihood of receiving the recommended treatments for these conditions compared to the majority individuals with the same diagnosis (OR of receiving psychotherapy for anxiety disorder and depression: 0.71; 95% CI 0.62–0.95 and 0.50; 95% CI 0.33–0.75, respectively; OR for receiving ADHD-medication: 0.49; 95% CI 0.43–0.54).

Conclusions

Migrant children risk underdiagnosis of various mental health conditions, and, when reaching mental health services, risk not receiving the optimal care available.
Interannual Variability and Multiyear Trends of Sea Surface Salinity in the Amazon‐Orinoco Plume Region From Satellite Observations and an Ocean Reanalysis
Authors: Da Nguyen Dac , Foltz Gregory R.
Published: April 2022

The Amazon and Orinoco Rivers form the largest river system on Earth with wide‐reaching impacts on the biophysical climate of the region. Based on 11 years of satellite observations, here we show strong interannual variability of sea surface salinity (SSS) in the plume region that is about three times larger than in the surrounding region. This variability has been driven mainly by changes in horizontal advection of the plume with smaller contributions from precipitation, river discharge, and vertical mixing. Interannual variability of horizontal advection occurs mainly near the eastern boundary of the plume region and especially in the latitude range of the North Equatorial Countercurrent (3°–10°N). The North Atlantic Oscillation (NAO) and El Niño Southern Oscillation (ENSO) strongly modulate SSS in the plume region during the boreal spring‐summer (flood) and fall‐winter (dry) seasons, respectively, through their impacts on the tropical North Atlantic Ocean circulation. Overall, the NAO exerts a stronger influence on plume SSS than ENSO. The plume SSS also shows a significant upward trend during 2010–2016, corresponding to transitions of the NAO and ENSO from negative to positive phases. This was followed by a downward trend during 2017–2020 when both the NAO and ENSO decreased from their 2015–2016 peaks. These results show that year‐to‐year changes in the spatial mean SSS of the Amazon‐Orinoco plume are driven mainly by large‐scale climate forcings and their associated imprints on tropical Atlantic Ocean circulation and very little by changes in river outflow and associated rainfall over land.
Estimating Hydraulic Properties of the Shallow Subsurface Using the Groundwater Response to Earth and Atmospheric Tides: A Comparison With Pumping Tests
Authors: Valois Rémi , Rau Gabriel C. , Vouillamoz Jean‐Michel , Derode Benoit
Published: April 2022

Estimating subsurface hydraulic properties using the groundwater (GW) response to Earth tides (ET) and atmospheric pressure is an alternative approach to pumping or slug tests (passive vs. active methods). Yet testing the applicability of models under different subsurface conditions and comparing results with traditional hydraulic methods are lacking. We first review the assumptions of analytical models used to evaluate the GW response to ET and their applicability in unconfined to confined conditions. Second, we develop a robust approach to select the right model based on amplitude and phase pattern of the diurnal and semi‐diurnal tides. Third, based on earlier works we develop an approach to derive the hydraulic conductivity of the screened interval using the GW response to atmospheric tides, here named “atmospheric slug test” (AST). We estimate transmissivity and storativity at three shallow aquifers in Cambodia and compare the results with subsurface properties derived from pumping tests (PT). Transmissivity values from AST and PT are in good agreement. However, we show that storativity values derived from ET show large discrepancies if borehole skin effects are ignored. Further, the GW response to ET exhibits a strong decay in amplitude with frequency while maintaining close to zero and positive phase shifts. When supplemented with the calculated transmissivity values, none of the analytical models was able to reproduce this frequency dependent behavior. Our work emphasizes the need for evaluating passive methods robustness under different subsurface conditions. Further work is required to understand the frequency dependent GW response to natural or artificial forces.
RNA therapy: rich history, various applications and unlimited future prospects
Authors: Kim Young-Kook
Published: April 2022

RNA therapy refers to the treatment or prevention of diseases using RNA-based molecules. The recent advent of a series of effective messenger RNA-based vaccines in response to the COVID-19 pandemic has reignited research interest in RNA therapy. Based on the accumulated results of long-term research in the field of RNA therapy spanning several decades, therapeutic agents for various diseases are being rapidly developed. These therapeutics tend to target diseases that cannot be treated with other conventional drug groups, and several clinical studies are underway for a variety of RNA-based therapeutics against various incurable diseases. This review describes the history of several important discoveries in RNA biology and their impact on key developments in RNA therapy as well as the advantages of RNA therapy. In addition, it describes the action mechanisms and examples of drugs approved for RNA therapy. Finally, this review discusses methods for RNA drug delivery to target organs and cells. Given that RNA therapy is expected to advance and play an integral role in the development of novel therapeutic agents for human diseases in the future, this review is designed to offer an updated reference point for researchers in this field.
Metasurface-Based Imagers Enabled Arbitrary Optical Convolution Processing
Authors: Park Minsu , Park Yeonsang
Published: April 2022

Using meta-imagers composed of a meta-lens and a complex-amplitude meta-modulator, all-optical convolutional processing that arbitrarily reshapes the point spread function of an optical system can now be implemented.
Catestatin selects for colonization of antimicrobial-resistant gut bacterial communities
Authors: González-Dávila Pamela , Schwalbe Markus , Danewalia Arpit , Dalile Boushra , Verbeke Kristin , Mahata Sushil K , El Aidy Sahar
Published: April 2022

The gut microbiota is in continuous interaction with the innermost layer of the gut, namely the epithelium. One of the various functions of the gut epithelium, is to keep the microbes at bay to avoid overstimulation of the underlying mucosa immune cells. To do so, the gut epithelia secrete a variety of antimicrobial peptides, such as chromogranin A (CgA) peptide catestatin (CST: hCgA352-372). As a defense mechanism, gut microbes have evolved antimicrobial resistance mechanisms to counteract the killing effect of the secreted peptides. To this end, we treated wild-type mice and CST knockout (CST-KO) mice (where only the 63 nucleotides encoding CST have been deleted) with CST for 15 consecutive days. CST treatment was associated with a shift in the diversity and composition of the microbiota in the CST-KO mice. This effect was less prominent in WT mice. Levels of the microbiota-produced short-chain fatty acids, in particular, butyrate and acetate were significantly increased in CST-treated CST-KO mice but not the WT group. Both CST-treated CST-KO and WT mice showed a significant increase in microbiota-harboring phosphoethanolamine transferase-encoding genes, which facilitate their antimicrobial resistance. Finally, we show that CST was degraded by Escherichia coli via an omptin-protease and that the abundance of this gene was significantly higher in metagenomic datasets collected from patients with Crohn’s disease but not with ulcerative colitis. Overall, this study illustrates how the endogenous antimicrobial peptide, CST, shapes the microbiota composition in the gut and primes further research to uncover the role of bacterial resistance to CST in disease states such as inflammatory bowel disease.
First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study
Authors: Van Cutsem E. , Danielewicz I. , Saunders M. P. , Pfeiffer P. , Argilés G. , Borg C. , Glynne-Jones R. , Punt C. J. A. , Van de Wouw A. J. , Fedyanin M. , Stroyakovskiy D. , Kroening H. , Garcia-Alfonso P. , Wasan H. , Falcone A. , Fougeray R. , Egorov A. , Amellal N. , Moiseyenko V.
Published: April 2022

Background

Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results.

Methods

TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1–5 and 8–12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1–14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS.

Results

At 1 September 2020, median OS was 22.3 months (95% CI: 18.0–23.7) with TT-B and 17.7 months (95% CI: 12.6–19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55–1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings.

Conclusions

TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy.

Clinical trial information

NCT02743221 (clinicaltrials.gov)
Aberrant promoter methylation contributes to LRIG1 silencing in basal/triple-negative breast cancer
Authors: Umeh-Garcia Maxine , O’Geen Henriette , Simion Catalina , Gephart Melanie Hayden , Segal David J. , Sweeney Colleen A.
Published: April 2022

Background

LRIG1, the founding member of the LRIG (leucine-rich repeat and immunoglobulin-like domain) family of transmembrane proteins, is a negative regulator of receptor tyrosine kinases and a tumour suppressor. Decreased LRIG1 expression is consistently observed in cancer, across diverse tumour types, and is linked to poor patient prognosis. However, mechanisms by which LRIG1 is repressed are not fully understood. Silencing of LRIG1 through promoter CpG island methylation has been reported in colorectal and cervical cancer but studies in breast cancer remain limited.

Methods

In silico analysis of human breast cancer patient data were used to demonstrate a correlation between DNA methylation and LRIG1 silencing in basal/triple-negative breast cancer, and its impact on patient survival. LRIG1 gene expression, protein abundance, and methylation enrichment were examined by quantitative reverse-transcription PCR, immunoblotting, and methylation immunoprecipitation, respectively, in breast cancer cell lines in vitro. We examined the impact of global demethylation on LRIG1 expression and methylation enrichment using 5-aza-2’-deoxycytidine. We also examined the effects of targeted demethylation of the LRIG1 CpG island, and transcriptional activation of LRIG1 expression, using the RNA guided deadCas9 transactivation system.

Results

Across breast cancer subtypes, LRIG1 expression is lowest in the basal/triple-negative subtype so we investigated whether differential methylation may contribute to this. Indeed, we find that LRIG1 CpG island methylation is most prominent in basal/triple-negative cell lines and patient samples. Use of the global demethylating agent 5-aza-2’-deoxycytidine decreases methylation leading to increased LRIG1 transcript expression in basal/triple-negative cell lines, while having no effect on LRIG1 expression in luminal/ER-positive cell lines. Using a CRISPR/deadCas9 (dCas9)-based targeting approach, we demonstrate that TET1-mediated demethylation (Tet1-dCas9) along with VP64-mediated transcriptional activation (VP64-dCas9) at the CpG island, increased endogenous LRIG1 expression in basal/triple-negative breast cancer cells, without transcriptional upregulation at predicted off-target sites. Activation of LRIG1 by the dCas9 transactivation system significantly increased LRIG1 protein abundance, reduced site-specific methylation, and reduced cancer cell viability. Our findings suggest that CRISPR-mediated targeted activation may be a feasible way to restore LRIG1 expression in cancer.

Conclusions

Our study contributes novel insight into mechanisms which repress LRIG1 in triple-negative breast cancer and demonstrates for the first time that targeted de-repression of LRIG1 in cancer cells is possible. Understanding the epigenetic mechanisms associated with repression of tumour suppressor genes holds potential for the advancement of therapeutic approaches.
ROR activation by Nobiletin enhances antitumor efficacy via suppression of IκB/NF-κB signaling in triple-negative breast cancer
Authors: Kim Eunju , Kim Yoon-Jin , Ji Zhiwei , Kang Jin Muk , Wirianto Marvin , Paudel Keshav Raj , Smith Joshua A. , Ono Kaori , Kim Jin-Ah , Eckel-Mahan Kristin , Zhou Xiaobo , Lee Hyun Kyoung , Yoo Ji Young , Yoo Seung-Hee , Chen Zheng
Published: April 2022

Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by poor response to standard therapies and therefore unfavorable clinical outcomes. Better understanding of TNBC and new therapeutic strategies are urgently needed. ROR nuclear receptors are multifunctional transcription factors with important roles in circadian pathways and other processes including immunity and tumorigenesis. Nobiletin (NOB) is a natural compound known to display anticancer effects, and our previous studies showed that NOB activates RORs to enhance circadian rhythms and promote physiological fitness in mice. Here, we identified several TNBC cell lines being sensitive to NOB, by itself or in combination. Cell and xenograft experiments showed that NOB significantly inhibited TNBC cell proliferation and motility in vitro and in vivo. ROR loss- and gain-of-function studies showed concordant effects of the NOB–ROR axis on MDA-MB-231 cell growth. Mechanistically, we found that NOB activates ROR binding to the ROR response elements (RRE) of the IκBα promoter, and NOB strongly inhibited p65 nuclear translocation. Consistent with transcriptomic analysis indicating cancer and NF-κB signaling as major pathways altered by NOB, p65-inducible expression abolished NOB effects, illustrating a requisite role of NF-κB suppression mediating the anti-TNBC effect of NOB. Finally, in vivo mouse xenograft studies showed that NOB enhanced the antitumor efficacy in mammary fat pad implanted TNBC, as a single agent or in combination with the chemotherapy agent Docetaxel. Together, our study highlights an anti-TNBC mechanism of ROR-NOB via suppression of NF-κB signaling, suggesting novel preventive and chemotherapeutic strategies against this devastating disease.
UHRF1 establishes crosstalk between somatic and germ cells in male reproduction
Authors: Wu Yanqing , Duan Peng , Wen Yujiao , Zhang Jin , Wang Xiaoli , Dong Juan , Zhao Qiang , Feng Shenglei , Lv Chunyu , Guo Yang , Namekawa Satoshi H. , Yuan Shuiqiao
Published: April 2022

Sertoli cells (SCs) support and nourish germ cells (GCs) through their crosstalk during spermatogenesis. However, the underlying epigenetic mechanism that ensures SCs’ functions in this process remains unclear. Here, we report that UHRF1, a critical epigenetic regulator, is mainly expressed in human and mouse pre-mature SCs, and is essential for establishing Sertoli-Germ cell crosstalk. SC-specific UHRF1 knockout mice exhibit complete sterility with Sertoli cell (SC) proliferation and differentiation aberrance, blood-testis barrier (BTB) disruption, and immature germ cell (GC) sloughing. RNA sequencing and Whole Genome Bisulfite Sequencing (WGBS) revealed that many extracellular matrix (ECM)-related genes (e.g., Timp1, Trf, and Spp1) appeared upregulated with the DNA hypomethylation status in UHRF1-deficient SCs. Strikingly, overexpression of Timp1, Trf, and Spp1 in SCs in vitro and in vivo could phenocopy the SC-specific UHRF1-deficient mice. Our data demonstrated that UHRF1 regulates the transcriptional program of ECM-related genes in SCs and establishes SC-GC crosstalk.
Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes
Authors: Lehman Norman L. , Spassky Nathalie , Sak Müge , Webb Amy , Zumbar Cory T. , Usubalieva Aisulu , Alkhateeb Khaled J. , McElroy Joseph P. , Maclean Kirsteen H. , Fadda Paolo , Liu Tom , Gangalapudi Vineela , Carver Jamie , Abdullaev Zied , Timmers Cynthia , Parker John R. , Pierson Christopher R. , Mobley Bret C. , Gokden Murat , Hattab Eyas M. , Parrett Timothy , Cooke Ralph X. , Lehman Trang D. , Costinean Stefan , Parwani Anil , Williams Brian J. , Jensen Randy L. , Aldape Kenneth , Mistry Akshitkumar M.
Published: April 2022

Astroblastomas (ABs) are rare brain tumors of unknown origin. We performed an integrative genetic and epigenetic analysis of AB-like tumors. Here, we show that tumors traceable to neural stem/progenitor cells (radial glia) that emerge during early to later brain development occur in children and young adults, respectively. Tumors with MN1-BEND2 fusion appear to present exclusively in females and exhibit overexpression of genes expressed prior to 25 post-conception weeks (pcw), including genes enriched in early ventricular zone radial glia and ependymal tumors. Other, histologically classic ABs overexpress or harbor mutations of mitogen-activated protein kinase pathway genes, outer and truncated radial glia genes, and genes expressed after 25 pcw, including neuronal and astrocyte markers. Findings support that AB-like tumors arise in the context of epigenetic and genetic changes in neural progenitors. Selective gene fusion, variable imprinting and/or chromosome X-inactivation escape resulting in biallelic overexpression may contribute to female predominance of AB molecular subtypes.
Normalizing and denoising protein expression data from droplet-based single cell profiling
Authors: Mulè Matthew P. , Martins Andrew J. , Tsang John S.
Published: April 2022

Multimodal single-cell profiling methods that measure protein expression with oligo-conjugated antibodies hold promise for comprehensive dissection of cellular heterogeneity, yet the resulting protein counts have substantial technical noise that can mask biological variations. Here we integrate experiments and computational analyses to reveal two major noise sources and develop a method called “dsb” (denoised and scaled by background) to normalize and denoise droplet-based protein expression data. We discover that protein-specific noise originates from unbound antibodies encapsulated during droplet generation; this noise can thus be accurately estimated and corrected by utilizing protein levels in empty droplets. We also find that isotype control antibodies and the background protein population average in each cell exhibit significant correlations across single cells, we thus use their shared variance to correct for cell-to-cell technical noise in each cell. We validate these findings by analyzing the performance of dsb in eight independent datasets spanning multiple technologies, including CITE-seq, ASAP-seq, and TEA-seq. Compared to existing normalization methods, our approach improves downstream analyses by better unmasking biologically meaningful cell populations. Our method is available as an open-source R package that interfaces easily with existing single cell software platforms such as Seurat, Bioconductor, and Scanpy and can be accessed at “dsb [https://cran.r-project.org/package=dsb]”.
The statistical geometry of material loops in turbulence
Authors: Bentkamp Lukas , Drivas Theodore D. , Lalescu Cristian C. , Wilczek Michael
Published: April 2022

Material elements – which are lines, surfaces, or volumes behaving as passive, non-diffusive markers – provide an inherently geometric window into the intricate dynamics of chaotic flows. Their stretching and folding dynamics has immediate implications for mixing in the oceans or the atmosphere, as well as the emergence of self-sustained dynamos in astrophysical settings. Here, we uncover robust statistical properties of an ensemble of material loops in a turbulent environment. Our approach combines high-resolution direct numerical simulations of Navier-Stokes turbulence, stochastic models, and dynamical systems techniques to reveal predictable, universal features of these complex objects. We show that the loop curvature statistics become stationary through a dynamical formation process of high-curvature folds, leading to distributions with power-law tails whose exponents are determined by the large-deviations statistics of finite-time Lyapunov exponents of the flow. This prediction applies to advected material lines in a broad range of chaotic flows. To complement this dynamical picture, we confirm our theory in the analytically tractable Kraichnan model with an exact Fokker-Planck approach.
Double ridge formation over shallow water sills on Jupiter’s moon Europa
Authors: Culberg Riley , Schroeder Dustin M. , Steinbrügge Gregor
Published: April 2022

Jupiter’s moon Europa is a prime candidate for extraterrestrial habitability in our solar system. The surface landforms of its ice shell express the subsurface structure, dynamics, and exchange governing this potential. Double ridges are the most common surface feature on Europa and occur across every sector of the moon, but their formation is poorly understood, with current hypotheses providing competing and incomplete mechanisms for the development of their distinct morphology. Here we present the discovery and analysis of a double ridge in Northwest Greenland with the same gravity-scaled geometry as those found on Europa. Using surface elevation and radar sounding data, we show that this double ridge was formed by successive refreezing, pressurization, and fracture of a shallow water sill within the ice sheet. If the same process is responsible for Europa’s double ridges, our results suggest that shallow liquid water is spatially and temporally ubiquitous across Europa’s ice shell.
Regulated interaction of ID2 with the anaphase-promoting complex links progression through mitosis with reactivation of cell-type-specific transcription
Authors: Lee Sang Bae , Garofano Luciano , Ko Aram , D’Angelo Fulvio , Frangaj Brulinda , Sommer Danika , Gan Qiwen , Kim KyeongJin , Cardozo Timothy , Iavarone Antonio , Lasorella Anna
Published: April 2022

Tissue-specific transcriptional activity is silenced in mitotic cells but it remains unclear whether the mitotic regulatory machinery interacts with tissue-specific transcriptional programs. We show that such cross-talk involves the controlled interaction between core subunits of the anaphase-promoting complex (APC) and the ID2 substrate. The N-terminus of ID2 is independently and structurally compatible with a pocket composed of core APC/C subunits that may optimally orient ID2 onto the APCCDH1 complex. Phosphorylation of serine-5 by CDK1 prevented the association of ID2 with core APC, impaired ubiquitylation and stabilized ID2 protein at the mitosis-G1 transition leading to inhibition of basic Helix-Loop-Helix (bHLH)-mediated transcription. The serine-5 phospho-mimetic mutant of ID2 that inefficiently bound core APC remained stable during mitosis, delayed exit from mitosis and reloading of bHLH transcription factors on chromatin. It also locked cells into a “mitotic stem cell” transcriptional state resembling the pluripotent program of embryonic stem cells. The substrates of APCCDH1 SKP2 and Cyclin B1 share with ID2 the phosphorylation-dependent, D-box-independent interaction with core APC. These results reveal a new layer of control of the mechanism by which substrates are recognized by APC.
Skeletal Ni electrode-catalyzed C-O cleavage of diaryl ethers entails direct elimination via benzyne intermediates
Authors: Zhou Yuting , Klinger Grace E. , Hegg Eric L. , Saffron Christopher M. , Jackson James E.
Published: April 2022

Diaryl ethers undergo electrocatalytic hydrogenolysis (ECH) over skeletal Ni cathodes in a mild, aqueous process that achieves direct C-O cleavage without initial benzene ring saturation. Mechanistic studies find that aryl phenyl ethers with a single para or meta functional group (methyl, methoxy, or hydroxy) are selectively cleaved to the substituted benzene and phenol, in contrast to recently reported homogeneous catalytic cleavage processes. Ortho positioning of substituents reverses this C-O bond selectivity, except for the 2-phenoxyphenol case. Together with isotope labeling and co-solvent studies, these results point to two distinct cleavage mechanisms: (a) dual-ring coordination and C-H activation, leading to vicinal elimination to form phenol and a surface-bound aryne intermediate which is then hydrogenated and released as the arene; and (b) surface binding in keto form by the phenolic ring of the hydroxy-substituted substrates, followed by direct displacement of the departing phenol. Notably, acetone inhibits the well-known reduction of phenol to cyclohexanol, affording control of product ring saturation. A byproduct of this work is the discovery that the ECH treatment completely defluorinates substrates bearing aromatic C-F and C-CF3 groupings.
Trilobite-inspired neural nanophotonic light-field camera with extreme depth-of-field
Authors: Fan Qingbin , Xu Weizhu , Hu Xuemei , Zhu Wenqi , Yue Tao , Zhang Cheng , Yan Feng , Chen Lu , Lezec Henri J. , Lu Yanqing , Agrawal Amit , Xu Ting
Published: April 2022

A unique bifocal compound eye visual system found in the now extinct trilobite, Dalmanitina socialis, may enable them to be sensitive to the light-field information and simultaneously perceive both close and distant objects in the environment. Here, inspired by the optical structure of their eyes, we demonstrate a nanophotonic light-field camera incorporating a spin-multiplexed bifocal metalens array capable of capturing high-resolution light-field images over a record depth-of-field ranging from centimeter to kilometer scale, simultaneously enabling macro and telephoto modes in a snapshot imaging. By leveraging a multi-scale convolutional neural network-based reconstruction algorithm, optical aberrations induced by the metalens are eliminated, thereby significantly relaxing the design and performance limitations on metasurface optics. The elegant integration of nanophotonic technology with computational photography achieved here is expected to aid development of future high-performance imaging systems.
Magic angle spinning NMR structure of human cofilin-2 assembled on actin filaments reveals isoform-specific conformation and binding mode
Authors: Kraus Jodi , Russell Ryan W. , Kudryashova Elena , Xu Chaoyi , Katyal Nidhi , Perilla Juan R. , Kudryashov Dmitri S. , Polenova Tatyana
Published: April 2022

Actin polymerization dynamics regulated by actin-binding proteins are essential for various cellular functions. The cofilin family of proteins are potent regulators of actin severing and filament disassembly. The structural basis for cofilin-isoform-specific severing activity is poorly understood as their high-resolution structures in complex with filamentous actin (F-actin) are lacking. Here, we present the atomic-resolution structure of the muscle-tissue-specific isoform, cofilin-2 (CFL2), assembled on ADP-F-actin, determined by magic-angle-spinning (MAS) NMR spectroscopy and data-guided molecular dynamics (MD) simulations. We observe an isoform-specific conformation for CFL2. This conformation is the result of a unique network of hydrogen bonding interactions within the α2 helix containing the non-conserved residue, Q26. Our results indicate F-site interactions that are specific between CFL2 and ADP-F-actin, revealing mechanistic insights into isoform-dependent F-actin disassembly.
Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations
Authors: Bell Charlotte R. , Pelly Victoria S. , Moeini Agrin , Chiang Shih-Chieh , Flanagan Eimear , Bromley Christian P. , Clark Christopher , Earnshaw Charles H. , Koufaki Maria A. , Bonavita Eduardo , Zelenay Santiago
Published: April 2022

Cytotoxic therapies, besides directly inducing cancer cell death, can stimulate immune-dependent tumor growth control or paradoxically accelerate tumor progression. The underlying mechanisms dictating these opposing outcomes are poorly defined. Here, we show that cytotoxic therapy acutely upregulates cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) production in cancer cells with pre-existing COX-2 activity. Screening a compound library of 1280 approved drugs, we find that all classes of chemotherapy drugs enhance COX-2 transcription whilst arresting cancer cell proliferation. Genetic manipulation of COX-2 expression or its gene promoter region uncover how augmented COX-2/PGE2 activity post-treatment profoundly alters the inflammatory properties of chemotherapy-treated cancer cells in vivo. Pharmacological COX-2 inhibition boosts the efficacy of the combination of chemotherapy and PD-1 blockade. Crucially, in a poorly immunogenic breast cancer model, only the triple therapy unleashes tumor growth control and significantly reduces relapse and spontaneous metastatic spread in an adjuvant setting. Our findings suggest COX-2/PGE2 upregulation by dying cancer cells acts as a major barrier to cytotoxic therapy-driven tumor immunity and uncover a strategy to improve the outcomes of immunotherapy and chemotherapy combinations.
A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation
Authors: Cohen S. , Guenolé A. , Lazar I. , Marnef A. , Clouaire T. , Vernekar D. V. , Puget N. , Rocher V. , Arnould C. , Aguirrebengoa M. , Genais M. , Firmin N. , Shamanna R. A. , Mourad R. , Bohr V. A. , Borde V. , Legube G.
Published: April 2022

Transcriptionally active loci are particularly prone to breakage and mounting evidence suggests that DNA Double-Strand Breaks arising in active genes are handled by a dedicated repair pathway, Transcription-Coupled DSB Repair (TC-DSBR), that entails R-loop accumulation and dissolution. Here, we uncover a function for the Bloom RecQ DNA helicase (BLM) in TC-DSBR in human cells. BLM is recruited in a transcription dependent-manner at DSBs where it fosters resection, RAD51 binding and accurate Homologous Recombination repair. However, in an R-loop dissolution-deficient background, we find that BLM promotes cell death. We report that upon excessive RNA:DNA hybrid accumulation, DNA synthesis is enhanced at DSBs, in a manner that depends on BLM and POLD3. Altogether our work unveils a role for BLM at DSBs in active chromatin, and highlights the toxic potential of RNA:DNA hybrids that accumulate at transcription-associated DSBs.
A fully automatic AI system for tooth and alveolar bone segmentation from cone-beam CT images
Authors: Cui Zhiming , Fang Yu , Mei Lanzhuju , Zhang Bojun , Yu Bo , Liu Jiameng , Jiang Caiwen , Sun Yuhang , Ma Lei , Huang Jiawei , Liu Yang , Zhao Yue , Lian Chunfeng , Ding Zhongxiang , Zhu Min , Shen Dinggang
Published: April 2022

Accurate delineation of individual teeth and alveolar bones from dental cone-beam CT (CBCT) images is an essential step in digital dentistry for precision dental healthcare. In this paper, we present an AI system for efficient, precise, and fully automatic segmentation of real-patient CBCT images. Our AI system is evaluated on the largest dataset so far, i.e., using a dataset of 4,215 patients (with 4,938 CBCT scans) from 15 different centers. This fully automatic AI system achieves a segmentation accuracy comparable to experienced radiologists (e.g., 0.5% improvement in terms of average Dice similarity coefficient), while significant improvement in efficiency (i.e., 500 times faster). In addition, it consistently obtains accurate results on the challenging cases with variable dental abnormalities, with the average Dice scores of 91.5% and 93.0% for tooth and alveolar bone segmentation. These results demonstrate its potential as a powerful system to boost clinical workflows of digital dentistry.
A hierarchy of biomolecular proportional-integral-derivative feedback controllers for robust perfect adaptation and dynamic performance
Authors: Filo Maurice , Kumar Sant , Khammash Mustafa
Published: April 2022

Proportional-Integral-Derivative (PID) feedback controllers are the most widely used controllers in industry. Recently, the design of molecular PID-controllers has been identified as an important goal for synthetic biology and the field of cybergenetics. In this paper, we consider the realization of PID-controllers via biomolecular reactions. We propose an array of topologies offering a compromise between simplicity and high performance. We first demonstrate that different biomolecular PI-controllers exhibit different performance-enhancing capabilities. Next, we introduce several derivative controllers based on incoherent feedforward loops acting in a feedback configuration. Alternatively, we show that differentiators can be realized by placing molecular integrators in a negative feedback loop, which can be augmented by PI-components to yield PID-controllers. We demonstrate that PID-controllers can enhance stability and dynamic performance, and can also reduce stochastic noise. Finally, we provide an experimental demonstration using a hybrid setup where in silico PID-controllers regulate a genetic circuit in single yeast cells.
Creating three-dimensional magnetic functional microdevices via molding-integrated direct laser writing
Authors: Liu Zemin , Li Meng , Dong Xiaoguang , Ren Ziyu , Hu Wenqi , Sitti Metin
Published: April 2022

Magnetically driven wireless miniature devices have become promising recently in healthcare, information technology, and many other fields. However, they lack advanced fabrication methods to go down to micrometer length scales with heterogeneous functional materials, complex three-dimensional (3D) geometries, and 3D programmable magnetization profiles. To fill this gap, we propose a molding-integrated direct laser writing-based microfabrication approach in this study and showcase its advanced enabling capabilities with various proof-of-concept functional microdevice prototypes. Unique motions and functionalities, such as metachronal coordinated motion, fluid mixing, function reprogramming, geometrical reconfiguring, multiple degrees-of-freedom rotation, and wireless stiffness tuning are exemplary demonstrations of the versatility of this fabrication method. Such facile fabrication strategy can be applied toward building next-generation smart microsystems in healthcare, robotics, metamaterials, microfluidics, and programmable matter.
Salt marshes create more extensive channel networks than mangroves
Authors: Schwarz Christian , van Rees Floris , Xie Danghan , Kleinhans Maarten G. , van Maanen Barend
Published: April 2022

Coastal wetlands fulfil important functions for biodiversity conservation and coastal protection, which are inextricably linked to typical morphological features like tidal channels. Channel network configurations in turn are shaped by bio-geomorphological feedbacks between vegetation, hydrodynamics and sediment transport. This study investigates the impact of two starkly different recruitment strategies between mangroves (fast/homogenous) and salt marshes (slow/patchy) on channel network properties. We first compare channel networks found in salt marshes and mangroves around the world and then demonstrate how observed channel patterns can be explained by vegetation establishment strategies using controlled experimental conditions. We find that salt marshes are dissected by more extensive channel networks and have shorter over-marsh flow paths than mangrove systems, while their branching patterns remain similar. This finding is supported by our laboratory experiments, which reveal that different recruitment strategies of mangroves and salt marshes hamper or facilitate channel development, respectively. Insights of our study are crucial to understand wetland resilience with rising sea-levels especially under climate-driven ecotone shifts.
Global ubiquitinome profiling identifies NEDD4 as a regulator of Profilin 1 and actin remodelling in neural crest cells
Authors: Lohraseb Iman , McCarthy Peter , Secker Genevieve , Marchant Ceilidh , Wu Jianmin , Ali Naveid , Kumar Sharad , Daly Roger J. , Harvey Natasha L. , Kawabe Hiroshi , Kleifeld Oded , Wiszniak Sophie , Schwarz Quenten
Published: April 2022

The ubiquitin ligase NEDD4 promotes neural crest cell (NCC) survival and stem-cell like properties to regulate craniofacial and peripheral nervous system development. However, how ubiquitination and NEDD4 control NCC development remains unknown. Here we combine quantitative analysis of the proteome, transcriptome and ubiquitinome to identify key developmental signalling pathways that are regulated by NEDD4. We report 276 NEDD4 targets in NCCs and show that loss of NEDD4 leads to a pronounced global reduction in specific ubiquitin lysine linkages. We further show that NEDD4 contributes to the regulation of the NCC actin cytoskeleton by controlling ubiquitination and turnover of Profilin 1 to modulate filamentous actin polymerization. Taken together, our data provide insights into how NEDD4-mediated ubiquitination coordinates key regulatory processes during NCC development.
Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms
Authors: Grohmann Christoph , Magtoto Charlene M. , Walker Joel R. , Chua Ngee Kiat , Gabrielyan Anna , Hall Mary , Cobbold Simon A. , Mieruszynski Stephen , Brzozowski Martin , Simpson Daniel S. , Dong Hao , Dorizzi Bridget , Jacobsen Annette V. , Morrish Emma , Silke Natasha , Murphy James M. , Heath Joan K. , Testa Andrea , Maniaci Chiara , Ciulli Alessio , Lessene Guillaume , Silke John , Feltham Rebecca
Published: April 2022

Modulation of protein abundance using tag-Targeted Protein Degrader (tTPD) systems targeting FKBP12F36V (dTAGs) or HaloTag7 (HaloPROTACs) are powerful approaches for preclinical target validation. Interchanging tags and tag-targeting degraders is important to achieve efficient substrate degradation, yet limited degrader/tag pairs are available and side-by-side comparisons have not been performed. To expand the tTPD repertoire we developed catalytic NanoLuc-targeting PROTACs (NanoTACs) to hijack the CRL4CRBN complex and degrade NanoLuc tagged substrates, enabling rapid luminescence-based degradation screening. To benchmark NanoTACs against existing tTPD systems we use an interchangeable reporter system to comparatively test optimal degrader/tag pairs. Overall, we find the dTAG system exhibits superior degradation. To align tag-induced degradation with physiology we demonstrate that NanoTACs limit MLKL-driven necroptosis. In this work we extend the tTPD platform to include NanoTACs adding flexibility to tTPD studies, and benchmark each tTPD system to highlight the importance of comparing each system against each substrate.
A single-cell nanocoating of probiotics for enhanced amelioration of antibiotic-associated diarrhea
Authors: Pan Jiezhou , Gong Guidong , Wang Qin , Shang Jiaojiao , He Yunxiang , Catania Chelsea , Birnbaum Dan , Li Yifei , Jia Zhijun , Zhang Yaoyao , Joshi Neel S. , Guo Junling
Published: April 2022

The gut microbiota represents a large community of microorganisms that play an important role in immune regulation and maintenance of homeostasis. Living bacteria receive increasing interest as potential therapeutics for gut disorders, because they inhibit the colonization of pathogens and positively regulate the composition of bacteria in gut. However, these treatments are often accompanied by antibiotic administration targeting pathogens. In these cases, the efficacy of therapeutic bacteria is compromised by their susceptibility to antibiotics. Here, we demonstrate that a single-cell coating composed of tannic acids and ferric ions, referred to as ‘nanoarmor’, can protect bacteria from the action of antibiotics. The nanoarmor protects both Gram-positive and Gram-negative bacteria against six clinically relevant antibiotics. The multiple interactions between the nanoarmor and antibiotic molecules allow the antibiotics to be effectively absorbed onto the nanoarmor. Armored probiotics have shown the ability to colonize inside the gastrointestinal tracts of levofloxacin-treated rats, which significantly reduced antibiotic-associated diarrhea (AAD) resulting from the levofloxacin-treatment and improved some of the pre-inflammatory symptoms caused by AAD. This nanoarmor strategy represents a robust platform to enhance the potency of therapeutic bacteria in the gastrointestinal tracts of patients receiving antibiotics and to avoid the negative effects of antibiotics in the gastrointestinal tract.
Single cell analyses identify a highly regenerative and homogenous human CD34+ hematopoietic stem cell population
Authors: Anjos-Afonso Fernando , Buettner Florian , Mian Syed A. , Rhys Hefin , Perez-Lloret Jimena , Garcia-Albornoz Manuel , Rastogi Namrata , Ariza-McNaughton Linda , Bonnet Dominique
Published: April 2022

The heterogeneous nature of human CD34+ hematopoietic stem cells (HSCs) has hampered our understanding of the cellular and molecular trajectories that HSCs navigate during lineage commitment. Using various platforms including single cell RNA-sequencing and extensive xenotransplantation, we have uncovered an uncharacterized human CD34+ HSC population. These CD34+EPCR+(CD38/CD45RA)− (simply as EPCR+) HSCs have a high repopulating and self-renewal abilities, reaching a stem cell frequency of ~1 in 3 cells, the highest described to date. Their unique transcriptomic wiring in which many gene modules associated with differentiated cell lineages confers their multilineage lineage output both in vivo and in vitro. At the single cell level, EPCR+ HSCs are the most transcriptomically and functionally homogenous human HSC population defined to date and can also be easily identified in post-natal tissues. Therefore, this EPCR+ population not only offers a high human HSC resolution but also a well-structured human hematopoietic hierarchical organization at the most primitive level.
Aeolian sediment transport on Io from lava–frost interactions
Authors: McDonald George D. , Méndez Harper Joshua , Ojha Lujendra , Corlies Paul , Dufek Josef , Ewing Ryan C. , Kerber Laura
Published: April 2022

Surface modification on Jupiter’s volcanically active moon, Io, has to date been attributed almost exclusively to lava emplacement and volcanic plume deposits. Here we demonstrate that wind-blown transport of sediment may also be altering the Ionian surface. Specifically, shallow subsurface interactions between lava and Io’s widespread sulfur dioxide (SO2) frost can produce localized sublimation vapor flows with sufficient gas densities to enable particle saltation. We calculate anticipated outgassing velocities from lava–SO2 frost interactions, and compare these to the saltation thresholds predicted when accounting for the tenuous nature of the sublimated vapor. We find that saltation may occur if frost temperatures surpass 155 K. Finally we make the first measurements of the dimensions of linear features in images from the Galileo probe, previously termed “ridges”, which demonstrate certain similarities to dunes on other planetary bodies. Io joins a growing list of bodies with tenuous and transient atmospheres where aeolian sediment transport may be an important control on the landscape.
USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer
Authors: Nelson Jessica K. , Thin May Zaw , Evan Theodore , Howell Steven , Wu Mary , Almeida Bruna , Legrave Nathalie , Koenis Duco S. , Koifman Gabriela , Sugimoto Yoichiro , Llorian Sopena Miriam , MacRae James , Nye Emma , Howell Michael , Snijders Ambrosius P. , Prachalias Andreas , Zen Yoh , Sarker Debashis , Behrens Axel
Published: April 2022

Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ductal adenocarcinoma (PDAC) has not been explored. Here, we develop a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identifies USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition results in potent growth impairment in PDAC organoids, while normal pancreatic organoids are insensitive, and causes dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinates and stabilizes the HIF-1α transcription factor. PDAC is characterized by a severely hypoxic microenvironment, and USP25 depletion abrogates HIF-1α transcriptional activity and impairs glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1α axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.