bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac and vascular health in late preterm infants
Authors: Dissanayake Hasthi U. , McMullan Rowena L. , Kong Yang , Caterson Ian D. , Celermajer David S. , Phang Melinda , Raynes-Greenow Camille , Polson Jaimie W. , Gordon Adrienne , Skilton Michael R.
Published: March 2021

Adults who were born preterm are at increased risk of hypertension and cardiovascular disease in later life. Infants born late preterm are the majority of preterm births; however, the effect of late preterm on risk of cardiovascular disease is unclear. The objective of this study was to assess whether vascular health and cardiac autonomic control differ in a group of late preterm newborn infants compared to a group of term-born infants.

A total of 35 healthy late preterm newborn infants, with normal growth (34–36 completed weeks’ gestation) and 139 term-born infants (37–42 weeks’ gestation) were compared in this study. Aortic wall thickening, assessed as aortic intima–media thickness (IMT) by high-resolution ultrasound, and cardiac autonomic control, assessed by heart rate variability, were measured during the first week of life. Postnatal age of full-term and late preterm infants at the time of the study was 5 days (standard deviation [SD] 5) and 4 days (SD 3), respectively.

Infants born late preterm show reduced aortic IMT (574 μm [SD 51] vs. 612 μm [SD 73]) and reduced heart rate variability [log total power 622.3 (606.5) ms2 vs. 1180. 6 (1114.3) ms2], compared to term infants. These associations remained even after adjustment for sex and birth weight.

Infants born late preterm show selective differences in markers of cardiovascular risk, with potentially beneficial differences in aortic wall thickness in contrast to potentially detrimental differences in autonomic control, when compared with term-born control infants. These findings provide pathophysiologic evidence to support an increased risk of hypertension and sudden cardiac death in individuals born late preterm.
A three-arm randomised controlled trial to evaluate the efficacy of a positive psychology and social networking intervention in promoting mental health among HIV-infected men who have sex with men in China
Authors: Li J. , Mo P. K. H. , Kahler C. W. , Lau J. T. F.
Published: March 2021

Aims

There is a lack of mental health promotion and treatment services targeting HIV-positive men who have sex with men (HIVMSM) in China. The aim of this study was to evaluate the mental health promotion efficacy of an online intervention that combined Three Good Things (TGT) with electronic social networking (TGT-SN) and an intervention that used TGT only (TGT-only), compared with a control group.

Methods

We conducted a randomised controlled trial among HIVMSM in Chengdu, China. The participants were randomly assigned to the TGT-SN, TGT-only, and control groups. The participants in the TGT-SN group were divided into five social network groups and asked to post brief messages to the group about three good things that they had experienced and for which they felt grateful. The participants in the TGT-only group were only required to write down their three good things daily without sharing them with others. The control group received information about mental health promotion once a week for a month. The primary outcome was probable depression. Secondary outcomes were anxiety, positive and negative affect, gratitude, happiness and social support. These outcomes were assessed at baseline, 1, 3, 6 and 12 months after the intervention. Repeated-measures analyses were conducted using generalised estimation equations. The study was registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-13003252).

Results

Between June 2013 and May 2015, 404 participants were enrolled and randomly assigned to either the TGT-SN (n = 129), TGT-only (n = 139) or control group (n = 136). The main effects of TGT-SN (adjusted odds ratio (aOR) = 0.75, 95% CI 0.52–1.09; p = 0.131) and TGT-only (aOR = 0.83, 95% CI 0.57–1.21; p = 0.332) in reducing depression were statistically non-significant. The participants of the TGT-SN group showed significantly lower anxiety symptoms (aOR = 0.62, 95% CI 0.43–0.89; p = 0.009) and negative affect (β = −1.62, 95% CI 2.98 to −0.26; p = 0.019) over time compared with those of the control group. No significant main effect was found for any secondary outcomes for the TGT-only group.

Conclusions

The novel intervention combining the TGT exercise with electronic social networking was found effective in reducing anxiety and negative affect among HIVMSM.
Do Males Affect Twinning Events? A Review of Current Findings/Twin Research Reviews: Monozygotic Twins Discordant for Parkinson’s Disease; Fetal Loss in Twin Pregnancies Following Prenatal Diagnosis; Uterine Rupture and Repair in an Early Twin Pregnancy; Twin Study of Affectionate Communication/Human Interest: Conjoined Twins in a Triplet Set; Identical Twin Nurses Deliver Identical Twins; Identical Twins Discordant for COVID-19 Recovery Course; Identical Twins Pass Away from COVID-19; Archeological Finds of Oldest Identical Twins
Authors: Segal Nancy L.
Published: March 2021

Research into the origins of twinning has focused mostly on contributions from the female side of the family. A review of current findings suggests that possible male contributions to twinning events have been overlooked. This section is followed by brief reviews of twin research concerning monozygotic twins discordant for Parkinson’s disease, fetal loss in twin pregnancies following prenatal diagnosis, uterine rupture and repair in an early twin pregnancy and a twin study of affectionate communication. The concluding portion of this article presents human interest stories involving twins that are both informative and poignant, namely conjoined twins in a triplet set, identical twin nurses who delivered identical twins, identical twins discordant for COVID-19 recovery course, identical twins who passed away from COVID-19 and archeological finds of the oldest identical twins.
Deep Chlorophyll Maxima in the Global Ocean: Occurrences, Drivers and Characteristics
Authors: Cornec M. , Claustre H. , Mignot A. , Guidi L. , Lacour L. , Poteau A. , D'Ortenzio F. , Gentili B. , Schmechtig C.
Published: March 2021

Stratified oceanic systems are characterized by the presence of a so‐called Deep Chlorophyll a Maximum (DCM) not detectable by ocean color satellites. A DCM can either be a phytoplankton (carbon) biomass maximum (Deep Biomass Maximum, DBM), or the consequence of photoacclimation processes (Deep photoAcclimation Maximum, DAM) resulting in the increase of chlorophyll a per phytoplankton carbon. Even though these DCM (further qualified as either DBMs or DAMs) have long been studied, no global‐scale assessment has yet been undertaken and large knowledge gaps still remain in relation to the environmental drivers responsible for their formation and maintenance. In order to investigate their spatial and temporal variability in the open ocean, we use a global data set acquired by more than 500 Biogeochemical‐Argo floats given that DCMs can be detected from the comparative vertical distribution of chlorophyll a concentrations and particulate backscattering coefficients. Our findings show that the seasonal dynamics of the DCMs are clearly region‐dependent. High‐latitude environments are characterized by a low occurrence of intense DBMs, restricted to summer. Meanwhile, oligotrophic regions host permanent DAMs, occasionally replaced by DBMs in summer, while subequatorial waters are characterized by permanent DBMs benefiting from favorable conditions in terms of both light and nutrients. Overall, the appearance and depth of DCMs are primarily driven by light attenuation in the upper layer. Our present assessment of DCM occurrence and of environmental conditions prevailing in their development lay the basis for a better understanding and quantification of their role in carbon budgets (primary production and export).
Freshwater Variability and Transport in the Labrador Sea From In Situ and Satellite Observations
Authors: Majumder Sudip , Castelao Renato M. , Amos Caitlin M.
Published: March 2021

The Greenland ice sheet is melting at increasing rates. Changes in freshwater input to the Labrador Sea can influence coastal circulation and biological processes, stratification, and potentially winter convection. Many recent studies have investigated freshwater variability in the region based on model simulations or observations with limited spatial/temporal coverage. Here, we use in situ (1990–2019) and satellite (2011–2017) observations of surface salinity to characterize freshwater content and to identify transport pathways in the Labrador Sea over multiple years. Large freshening is observed in coastal waters off southwest Greenland from July to November. Interannual variability in freshening near the coast seems to be at least partially related to variability in meltwater input, although the sparseness of in situ data precludes a quantitative assessment. The seasonal westward transport of freshwater is enhanced between 60°–62°N and especially between 63°–64.8°N from August to October, with the low‐salinity waters circumnavigating the basin following the 1,000–2,000 m isobaths. That pathway coincides with intensifications in the component of the surface geostrophic flow that is directed offshore, highlighting the role played by the large‐scale circulation on the westward transport of the freshwater. Low‐salinity water can be transported toward the central Labrador Sea at synoptic scales, however, where it can potentially influence stratification. Consistent with previous modeling studies, offshore freshening is reduced in years with persistent downwelling‐favorable wind conditions. Despite limitations under cold water conditions, satellite observations of surface salinity compare well with in situ data suggesting that they can be useful for monitoring freshwater content in high latitudes.
Biweekly Mixed Rossby‐Gravity Waves in the Equatorial Indian Ocean
Authors: Pujiana Kandaga , McPhaden Michael J.
Published: March 2021

This study describes biweekly (defined as periods between 10 and 15 days) ocean variability in relation to equatorial wave theory using a comprehensive set of moored ocean current velocities as well as satellite‐retrieved oceanic and atmospheric parameters in the Indian Ocean. Moored biweekly current velocities exhibit the meridional structure of mixed Rossby‐gravity waves: Symmetric for meridional velocity and antisymmetric for zonal velocity around the equator with a decay scale of 228–309 km. The biweekly meridional velocity along the equator has average zonal and vertical wavelengths of 3,430 ± 550 km and 0.76 ± 0.15 km, respectively, with phase propagating westward at speeds of 2.8–3.1 m s−1 and upward at 54–56 m day−1. Conversely, wave energy is inferred to propagate eastward and downward. The range of best fit constants (1.4–2.0 m s−1) that result from the linear separation of horizontal and vertical wave structures suggests the second baroclinic wave mode is dominant over other low baroclinic modes in accounting for the velocity variability. The biweekly waves are forced by surface winds; satellite‐derived wind stress, sea level, and surface current anomalies, regressed against the first principal component of the biweekly moored velocities, illustrate the basin‐scale structure and temporal evolution of the waves.
Transitioning out of Open Access: A Closer Look at Institutions for Management of Groundwater Rights in France, California, and Spain
Authors: Rouillard J. , Babbitt C. , Pulido‐Velazquez M. , Rinaudo J.‐D.
Published: March 2021

Many regions around the world are transitioning out of open access to groundwater resources in order to tackle over extraction by irrigated agriculture. However, the state has limited capacities to regulate effectively agricultural groundwater use. This paper evaluates how users and public authorities can co‐manage groundwater extraction by agriculture. Based on Schlager and Ostrom’s “bundle of rights” framework, the paper examines how decisions over access and use of groundwater resources are made in France, Spain and California. The three cases share a common strive to involve groundwater users in decisions over how to reduce over extraction of groundwater resources. However, different choices were made regarding the institutional set‐up for user involvement in allocation decisions. The paper presents the diversity of institutional arrangements influencing groundwater allocations in the three cases, and the relative involvement and power of users and public authorities over these institutions. The papers show the different ways in which “comanagement” may be made operational for managing agricultural groundwater use.
The role of neuropeptide somatostatin in the brain and its application in treating neurological disorders
Authors: Song You-Hyang , Yoon Jiwon , Lee Seung-Hee
Published: March 2021

Somatostatin (SST) is a well-known neuropeptide that is expressed throughout the brain. In the cortex, SST is expressed in a subset of GABAergic neurons and is known as a protein marker of inhibitory interneurons. Recent studies have identified the key functions of SST in modulating cortical circuits in the brain and cognitive function. Furthermore, reduced expression of SST is a hallmark of various neurological disorders, including Alzheimer’s disease and depression. In this review, we summarize the current knowledge on SST expression and function in the brain. In particular, we describe the physiological roles of SST-positive interneurons in the cortex. We further describe the causal relationship between pathophysiological changes in SST function and various neurological disorders, such as Alzheimer’s disease. Finally, we discuss potential treatments and possibility of novel drug developments for neurological disorders based on the current knowledge on the function of SST and SST analogs in the brain derived from experimental and clinical studies.
Transmembrane and coiled-coil domain family 3 (TMCC3) regulates breast cancer stem cell and AKT activation
Authors: Wang Ya-Hui , Chan Yu-Tzu , Hung Tsai-Hsien , Hung Jung-Tung , Kuo Ming-Wei , Wang Sheng-Hung , Huang Yenlin , Lin Yu-Ju , Chen Shin-Cheh , Yu Jyh-Cherng , Wu Jen-Chine , Yu John , Yu Alice L.
Published: March 2021

Cancer stem cells (CSC) play a pivotal role in cancer metastasis and resistance to therapy. Previously, we compared the phosphoproteomes of breast cancer stem cells (BCSCs) enriched subpopulation and non-BCSCs sorted from breast cancer patient-derived xenograft (PDX), and identified a function unknown protein, transmembrane and coiled-coil domain family 3 (TMCC3) to be a potential enrichment marker for BCSCs. We demonstrated greater expression of TMCC3 in BCSCs than non-BCSCs and higher expression of TMCC3 in metastatic lymph nodes and lungs than in primary tumor of breast cancer PDXs. TMCC3 silencing suppressed mammosphere formation, ALDH activity and cell migration in vitro, along with reduced tumorigenicity and metastasis in vivo. Mechanistically, we found that AKT activation was reduced by TMCC3 silencing, but enhanced by TMCC3 overexpression. We further demonstrated that TMCC3 interacted directly with AKT through its 1-153 a.a. domain by cell-free biochemical assay in vitro and co-immunoprecipitation and interaction domain mapping assays in vivo. Based on domain truncation studies, we showed that the AKT-interacting domain of TMCC3 was essential for TMCC3-induced AKT activation, self-renewal, and metastasis. Clinically, TMCC3 mRNA expression in 202 breast cancer specimens as determined by qRT-PCR assay showed that higher TMCC3 expression correlated with poorer clinical outcome of breast cancer, including early-stage breast cancer. Multivariable analysis identified TMCC3 expression as an independent risk factor for survival. These findings suggest that TMCC3 is crucial for maintenance of BCSCs features through AKT regulation, and TMCC3 expression has independent prognostic significance in breast cancer. Thus, TMCC3 may serve as a new target for therapy directed against CSCs.
Olaparib increases the therapeutic index of hemithoracic irradiation compared with hemithoracic irradiation alone in a mouse lung cancer model
Authors: Jiang Yanyan , Martin Jennifer , Alkadhimi Maryam , Shigemori Kay , Kinchesh Paul , Gilchrist Stuart , Kersemans Veerle , Smart Sean , Thompson James M. , Hill Mark A. , O’Connor Mark J. , Davies Barry R. , Ryan Anderson J.
Published: March 2021

Background

The radiosensitising effect of the poly(ADP-ribose) polymerase inhibitor olaparib on tumours has been reported. However, its effect on normal tissues in combination with radiation has not been well studied. Herein, we investigated the therapeutic index of olaparib combined with hemithoracic radiation in a urethane-induced mouse lung cancer model.

Methods

To assess tolerability, A/J mice were treated with olaparib plus whole thorax radiation (13 Gy), body weight changes were monitored and normal tissue effects were assessed by histology. In anti-tumour (intervention) studies, A/J mice were injected with urethane to induce lung tumours, and were then treated with olaparib alone, left thorax radiation alone or the combination of olaparib plus left thorax radiation at 8 weeks (early intervention) or 18 weeks (late intervention) after urethane injection. Anti-tumour efficacy and normal tissue effects were assessed by visual inspection, magnetic resonance imaging and histology.

Results

Enhanced body weight loss and oesophageal toxicity were observed when olaparib was combined with whole thorax but not hemithorax radiation. In both the early and late intervention studies, olaparib increased the anti-tumour effects of hemithoracic irradiation without increasing lung toxicity.

Conclusions

The addition of olaparib increased the therapeutic index of hemithoracic radiation in a mouse model of lung cancer.
PKA compartmentalization links cAMP signaling and autophagy
Authors: Grisan Francesca , Iannucci Liliana F. , Surdo Nicoletta C. , Gerbino Andrea , Zanin Sofia , Di Benedetto Giulietta , Pozzan Tullio , Lefkimmiatis Konstantinos
Published: March 2021

Autophagy is a highly regulated degradative process crucial for maintaining cell homeostasis. This important catabolic mechanism can be nonspecific, but usually occurs with fine spatial selectivity (compartmentalization), engaging only specific subcellular sites. While the molecular machines driving autophagy are well understood, the involvement of localized signaling events in this process is not well defined. Among the pathways that regulate autophagy, the cyclic AMP (cAMP)/protein kinase A (PKA) cascade can be compartmentalized in distinct functional units called microdomains. However, while it is well established that, depending on the cell type, cAMP can inhibit or promote autophagy, the role of cAMP/PKA microdomains has not been tested. Here we show not only that the effects on autophagy of the same cAMP elevation differ in different cell types, but that they depend on a highly complex sub-compartmentalization of the signaling cascade. We show in addition that, in HT-29 cells, in which autophagy is modulated by cAMP rising treatments, PKA activity is strictly regulated in space and time by phosphatases, which largely prevent the phosphorylation of soluble substrates, while membrane-bound targets are less sensitive to the action of these enzymes. Interestingly, we also found that the subcellular distribution of PKA type-II regulatory PKA subunits hinders the effect of PKA on autophagy, while displacement of type-I regulatory PKA subunits has no effect. Our data demonstrate that local PKA activity can occur independently of local cAMP concentrations and provide strong evidence for a link between localized PKA signaling events and autophagy.
The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53
Authors: Su Xi , Feng Chao , Wang Simeng , Shi Liang , Gu Qingqing , Zhang Haihong , Lan Xinhui , Zhao Yuelei , Qiang Wei , Ji Meiju , Hou Peng
Published: March 2021

Small nucleolar RNA SNORD50A and SNORD50B (SNORD50A/B) has been reported to be recurrently deleted and function as a putative tumor suppressor in different types of cancer by binding to and suppressing the activity of the KRAS oncoproteins. Its deletion correlates with poorer patient survival. However, in this study, we surprisingly found that SNORD50A/B loss predicted a better survival in breast cancer patients carrying wild-type p53. Functional studies showed that SNORD50A/B deletion strongly inhibited the proliferation, migration, invasion and tumorigenic potential, and induced cell cycle arrest and apoptosis in p53 wild-type breast cancer cells, while exerted the opposite effects in p53 mutated breast cancer cells. This was also supported by ectopically expressing SNORD50A/B in both p53 wild-type and mutated breast cancer cells. Mechanistically, SNORD50A/B clearly enhances the interaction between E3 ubiquitin ligase TRIM21 and its substrate GMPS by forming a complex among them, thereby promoting GMPS ubiquitination and its subsequent cytoplasmic sequestration. SNORD50A/B deletion in p53 wild-type breast cancer cells will release GMPS and induce the translocation of GMPS into the nucleus, where GMPS can recruit USP7 and form a complex with p53, thereby decreasing p53 ubiquitination, stabilizing p53 proteins, and inhibiting malignant phenotypes of cancer cells. Altogether, the present study first reports that SNORD50A/B plays an oncogenic role in p53 wild-type breast cancers by mediating TRIM21-GMPS interaction.
Immunotherapy for recurrent glioblastoma: practical insights and challenging prospects
Authors: Wang Xin , Lu Jie , Guo Gaochao , Yu Jinming
Published: March 2021

Glioblastoma (GB) is the most common high-grade intracranial malignant tumor with highly malignant biological behavior and a high recurrence rate. Although anti-PD-1/PD-L1 antibodies have achieved significant survival benefits in several kinds of solid tumors, the phase III clinical trial Checkmate 143 demonstrated that nivolumab, which targets PD-1, did not achieve survival benefits compared with bevacizumab in recurrent glioblastoma (rGB) patients. Nevertheless, neoadjuvant anti-PD-1 therapy followed by surgery and adjuvant anti-PD-1 therapy could effectively activate local and systemic immune responses and significantly improve the OS of rGB patients. Furthermore, several studies have also confirmed the progress made in applying tumor-specific peptide vaccination or chimeric antigen receptor-T (CAR-T) cell therapy to treat rGB patients, and successes with antibodies targeting other inhibitory checkpoints or costimulatory molecules have also been reported. These successes inspired us to explore candidate combination treatments based on anti-PD-1/PD-L1 antibodies. However, effective predictive biomarkers for clinical efficacy are urgently needed to avoid economic waste and treatment delay. Attempts to prolong the CAR-T cell lifespan and increase T cell infiltration through engineering techniques are addressing the challenge of strengthening T cell function. In this review, we describe the immunosuppressive molecular characteristics of rGB; clinical trials exploring anti-PD-1/PD-L1 therapy, tumor-specific peptide vaccination, and CAR-T cell therapy; candidate combination strategies; and issues related to strengthening T cell function.
Cost function dependent barren plateaus in shallow parametrized quantum circuits
Authors: Cerezo M. , Sone Akira , Volkoff Tyler , Cincio Lukasz , Coles Patrick J.
Published: March 2021

Variational quantum algorithms (VQAs) optimize the parameters θ of a parametrized quantum circuit V(θ) to minimize a cost function C. While VQAs may enable practical applications of noisy quantum computers, they are nevertheless heuristic methods with unproven scaling. Here, we rigorously prove two results, assuming V(θ) is an alternating layered ansatz composed of blocks forming local 2-designs. Our first result states that defining C in terms of global observables leads to exponentially vanishing gradients (i.e., barren plateaus) even when V(θ) is shallow. Hence, several VQAs in the literature must revise their proposed costs. On the other hand, our second result states that defining C with local observables leads to at worst a polynomially vanishing gradient, so long as the depth of V(θ) is $${\mathcal{O}}(\mathrm{log}\,n)$$
O

(

log

n

)

. Our results establish a connection between locality and trainability. We illustrate these ideas with large-scale simulations, up to 100 qubits, of a quantum autoencoder implementation.
FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell
Authors: Relier Sébastien , Ripoll Julie , Guillorit Hélène , Amalric Amandine , Achour Cyrinne , Boissière Florence , Vialaret Jérôme , Attina Aurore , Debart Françoise , Choquet Armelle , Macari Françoise , Marchand Virginie , Motorin Yuri , Samalin Emmanuelle , Vasseur Jean-Jacques , Pannequin Julie , Aguilo Francesca , Lopez-Crapez Evelyne , Hirtz Christophe , Rivals Eric , Bastide Amandine , David Alexandre
Published: March 2021

Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its N6,2’-O-dimethyladenosine (m6Am) demethylase activity. While m6Am is strategically located next to the m7G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m6Am level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m6Am methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of m6Am modification in stem-like properties acquisition. FTO-mediated regulation of m6Am marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the m6Am modification and its potential adverse consequences for colorectal cancer management.
Identification of disease treatment mechanisms through the multiscale interactome
Authors: Ruiz Camilo , Zitnik Marinka , Leskovec Jure
Published: March 2021

Most diseases disrupt multiple proteins, and drugs treat such diseases by restoring the functions of the disrupted proteins. How drugs restore these functions, however, is often unknown as a drug’s therapeutic effects are not limited to the proteins that the drug directly targets. Here, we develop the multiscale interactome, a powerful approach to explain disease treatment. We integrate disease-perturbed proteins, drug targets, and biological functions into a multiscale interactome network. We then develop a random walk-based method that captures how drug effects propagate through a hierarchy of biological functions and physical protein-protein interactions. On three key pharmacological tasks, the multiscale interactome predicts drug-disease treatment, identifies proteins and biological functions related to treatment, and predicts genes that alter a treatment’s efficacy and adverse reactions. Our results indicate that physical interactions between proteins alone cannot explain treatment since many drugs treat diseases by affecting the biological functions disrupted by the disease rather than directly targeting disease proteins or their regulators. We provide a general framework for explaining treatment, even when drugs seem unrelated to the diseases they are recommended for.
Recruited macrophages that colonize the post-inflammatory peritoneal niche convert into functionally divergent resident cells
Authors: Louwe P. A. , Badiola Gomez L. , Webster H. , Perona-Wright G. , Bain C. C. , Forbes S. J. , Jenkins S. J.
Published: March 2021

Inflammation generally leads to recruitment of monocyte-derived macrophages. What regulates the fate of these cells and to what extent they can assume the identity and function of resident macrophages is unclear. Here, we show that macrophages elicited into the peritoneal cavity during mild inflammation persist long-term but are retained in an immature transitory state of differentiation due to the presence of enduring resident macrophages. By contrast, severe inflammation results in ablation of resident macrophages and a protracted phase wherein the cavity is incapable of sustaining a resident phenotype, yet ultimately elicited cells acquire a mature resident identity. These macrophages also have transcriptionally and functionally divergent features that result from inflammation-driven alterations to the peritoneal cavity micro-environment and, to a lesser extent, effects of origin and time-of-residency. Hence, rather than being predetermined, the fate of inflammation-elicited peritoneal macrophages seems to be regulated by the environment.
Synchronous RNA conformational changes trigger ordered phase transitions in crystals
Authors: Ramakrishnan Saminathan , Stagno Jason R. , Conrad Chelsie E. , Ding Jienyu , Yu Ping , Bhandari Yuba R. , Lee Yun-Tzai , Pauly Gary , Yefanov Oleksandr , Wiedorn Max O. , Knoska Juraj , Oberthür Dominik , White Thomas A. , Barty Anton , Mariani Valerio , Li Chufeng , Brehm Wolfgang , Heinz William F. , Magidson Valentin , Lockett Stephen , Hunter Mark S. , Boutet Sébastien , Zatsepin Nadia A. , Zuo Xiaobing , Grant Thomas D. , Pandey Suraj , Schmidt Marius , Spence John C. H. , Chapman Henry N. , Wang Yun-Xing
Published: March 2021

Time-resolved studies of biomacromolecular crystals have been limited to systems involving only minute conformational changes within the same lattice. Ligand-induced changes greater than several angstroms, however, are likely to result in solid-solid phase transitions, which require a detailed understanding of the mechanistic interplay between conformational and lattice transitions. Here we report the synchronous behavior of the adenine riboswitch aptamer RNA in crystal during ligand-triggered isothermal phase transitions. Direct visualization using polarized video microscopy and atomic force microscopy shows that the RNA molecules undergo cooperative rearrangements that maintain lattice order, whose cell parameters change distinctly as a function of time. The bulk lattice order throughout the transition is further supported by time-resolved diffraction data from crystals using an X-ray free electron laser. The synchronous molecular rearrangements in crystal provide the physical basis for studying large conformational changes using time-resolved crystallography and micro/nanocrystals.
CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer
Authors: Ahmed Musaddeque , Soares Fraser , Xia Ji-Han , Yang Yue , Li Jing , Guo Haiyang , Su Peiran , Tian Yijun , Lee Hyung Joo , Wang Miranda , Akhtar Nayeema , Houlahan Kathleen E. , Bosch Almudena , Zhou Stanley , Mazrooei Parisa , Hua Junjie T. , Chen Sujun , Petricca Jessica , Zeng Yong , Davies Alastair , Fraser Michael , Quigley David A. , Feng Felix Y. , Boutros Paul C. , Lupien Mathieu , Zoubeidi Amina , Wang Liang , Walsh Martin J. , Wang Ting , Ren Shancheng , Wei Gong-Hong , He Housheng Hansen
Published: March 2021

Prostate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of 260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.
The transcriptional landscape of Shh medulloblastoma
Authors: Skowron Patryk , Farooq Hamza , Cavalli Florence M. G. , Morrissy A. Sorana , Ly Michelle , Hendrikse Liam D. , Wang Evan Y. , Djambazian Haig , Zhu Helen , Mungall Karen L. , Trinh Quang M. , Zheng Tina , Dai Shizhong , Stucklin Ana S. Guerreiro , Vladoiu Maria C. , Fong Vernon , Holgado Borja L. , Nor Carolina , Wu Xiaochong , Abd-Rabbo Diala , Bérubé Pierre , Wang Yu Chang , Luu Betty , Suarez Raul A. , Rastan Avesta , Gillmor Aaron H. , Lee John J. Y. , Zhang Xiao Yun , Daniels Craig , Dirks Peter , Malkin David , Bouffet Eric , Tabori Uri , Loukides James , Doz François P. , Bourdeaut Franck , Delattre Olivier O. , Masliah-Planchon Julien , Ayrault Olivier , Kim Seung-Ki , Meyronet David , Grajkowska Wieslawa A. , Carlotti Carlos G. , de Torres Carmen , Mora Jaume , Eberhart Charles G. , Van Meir Erwin G. , Kumabe Toshihiro , French Pim J. , Kros Johan M. , Jabado Nada , Lach Boleslaw , Pollack Ian F. , Hamilton Ronald L. , Rao Amulya A. Nageswara , Giannini Caterina , Olson James M. , Bognár László , Klekner Almos , Zitterbart Karel , Phillips Joanna J. , Thompson Reid C. , Cooper Michael K. , Rubin Joshua B. , Liau Linda M. , Garami Miklós , Hauser Peter , Li Kay Ka Wai , Ng Ho-Keung , Poon Wai Sang , Yancey Gillespie G. , Chan Jennifer A. , Jung Shin , McLendon Roger E. , Thompson Eric M. , Zagzag David , Vibhakar Rajeev , Ra Young Shin , Garre Maria Luisa , Schüller Ulrich , Shofuda Tomoko , Faria Claudia C. , López-Aguilar Enrique , Zadeh Gelareh , Hui Chi-Chung , Ramaswamy Vijay , Bailey Swneke D. , Jones Steven J. , Mungall Andrew J. , Moore Richard A. , Calarco John A. , Stein Lincoln D. , Bader Gary D. , Reimand Jüri , Ragoussis Jiannis , Weiss William A. , Marra Marco A. , Suzuki Hiromichi , Taylor Michael D.
Published: March 2021

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
Chemical feedbacks during magma degassing control chlorine partitioning and metal extraction in volcanic arcs
Authors: Tattitch B. , Chelle-Michou C. , Blundy J. , Loucks R. R.
Published: March 2021

Hydrous fluids released from subducting oceanic lithosphere fuel arc magmatism and associated hydrothermal mineralization, including formation of porphyry copper deposits. Critical magma degassing parameters are the depth, chemistry and style of fluid release during magma ascent, notably the behaviour of chlorine, a key metal-transporting ligand. Currently, understanding is limited by restricted data on fluid-melt partitioning of chlorine as a function of pressure and magma chemistry, and the complex interplay between the two that occurs in polybaric magmatic systems. Here we present experimental determinations of chlorine partitioning as a function of fluid and melt composition at pressures from 50 to 800 MPa. We provide, for the first time, a quantitative understanding of chlorine and copper evolution that is valid for shallow, deep or transcrustal differentiation and degassing. Monte Carlo simulations using our new data reproduce the chemical evolution of melt inclusions from arc volcanoes and fluid inclusions from upper crustal intrusions and porphyry copper deposits. Our results not only provide a novel chemical framework for understanding magma degassing, but quantify the primacy of magmatic chlorine concentration at the point of fluid saturation in promoting efficient copper extraction from magmas.
In situ microbeam surface X-ray scattering reveals alternating step kinetics during crystal growth
Authors: Ju Guangxu , Xu Dongwei , Thompson Carol , Highland Matthew J. , Eastman Jeffrey A. , Walkosz Weronika , Zapol Peter , Stephenson G. Brian
Published: March 2021

The stacking sequence of hexagonal close-packed and related crystals typically results in steps on vicinal {0001} surfaces that have alternating A and B structures with different growth kinetics. However, because it is difficult to experimentally identify which step has the A or B structure, it has not been possible to determine which has faster adatom attachment kinetics. Here we show that in situ microbeam surface X-ray scattering can determine whether A or B steps have faster kinetics under specific growth conditions. We demonstrate this for organo-metallic vapor phase epitaxy of (0001) GaN. X-ray measurements performed during growth find that the average width of terraces above A steps increases with growth rate, indicating that attachment rate constants are higher for A steps, in contrast to most predictions. Our results have direct implications for understanding the atomic-scale mechanisms of GaN growth and can be applied to a wide variety of related crystals.
Stabilisation of half MCM ring by Cdt1 during DNA insertion
Authors: Guerrero-Puigdevall Marina , Fernandez-Fuentes Narcis , Frigola Jordi
Published: March 2021

Origin licensing ensures precise once per cell cycle replication in eukaryotic cells. The Origin Recognition Complex, Cdc6 and Cdt1 load Mcm2-7 helicase (MCM) into a double hexamer, bound around duplex DNA. The complex formed by ORC-Cdc6 bound to duplex DNA (OC) recruits the MCM-Cdt1 complex into the replication origins. Through the stacking of both complexes, the duplex DNA is inserted inside the helicase by an unknown mechanism. In this paper we show that the DNA insertion comes with a topological problem in the stacking of OC with MCM-Cdt1. Unless an essential, conserved C terminal winged helix domain (C-WHD) of Cdt1 is present, the MCM splits into two halves. The binding of this domain with the essential C-WHD of Mcm6, allows the latching between the MCM-Cdt1 and OC, through a conserved Orc5 AAA-lid interaction. Our work provides new insights into how DNA is inserted into the eukaryotic replicative helicase, through a series of synchronized events.
A molecular photosensitizer achieves a Voc of 1.24 V enabling highly efficient and stable dye-sensitized solar cells with copper(II/I)-based electrolyte
Authors: Zhang Dan , Stojanovic Marko , Ren Yameng , Cao Yiming , Eickemeyer Felix T. , Socie Etienne , Vlachopoulos Nick , Moser Jacques-E. , Zakeeruddin Shaik M. , Hagfeldt Anders , Grätzel Michael
Published: March 2021

To develop photosensitizers with high open-circuit photovoltage (Voc) is a crucial strategy to enhance the power conversion efficiency (PCE) of co-sensitized solar cells. Here, we show a judiciously tailored organic photosensitizer, coded MS5, featuring the bulky donor N-(2’,4’-bis(dodecyloxy)-[1,1’-biphenyl]-4-yl)-2’,4’-bis(dodecyloxy)-N-phenyl-[1,1’-biphenyl]-4-amine and the electron acceptor 4-(benzo[c][1,2,5]thiadiazol-4-yl)benzoic acid. Employing MS5 with a copper (II/I) electrolyte enables a dye-sensitized solar cell (DSC) to achieve a strikingly high Voc of 1.24 V, with the Voc deficit as low as 130 mV and an ideality factor of merely 1.08. The co-sensitization of MS5 with the wider spectral-response dye XY1b produces a highly efficient and stable DSC with the PCE of 13.5% under standard AM1.5 G, 100 mW cm−2 solar radiation. Remarkably, the co-sensitized solar cell (active area of 2.8 cm2) presents a record PCE of 34.5% under ambient light, rendering it very attractive as an ambient light harvesting energy source for low power electronics.
Citrullination of pyruvate kinase M2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation
Authors: Coassolo Sébastien , Davidson Guillaume , Negroni Luc , Gambi Giovanni , Daujat Sylvain , Romier Christophe , Davidson Irwin
Published: March 2021

Chromodomain helicase DNA binding protein 4 (CHD4) is an ATPase subunit of the Nucleosome Remodelling and Deacetylation (NuRD) complex that regulates gene expression. CHD4 is essential for growth of multiple patient derived melanoma xenografts and for breast cancer. Here we show that CHD4 regulates expression of PADI1 (Protein Arginine Deiminase 1) and PADI3 in multiple cancer cell types modulating citrullination of arginine residues of the allosterically-regulated glycolytic enzyme pyruvate kinase M2 (PKM2). Citrullination of PKM2 R106 reprogrammes cross-talk between PKM2 ligands lowering its sensitivity to the inhibitors Tryptophan, Alanine and Phenylalanine and promoting activation by Serine. Citrullination thus bypasses normal physiological regulation by low Serine levels to promote excessive glycolysis and reduced cell proliferation. We further show that PADI1 and PADI3 expression is up-regulated by hypoxia where PKM2 citrullination contributes to increased glycolysis. We provide insight as to how conversion of arginines to citrulline impacts key interactions within PKM2 that act in concert to reprogramme its activity as an additional mechanism regulating this important enzyme.
An endothelial activin A-bone morphogenetic protein receptor type 2 link is overdriven in pulmonary hypertension
Authors: Ryanto Gusty R. T. , Ikeda Koji , Miyagawa Kazuya , Tu Ly , Guignabert Christophe , Humbert Marc , Fujiyama Tomoyuki , Yanagisawa Masashi , Hirata Ken-ichi , Emoto Noriaki
Published: March 2021

Pulmonary arterial hypertension is a progressive fatal disease that is characterized by pathological pulmonary artery remodeling, in which endothelial cell dysfunction is critically involved. We herein describe a previously unknown role of endothelial angiocrine in pulmonary hypertension. By searching for genes highly expressed in lung microvascular endothelial cells, we identify inhibin-β-A as an angiocrine factor produced by pulmonary capillaries. We find that excess production of inhibin-β-A by endothelial cells impairs the endothelial function in an autocrine manner by functioning as activin-A. Mechanistically, activin-A induces bone morphogenetic protein receptor type 2 internalization and targeting to lysosomes for degradation, resulting in the signal deficiency in endothelial cells. Of note, endothelial cells isolated from the lung of patients with idiopathic pulmonary arterial hypertension show higher inhibin-β-A expression and produce more activin-A compared to endothelial cells isolated from the lung of normal control subjects. When endothelial activin-A-bone morphogenetic protein receptor type 2 link is overdriven in mice, hypoxia-induced pulmonary hypertension was exacerbated, whereas conditional knockout of inhibin-β-A in endothelial cells prevents the progression of pulmonary hypertension. These data collectively indicate a critical role for the dysregulated endothelial activin-A-bone morphogenetic protein receptor type 2 link in the progression of pulmonary hypertension, and thus endothelial inhibin-β-A/activin-A might be a potential pharmacotherapeutic target for the treatment of pulmonary arterial hypertension.
Top-down control of visual cortex by the frontal eye fields through oscillatory realignment
Authors: Veniero Domenica , Gross Joachim , Morand Stephanie , Duecker Felix , Sack Alexander T. , Thut Gregor
Published: March 2021

Voluntary allocation of visual attention is controlled by top-down signals generated within the Frontal Eye Fields (FEFs) that can change the excitability of lower-level visual areas. However, the mechanism through which this control is achieved remains elusive. Here, we emulated the generation of an attentional signal using single-pulse transcranial magnetic stimulation to activate the FEFs and tracked its consequences over the visual cortex. First, we documented changes to brain oscillations using electroencephalography and found evidence for a phase reset over occipital sites at beta frequency. We then probed for perceptual consequences of this top-down triggered phase reset and assessed its anatomical specificity. We show that FEF activation leads to cyclic modulation of visual perception and extrastriate but not primary visual cortex excitability, again at beta frequency. We conclude that top-down signals originating in FEF causally shape visual cortex activity and perception through mechanisms of oscillatory realignment.
Removing leakage-induced correlated errors in superconducting quantum error correction
Authors: McEwen M. , Kafri D. , Chen Z. , Atalaya J. , Satzinger K. J. , Quintana C. , Klimov P. V. , Sank D. , Gidney C. , Fowler A. G. , Arute F. , Arya K. , Buckley B. , Burkett B. , Bushnell N. , Chiaro B. , Collins R. , Demura S. , Dunsworth A. , Erickson C. , Foxen B. , Giustina M. , Huang T. , Hong S. , Jeffrey E. , Kim S. , Kechedzhi K. , Kostritsa F. , Laptev P. , Megrant A. , Mi X. , Mutus J. , Naaman O. , Neeley M. , Neill C. , Niu M. , Paler A. , Redd N. , Roushan P. , White T. C. , Yao J. , Yeh P. , Zalcman A. , Chen Yu , Smelyanskiy V. N. , Martinis John M. , Neven H. , Kelly J. , Korotkov A. N. , Petukhov A. G. , Barends R.
Published: March 2021

Quantum computing can become scalable through error correction, but logical error rates only decrease with system size when physical errors are sufficiently uncorrelated. During computation, unused high energy levels of the qubits can become excited, creating leakage states that are long-lived and mobile. Particularly for superconducting transmon qubits, this leakage opens a path to errors that are correlated in space and time. Here, we report a reset protocol that returns a qubit to the ground state from all relevant higher level states. We test its performance with the bit-flip stabilizer code, a simplified version of the surface code for quantum error correction. We investigate the accumulation and dynamics of leakage during error correction. Using this protocol, we find lower rates of logical errors and an improved scaling and stability of error suppression with increasing qubit number. This demonstration provides a key step on the path towards scalable quantum computing.