bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐Term Moored Current and Temperature Measurements of the Atlantic Inflow Into the Nordic Seas in the Norwegian Atlantic Current; 1995–2020
Authors: Orvik Kjell Arild
Published: January 2022

Interannual variability of the Atlantic inflow (AI) into the Nordic Seas is studied using moored current and temperature measurements in the Norwegian Atlantic Current during the 25‐year period 1995–2020. We show that the properties of the AI are strongly connected to the dynamics of the Northern Atlantic and demonstrate the robustness of the average winter wind field in driving the variability with 3‐month winter maxima in the range of (40–50) cms−1. In that sense, the zero‐wind‐stress‐curl (ZWSC)‐lines aligned northeastward are crucial. Occasional events with slowdown of winter‐maxima are connected to a meridional and zonal shift of the ZWSC‐lines, and not the strength of the wind. This is manifested in a correlation of 0.3 versus the North Atlantic Oscillation (NAO) winter‐index, demonstrating that the NAO‐index is insufficient to explain the AI‐variability. The records show no long‐term‐trend over the 25‐year period 1995–2020, regarding volume flux, temperature, nor temperature flux.
Increased Erosion Rates Following the Onset of Pleistocene Periglaciation at Bear Meadows, Pennsylvania, USA
Authors: Del Vecchio J. , DiBiase R. A. , Corbett L. B. , Bierman P. R. , Caffee M. W. , Ivory S. J.
Published: January 2022

Direct measurements of erosional response to past climate change are scarce, but mid‐latitude landscapes can record how shifts between cold and warm periods altered erosion outside glacial margins. To study hillslope responses to periglaciation, we measured bulk geochemistry and cosmogenic 10Be and 26Al concentrations in colluvium and weathered bedrock in an 18 m regolith core from Bear Meadows, Pennsylvania, ∼100 km south of maximum glacial extent. Using core lithology, cosmogenic nuclide concentrations, and regional 10Be‐derived erosion rates, we show the onset of 100‐Kyr glacial cycles at the Mid‐Pleistocene Transition (1.2–0.7 Ma) instigated multiple periglacial episodes in central Appalachia, increasing erosion rates compared to the relatively warmer Neogene. Our results show the higher efficiency of periglacial versus temperate erosion processes and highlight a pervasive Pleistocene periglacial erosion signal preserved in the 10Be inventory of surface sediments in central Appalachia, where erosion rates are slow enough to integrate previous cold‐climate processes.
More or Less: How Do Inhomogeneous Sea‐Salt Aerosols Affect the Precipitation of Landfalling Tropical Cyclones?
Authors: Zhu Limin , Shu Shoujuan , Wang Zheng , Bi Lei
Published: January 2022

The evolution of landfalling Typhoon Fitow in the western North Pacific in 2013 is simulated with an emphasis on the direct radiative effect of sea‐salt aerosols (SSAs) on the precipitation of Fitow. The inhomogeneous SSAs, formed under the environment with low relative humidity (50%–70%), exhibit different optical properties (particular the decreased asymmetry factor) compared with the commonly used homogeneous sea‐salt droplets. We find that incorporating the inhomogeneity of SSAs in the Weather Research and Forecasting (WRF) model decreases the simulated rainfall of Fitow in coastal regions where the continental dry air intrudes. Fundamentally, the cooling effect induced by the particle inhomogeneity and its hysteresis increase atmospheric stability and weaken vertical velocity, which reduce the accumulated rainfall of Fitow. These findings of radiation‐related effects of SSAs provide a new clue for improving the physical processes responsible for precipitation of tropical cyclones in numerical models.
Contributions of Anthropogenic Aerosol Forcing and Multidecadal Internal Variability to Mid‐20th Century Arctic Cooling—CMIP6/DAMIP Multimodel Analysis
Authors: Aizawa Takuro , Oshima Naga , Yukimoto Seiji
Published: January 2022

In the Arctic, observed decadal mean surface air temperatures (SATs) were 0.70°C–0.95°C lower around 1970 than those around 1940. The 35‐multimodel ensemble mean of historical simulations in the Coupled Model Intercomparison Project Phase 6 (CMIP6) exhibited Arctic surface cooling trend in 1940–1970, which could be attributed to external forcings. Multimodel ensemble means of CMIP6 Detection and Attribution Model Intercomparison Project historical simulations exhibited Arctic surface cooling of −0.22°C (±0.24°C) in 1970 versus 1940 and showed that anthropogenic aerosol forcings contributed to a cooling of −0.65°C (±0.37°C), which was partially offset by a warming of 0.44°C (±0.22°C) due to well‐mixed greenhouse gases. In addition to the anthropogenic aerosol forcings, multidecadal internal variability with a magnitude of 0.47°C was the component primarily contributing to the observed Arctic cooling. We identified a spatial pattern of pan‐Arctic multidecadal cooling due to the internal variability that resembles the 1940–1970 cooling pattern.
Electromagnetic Ion Cyclotron Harmonic Waves Generated via Nonlinear Wave‐Wave Couplings
Authors: Deng Dan , Yuan Zhigang , Huang Shiyong , Xue Zuxiang , Huang Zheng , Yu Xiongdong
Published: January 2022

In this letter, we report an electromagnetic ion cyclotron (EMIC) harmonic event observed by the Van Allen Probe B, whose generation is demonstrated to result from nonlinear wave‐wave resonances through the bicoherence analysis. Hybrid simulation shows that the second to sixth harmonics could be excited in sequence after a pump EMIC wave is initially injected, which is in consistent with the observations of EMIC harmonic. It indicates the important role of the second harmonic in the generation of higher harmonics. Finally, the statistical distribution for the amplitude of EMIC second harmonic waves indicates that the energy transfer rate from the fundamental wave to the second harmonic is mainly less than 2%, which might be too low to result in third and other higher harmonics above the observational level. Our results will give some new insights into the excitation of EMIC harmonic waves in the inner magnetosphere.
Impact of Anthropogenic Emission Changes on the Occurrence of Equatorial Plasma Bubbles
Authors: Zhou Xu , Yue Xinan , Ren Zhipeng , Liu Yunbo , Cai Yihui , Ding Feng , Wei Yong
Published: January 2022

In this work, we examine the impact of increased anthropogenic emissions on equatorial plasma bubble (EPB) occurrence by modeling the growth rate of Rayleigh‐Taylor (R‐T) instability (), which is closely related to EPB generation. Using the global coupled ionosphere‐thermosphere‐electrodynamics model‐institute of geology and geophysics, Chinese Academy of Sciences model, is calculated under three different CO2 emission levels. As CO2 increases, significantly increases at low altitudes (<∼260 km) and decreases at high altitudes (>∼320 km). In the altitudes in between, increases (decreases) before (after) midnight. Longitudinal variability of the change is manifested apparently above ∼280 km, while it is insignificant for low altitudes. Term analysis revealed that changes in the gravity term and the electric‐field term are the main causes and that the neutral‐wind term is insignificant. The investigation indicates that increased anthropogenic emissions can change EPB occurrence and, in turn, the radio‐communication system and therefore influence modern technological systems, which is expected to be more serious in the future.
Effect of the Magnetospheric Plasma Interaction and Solar Illumination on Ion Sputtering of Europa’s Surface Ice
Authors: Addison Peter , Liuzzo Lucas , Simon Sven
Published: January 2022

For the entire ion energy range observed at Europa, we calculate spatially resolved maps of the surface sputtering rates of H2O, O2, and H2 from impacts by magnetospheric ions. We use the perturbed electromagnetic fields from a hybrid model of Europa’s plasma interaction, along with a particle‐tracing tool, to calculate the trajectories of magnetospheric ions impinging onto the surface and their resultant sputtering yields. We examine how the distribution of the sputtering rates depends on the electromagnetic field perturbations, the angle between the solar radiation and the corotating plasma flow, and the thickness of the oxygen‐bearing layer within Europa’s surface. Our major findings are: (a) Magnetic field‐line draping partially diverts the impinging ions around Europa, reducing the sputtering rates on the upstream hemisphere, but allowing for substantial sputtering from the downstream hemisphere. In contrast, zero sputtering occurs in much of the downstream hemisphere with uniform electromagnetic fields. (b) If the oxygen‐bearing surface layer is thin compared to the penetration depth of magnetospheric ions, thermal ions dominate the O2 sputtering rates, and the region of strongest sputtering is persistently located near the upstream apex. However, if the oxygen‐bearing layer is thick compared to the penetration depth, energetic ions sputter the most O2, and the location of maximum sputtering follows the sub‐solar point as Europa orbits Jupiter. (c) The global production rate of O2 from Europa’s surface varies by a factor of 3 depending upon the Moon’s orbital position, with the maximum particle release occurring when Europa’s Sun‐lit and upstream hemispheres coincide.
Vertical Transport Timescale of Surface‐Produced Particulate Material in the Chesapeake Bay
Authors: Xiong Jilian , Shen Jian
Published: January 2022

Accumulation and remineralization of surface‐produced particulate organic matter (POM) in the water column and seabed link closely to hypoxia and the health of aquatic ecosystems. The POM retention time provides a key timescale to interpret biochemical reaction processes. In this study, we investigated the spatiotemporal variations in the vertical particulate age (VPA) of surface‐produced POM, which is the mean time elapsed since the particulates last contact the surface, by incorporating major physical processes including sinking, resuspension, and deposition in the Chesapeake Bay. It was found that the vertical transport time for the particulates (i.e., VPA) is much longer than the dissolved counterparts as the former consists of new material from the surface and the resuspended aged material that has elongated resting on the seabed after deposition. The VPA is sensitive to settling velocity, especially in low‐frequent resuspension environments, and varies over 2 orders of magnitude with settling velocity from 0 to 10 m/day. Slow‐sinking material can remain in suspension and seldom settle to the seabed, thus mainly contribute to pelagic processes, while the fast‐sinking material connects closely with benthic processes. The seasonality of VPA decreases as the settling velocity increases. No significant difference in VPA was found between wet and dry years, yet the episodic strong flood events entrain old materials from the depositional lateral shoals to increase VPA in the channel. The transport age bridges cross disciplinaries by providing the fourth‐dimensional age information as a common currency to compare the physical transport timescale with the timescales for biochemical reactions.
Electron Dynamics in a Chorus Wave Field Generated From Particle‐In‐Cell Simulations
Authors: An Zeyu , Wu Yifan , Tao Xin
Published: January 2022

How to properly describe resonant interactions between electrons and quasi‐coherent chorus waves is still an open question. Previous studies have progressed from modeling chorus as a single wave to considering effects such as amplitude modulation or phase decoherence in wave particle resonance. However, incorporating realistic features of chorus waves in test particle calculations has always been a challenging but critically important step to evaluate their nonlinear effects. In this work, we use a rising‐tone chorus element generated by a particle‐in‐cell simulation in test‐particle simulations. The used chorus wave naturally has features including amplitude modulation, phase decoherence and dynamic evolution during propagation. Our results suggest that, while being latitudinal dependent, realistic features of chorus generally lead to significant suppression of nonlinear effects. This result should be important to understand phase space transport of electrons due to interactions with chorus waves.
Dust Rotation and Swirl Morphology in Lunar Magnetic Anomalies
Authors: Gerard Michael , Deca Jan , Horányi Mihály
Published: January 2022

The scattering of light off the bright regions of lunar swirls suggests a relatively higher fraction of fine‐grained dust compared to dust with similar optical maturity values found elsewhere on the lunar surface when assuming an isotropically oriented dust distribution, without preferred grain orientation. Here we propose a mechanism by which the ferromagnetic lunar fines, lofted by electrostatic effects or by meteoroid impacts, may rotate in a lunar magnetic anomaly and, upon landing, produce patches of organized alignments, generating anisotropic surface structures. We simulate these rotations for Reiner Gamma and provide a proof of concept for such a dust rotation model. While the magnetic forces remain negligibly small to influence the trajectories of the lofted particles, the magnetic torques have a significant effect on the rotation of magnetized dust, and can generate an organized landing pattern for elongated lunar fines, which offers a possible explanation for the lunar albedo patterns.
Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1
Authors: Melnyk James E. , Steri Veronica , Nguyen Hao G. , Hwang Y. Christina , Gordan John D. , Hann Byron , Feng Felix Y. , Shokat Kevan M.
Published: January 2022

The androgen receptor (AR) is a central driver of aggressive prostate cancer. After initial treatment with androgen receptor signaling inhibitors (ARSi), reactivation of AR signaling leads to resistance. Alternative splicing of AR mRNA yields the AR-V7 splice variant, which is currently an undruggable mechanism of ARSi resistance: AR-V7 lacks a ligand binding domain, where hormones and anti-androgen antagonists act, but still activates AR signaling. We reveal PKCβ as a druggable regulator of transcription and splicing at the AR genomic locus. We identify a clinical PKCβ inhibitor in combination with an FDA-approved anti-androgen as an approach for repressing AR genomic locus expression, including expression of AR-V7, while antagonizing full-length AR. PKCβ inhibition reduces total AR gene expression, thus reducing AR-V7 protein levels and sensitizing prostate cancer cells to current anti-androgen therapies. We demonstrate that this combination may be a viable therapeutic strategy for AR-V7-positive prostate cancer.
NEAR trial: A single-arm phase II trial of neoadjuvant apalutamide monotherapy and radical prostatectomy in intermediate- and high-risk prostate cancer
Authors: Lee Lui Shiong , Sim Adelene Y. L. , Ong Chee Wee , Yang Xinyan , Ng Cedric C. Y. , Liu Wei , Rajasegaran Vikneswari , Lim Abner M. S. , Aslim Edwin Jonathan , Ngo Nye-Thane , Khor Li-Yan , Kanesvaran Ravindran , Allen John Carson Jr , Tay Kae Jack , Yuen John Shyi Peng , Chong Tsung Wen , Ho Sun Sien Henry , Teh Bin Tean , Chua Melvin L. K.
Published: January 2022

Objective

Treatment efficacy of androgen deprivation therapy with radical prostatectomy for intermediate- to high-risk prostate cancer is less well-studied. The NEAR trial is a single-arm, phase II investigation of neoadjuvant apalutamide monotherapy and radical prostatectomy (RP) in the treatment of D’Amico intermediate- and high-risk prostate cancer (NCT03124433).

Materials and methods

Patients with histologically-proven, D’Amico intermediate- to high-risk prostate adenocarcinoma received apalutamide 240 mg once-daily for 12 weeks followed by RP + /−lymphadenectomy. Primary outcome was pathological complete response (pCR) rate. Secondary outcomes included rate of biochemical response (defined by PSA < 0.03 ng/mL at week 24 from starting apalutamide without subsequent PSA relapse), treatment-related adverse events, and RP complication rates. Correlative biomarker analyses were performed to examine for molecular predictors of treatment responses.

Results

From 2017 to 2019, 30 patients were recruited, of which 20 and 10 were high and intermediate risk, respectively; 25 completed treatment as per-protocol. We did not observe any pCR on trial; median reduction of cancer burden was 41.7% (IQR: 33.3%–60.0%). 18 out of 25 patients were classified as having a biochemical response (4 did not achieve PSA of <0.03 ng/mL at week 24 and 3 developed PSA relapse subsequently). Dry skin (N = 16; 53.3%), fatigue (N = 10; 33.3%) and skin rash (N = 9; 30.0%) were the most common adverse events, and there was no major peri-operative complication. We observed an association between tumours of low androgen receptor activity and PAM50 basal status with biochemical non-responders, albeit these molecular phenotypes were not associated with pathological response.

Conclusions

A 12-week course of neoadjuvant apalutamide prior to RP did not meet the primary endpoint of pCR in this trial. Tumours with low androgen receptor activity or of the PAM50 basal subtype may have a reduced response to apalutamide.
Phylogenetic divergence and adaptation of Nitrososphaeria across lake depths and freshwater ecosystems
Authors: Ren Minglei , Wang Jianjun
Published: January 2022

Thaumarchaeota (now the class Nitrososphaeria in the phylum Thermoproteota in GTDB taxonomy) are abundant across marine and soil habitats; however, their genomic diversity and evolutionary history in freshwater environments remain elusive. Here, we reconstructed 17 high-quality metagenome-assembled genomes of Nitrososphaeria from a deep lake and two great rivers, and compared all available genomes between freshwater and marine habitats regarding their phylogenetic positions, relative abundance, and genomic content. We found that freshwater Nitrososphaeria were dominated by the family Nitrosopumilaceae and could be grouped into three distinct clades closely related to the genera Nitrosopumilus, Nitrosoarchaeum, and Nitrosotenuis. The Nitrosopumilus-like clade was exclusively from deep lakes, while the Nitrosoarchaeum-like clade was dominated by species from deep lakes and rivers, and the Nitrosotenuis-like clade was mainly from rivers, deep lakes, and estuaries. Interestingly, there was vertical niche separation between two clades in deep lakes, showing that the Nitrosopumilus-like species dominated shallow layers, whereas the relative abundance of the Nitrosoarchaeum-like clade increased toward deep waters. Phylogenetic clustering patterns in the Nitrosopumilaceae supported at least one freshwater-to-marine and two marine-to-freshwater transitions, the former of which refined the potential terrestrial-to-marine evolutionary path as previously proposed. The occurrence of the two marine-to-freshwater transitions were accompanied by horizontal transfer of the genes involved in nutrition regulation, osmoregulation, and cell motility during their colonization to freshwater habitats. Specifically, the Nitrosopumilus-like clade showed losses of genes encoding flagella assembly and ion transport, whereas the Nitrosoarchaeum-like clade had losses of intact genes involved in urea uptake and utilization and gains of genes encoding osmolarity-mediated mechanosensitive channels. Collectively, our results reveal for the first time the high genomic diversity of the class Nitrososphaeria across freshwater ecosystems and provide novel insights into their adaptive mechanisms and evolutionary histories.
Mapping the expression of an ANK3 isoform associated with bipolar disorder in the human brain
Authors: Holmgren Asbjørn , Hansson Lars , Bjerkaas-Kjeldal Kristine , Impellizzeri Agata Antonia Rita , Gilfillan Gregor D. , Djurovic Srdjan , Hughes Timothy
Published: January 2022

The gene ankyrin-3 (ANK3) has been consistently associated with bipolar disorder (BD) in several genome-wide association studies (GWAS). The exact molecular mechanisms underlying this genetic association remain unknown. The discovery of a loss-of-function variant (rs41283526*G) in an alternatively spliced exon (ENSE00001786716) with a protective effect, suggested that elevated expression of this particular isoform could be a risk factor for developing the disorder. We developed a novel approach for measuring the expression level of all splice forms at a challenging genetic locus using a combination of droplet digital PCR and high-throughput sequencing of indexed PCR amplicons. The combined method was performed on a large collection of 568 postmortem brain samples of BD and SCZ cases and controls. We also studied the expression of the splice forms in a child-development cohort of 41 healthy males. We found that our approach can quantify the splice forms in brain samples, although with less precision than ddPCR. We detected highly significant differences in expression of splice forms and transcription start sites between brain regions, notably with higher expression of the BD-associated isoform in the corpus callosum compared to frontal tissue (mean fold change = 1.80, p < 1e-4). Although the patients in our sample expressed the BD-associated splice form at a similar level to controls, adolescents in our child-development cohort had a clearly higher expression level than younger children (mean fold change = 1.97, p = 5e-3). These results suggest that this ANK3 splice form may play a role in the myelin maturation of the human brain.
Brain network dysfunctions in addiction: a meta-analysis of resting-state functional connectivity
Authors: Tolomeo Serenella , Yu Rongjun
Published: January 2022

Resting-state functional connectivity (rsFC) provides novel insights into variabilities in neural networks associated with the use of addictive drugs or with addictive behavioral repertoire. However, given the broad mix of inconsistent findings across studies, identifying specific consistent patterns of network abnormalities is warranted. Here we aimed at integrating rsFC abnormalities and systematically searching for large-scale functional brain networks in substance use disorder (SUD) and behavioral addictions (BA), through a coordinate-based meta-analysis of seed-based rsFC studies. A total of fifty-two studies are eligible in the meta-analysis, including 1911 SUD and BA patients and 1580 healthy controls. In addition, we performed multilevel kernel density analysis (MKDA) for the brain regions reliably involved in hyperconnectivity and hypoconnectivity in SUD and BA. Data from fifty-two studies showed that SUD was associated with putamen, caudate and middle frontal gyrushyperconnectivityrelative to healthy controls. Eight BA studies showedhyperconnectivityclusters within the putamen and medio-temporal lobe relative to healthy controls. Alteredconnectivityin salience or emotion-processing areas may be related to dysregulated affective and cognitive control-related networks, such as deficits in regulating elevated sensitivity to drug-related stimuli. These findings confirm that SUD and BA might be characterized by dysfunctions in specific brain networks, particularly those implicated in the core cognitive and affective functions. These findings might provide insight into the development of neural mechanistic biomarkers for SUD and BA.
TRK-fused gene (TFG) regulates ULK1 stability via TRAF3-mediated ubiquitination and protects macrophages from LPS-induced pyroptosis
Authors: Shi Jian-Hong , Ling Chen , Wang Ting-Ting , Zhang Li-Nuo , Liu Wen-Wen , Qin Yan , Tan Ying-Hui , Cui Nai-Peng , Ni Zhi-Yu
Published: January 2022

TRK-fused gene (TFG) is known to be involved in protein secretion and plays essential roles in an antiviral innate immune response. However, its function in LPS-induced inflammation and pyroptotic cell death is still unknown. Here, we reported that TFG promotes the stabilization of Unc-51 like autophagy activating kinase (ULK1) and participates in LPS plus nigericin (Ng) induced pyroptotic cell death. Our results showed that TFG-deficient THP-1 macrophages exhibit higher mitochondrial ROS production. LPS/Ng stimulation triggers a much higher level of ROS and induces pyroptotic cell death. ULK1 undergoes a rapid turnover in TFG-deficient THP-1 cells. TFG forms complex with an E3 ligase, tumor necrosis factor receptor-associated factor 3 (TRAF3), and stabilizes ULK1 via disturbing ULK1-TRAF3 interaction. Knockdown of TFG facilitates the interaction of ULK1 with TRAF3 and subsequent K48-linked ULK1 ubiquitination and proteasome degradation. Rescue of ULK1 expression blocks LPS/Ng-induced cell death in TFG-deficient THP-1 macrophages. Taken together, TFG plays an essential role in LPS/Ng-induced pyroptotic cell death via regulating K48-linked ULK1 ubiquitination in macrophages.
Transcriptional changes in the mammary gland during lactation revealed by single cell sequencing of cells from human milk
Authors: Twigger Alecia-Jane , Engelbrecht Lisa K. , Bach Karsten , Schultz-Pernice Isabel , Pensa Sara , Stenning Jack , Petricca Stefania , Scheel Christina H. , Khaled Walid T.
Published: January 2022

Under normal conditions, the most significant expansion and differentiation of the adult mammary gland occurs in response to systemic reproductive hormones during pregnancy and lactation to enable milk synthesis and secretion to sustain the offspring. However, human mammary tissue remodelling that takes place during pregnancy and lactation remains poorly understood due to the challenge of acquiring samples. We report here single-cell transcriptomic analysis of 110,744 viable breast cells isolated from human milk or non-lactating breast tissue, isolated from nine and seven donors, respectively. We found that human milk largely contains epithelial cells belonging to the luminal lineage and a repertoire of immune cells. Further transcriptomic analysis of the milk cells identified two distinct secretory cell types that shared similarities with luminal progenitors, but no populations comparable to hormone-responsive cells. Taken together, our data offers a reference map and a window into the cellular dynamics that occur during human lactation and may provide further insights on the interplay between pregnancy, lactation and breast cancer.
Mesenchymal stromal cell-derived septoclasts resorb cartilage during developmental ossification and fracture healing
Authors: Sivaraj Kishor K. , Majev Paul-Georg , Jeong Hyun-Woo , Dharmalingam Backialakshmi , Zeuschner Dagmar , Schröder Silke , Bixel M. Gabriele , Timmen Melanie , Stange Richard , Adams Ralf H.
Published: January 2022

Developmental osteogenesis, physiological bone remodelling and fracture healing require removal of matrix and cellular debris. Osteoclasts generated by the fusion of circulating monocytes degrade bone, whereas the identity of the cells responsible for cartilage resorption is a long-standing and controversial question. Here we show that matrix degradation and chondrocyte phagocytosis are mediated by fatty acid binding protein 5-expressing cells representing septoclasts, which have a mesenchymal origin and are not derived from haematopoietic cells. The Notch ligand Delta-like 4, provided by endothelial cells, is necessary for septoclast specification and developmental bone growth. Consistent with the termination of growth, septoclasts disappear in adult and ageing bone, but re-emerge in association with growing vessels during fracture healing. We propose that cartilage degradation is mediated by rare, specialized cells distinct from osteoclasts. Our findings have implications for fracture healing, which is frequently impaired in aging humans.
Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors
Authors: Pantsar Tatu , Kaiser Philipp D. , Kudolo Mark , Forster Michael , Rothbauer Ulrich , Laufer Stefan A.
Published: January 2022

Target residence time plays a crucial role in the pharmacological activity of small molecule inhibitors. Little is known, however, about the underlying causes of inhibitor residence time at the molecular level, which complicates drug optimization processes. Here, we employ all-atom molecular dynamics simulations (~400 μs in total) to gain insight into the binding modes of two structurally similar p38α MAPK inhibitors (type I and type I½) with short and long residence times that otherwise show nearly identical inhibitory activities in the low nanomolar IC50range. Our results highlight the importance of protein conformational stability and solvent exposure, buried surface area of the ligand and binding site resolvation energy for residence time. These findings are further confirmed by simulations with a structurally diverse short residence time inhibitor SB203580. In summary, our data provide guidance in compound design when aiming for inhibitors with improved target residence time.
Multiphase flow detection with photonic crystals and deep learning
Authors: Feng Lang , Natu Stefan , Som de Cerff Edmonds Victoria , Valenza John J.
Published: January 2022

Multiphase flows are ubiquitous in industrial settings. It is often necessary to characterize these fluid mixtures in support of process optimization. Unfortunately, existing commercial technologies often fail to provide frequent, accurate, and cost-efficient data necessary to enable process optimization. Here we show a new physics-based concept and testing with lab and field prototypes leveraging photonic crystals for real-time characterization of multiphase flows. In particular, low power (~1 mW) microwave transmission through photonic crystals filled with fluid mixtures may be interrogated by deep learning analysis techniques to provide a fast and accurate characterization of phase fraction and flow morphology. Moreover when these flow characteristics are known, the flow rate is accurately inferred from the differential pressure necessary for the flow to pass through the photonic crystal. This insight provides a basis to develop a unique class of inexpensive, accurate, and convenient techniques to characterize multiphase flows.
Memory B cell repertoire from triple vaccinees against diverse SARS-CoV-2 variants
Authors: Wang Kang , Jia Zijing , Bao Linilin , Wang Lei , Cao Lei , Chi Hang , Hu Yaling , Li Qianqian , Zhou Yunjiao , Jiang Yinan , Zhu Qianhui , Deng Yongqiang , Liu Pan , Wang Nan , Wang Lin , Liu Min , Li Yurong , Zhu Boling , Fan Kaiyue , Fu Wangjun , Yang Peng , Pei Xinran , Cui Zhen , Qin Lili , Ge Pingju , Wu Jiajing , Liu Shuo , Chen Yiding , Huang Weijin , Wang Qiao , Qin Cheng-Feng , Wang Youchun , Qin Chuan , Wang Xiangxi
Published: January 2022

Omicron (B.1.1.529), the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising concerns about the effectiveness of antibody therapies and vaccines1,2. Here we examined whether sera from individuals who received two or three doses of inactivated SARS-CoV-2 vaccine could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2 out of 60) and 95% (57 out of 60) for individuals who had received 2 and 3 doses of vaccine, respectively. For recipients of three vaccine doses, the geometric mean neutralization antibody titre for Omicron was 16.5-fold lower than for the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in triple vaccinees, half of which recognized the receptor-binding domain, and showed that a subset (24 out of 163) potently neutralized all SARS-CoV-2 variants of concern, including Omicron. Therapeutic treatments with representative broadly neutralizing monoclonal antibodies were highly protective against infection of mice with SARS-CoV-2 Beta (B.1.351) and Omicron. Atomic structures of the Omicron spike protein in complex with three classes of antibodies that were active against all five variants of concern defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to a class of antibodies that bind on the right shoulder of the receptor-binding domain by altering local conformation at the binding interface. Our results rationalize the use of three-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are rational targets for a universal sarbecovirus vaccine.
Hypoxia-induced HIF1α activation regulates small extracellular vesicle release in human embryonic kidney cells
Authors: Muñiz-García Ana , Romero Montserrat , Falcόn-Perez Juan Manuel , Murray Patricia , Zorzano Antonio , Mora Silvia
Published: January 2022

Extracellular vesicles (EVs) are membrane enclosures released by eukaryotic cells that carry bioactive molecules and serve to modulate biological responses in recipient cells. Both increased EV release and altered EV composition are associated with the development and progression of many pathologies including cancer. Hypoxia, a feature of rapidly growing solid tumours, increases the release of EVs. However, the molecular mechanisms remain unknown. The hypoxia inducible factors (HIFs) are transcription factors that act as major regulators of the cellular adaptations to hypoxia. Here, we investigated the requirement of HIF pathway activation for EV release in Human Embryonic Kidney Cells (HEK293). Time course experiments showed that EV release increased concomitantly with sustained HIF1α and HIF2α activation following the onset of hypoxia. shRNA mediated knock-down of HIF1α but not HIF2α abrogated the effect of hypoxia on EV release, suggesting HIF1α is involved in this process. However, stabilization of HIF proteins in normoxic conditions through: (i) heterologous expression of oxygen insensitive HIF1α or HIF2α mutants in normoxic cells or (ii) chemical inhibition of the prolyl hydroxylase 2 (PHD2) repressor protein, did not increase EV release, suggesting HIF activation alone is not sufficient for this process. Our findings suggest HIF1α plays an important role in the regulation of EV release during hypoxia in HEK293 cells, however other hypoxia triggered mechanisms likely contribute as stabilization of HIF1α alone in normoxia is not sufficient for EV release.
Representing living architecture through skeleton reconstruction from point clouds
Authors: Middleton Wilfrid , Shu Qiguan , Ludwig Ferdinand
Published: January 2022

Living architecture, changing in structure with annual growth, requires precise, regular characterisation. However, its geometric irregularity and topological complexity make documentation using traditional methods difficult and presents challenges in creating useful models for mechanical and physiological analyses. Two kinds of living architecture are examined: historic living root bridges grown in Meghalaya, India, and contemporary ‘Baubotanik’ structures designed and grown in Germany. These structures exhibit common features, in particular network-like structures of varying complexity that result from inosculations between shoots or roots. As an answer to this modelling challenge, we present the first extensive documentation of living architecture using photogrammetry and a subsequent skeleton extraction workflow that solves two problems related to the anastomoses and varying nearby elements specific to living architecture. Photogrammetry was used as a low cost method, supplying detailed point clouds of the structures’ visible surfaces. A workflow based on voxel-thinning (using deletion templates and adjusted p-simplicity criteria) provides efficient, accurate skeletons. A volume reconstruction method is derived from the thinning process. The workflow is assessed on seven characteristics beneficial in representing living architecture in comparison with alternative skeleton extraction methods. The resulting models are ready for use in analytical tools, necessary for functional, responsible design.
Radiation dose enhancement using gold nanoparticles with a diamond linear accelerator target: a multiple cell type analysis
Authors: Piccolo Olivia , Lincoln John D. , Melong Nicole , Orr Benno C. , Fernandez Nicholas R. , Borsavage Jennifer , Berman Jason N. , Robar James , Ha Michael N.
Published: January 2022

Radiotherapy (RT) is an effective cancer treatment modality, but standard RT often causes collateral damage to nearby healthy tissues. To increase therapeutic ratio, radiosensitization via gold nanoparticles (GNPs) has been shown to be effective. One challenge is that megavoltage beams generated by clinical linear accelerators are poor initiators of the photoelectric effect. Previous computer models predicted that a diamond target beam (DTB) will yield 400% more low-energy photons, increasing the probability of interacting with GNPs to enhance the radiation dose by 7.7-fold in the GNP vicinity. After testing DTB radiation coupled with GNPs in multiple cell types, we demonstrate decreased head-and-neck cancer (HNC) cell viability in vitro and enhanced cell-killing in zebrafish xenografts compared to standard RT. HNC cell lines also displayed increased double-stranded DNA breaks with DTB irradiation in the presence of GNPs. This study presents preclinical responses to GNP-enhanced radiotherapy with the novel DTB, providing the first functional data to support the theoretical evidence for radiosensitization via GNPs in this context, and highlighting the potential of this approach to optimize the efficacy of RT in anatomically difficult-to-treat tumors.
Imaging through diffuse media using multi-mode vortex beams and deep learning
Authors: Balasubramaniam Ganesh M. , Biton Netanel , Arnon Shlomi
Published: January 2022

Optical imaging through diffuse media is a challenging issue and has attracted applications in many fields such as biomedical imaging, non-destructive testing, and computer-assisted surgery. However, light interaction with diffuse media leads to multiple scattering of the photons in the angular and spatial domain, severely degrading the image reconstruction process. In this article, a novel method to image through diffuse media using multiple modes of vortex beams and a new deep learning network named “LGDiffNet” is derived. A proof-of-concept numerical simulation is conducted using this method, and the results are experimentally verified. In this technique, the multiple modes of Gaussian and Laguerre-Gaussian beams illuminate the displayed digits dataset number, and the beams are then propagated through the diffuser before being captured on the beam profiler. Furthermore, we investigated whether imaging through diffuse media using multiple modes of vortex beams instead of Gaussian beams improves the imaging system's imaging capability and enhances the network's reconstruction ability. Our results show that illuminating the diffuser using vortex beams and employing the “LGDiffNet” network provides enhanced image reconstruction compared to existing modalities. When employing vortex beams for image reconstruction, the best NPCC is − 0.9850. However, when using Gaussian beams for imaging acquisition, the best NPCC is − 0.9837. An enhancement of 0.62 dB, in terms of PSNR, is achieved using this method when a highly scattering diffuser of grit 220 and width 2 mm (7.11 times the mean free path) is used. No additional optimizations or reference beams were used in the imaging system, revealing the robustness of the “LGDiffNet” network and the adaptability of the imaging system for practical applications in medical imaging.
Effect of the substrate on the electrical transport and fluctuation processes in NbRe and NbReN ultrathin films for superconducting electronics applications
Authors: Barone C. , Cirillo C. , Carapella G. , Granata V. , Santoro D. , Attanasio C. , Pagano S.
Published: January 2022

NbRe-based superconducting thin films recently received relevant interest in the field of low-temperature electronics. However, for these materials the electrical conduction mechanisms, in particular in the normal state, still need to be investigated in more detail. Here, NbRe and NbReN films of different thicknesses have been deposited on two different substrates, namely monocrystalline Si and $$\text {SiO}_2$$

SiO
2

buffered Si. The films were characterized by DC electrical transport measurements. Moreover, a connection with the charge carriers fluctuation processes has been made by analyzing the electrical noise generated in the normal state region. Despite the films morphology seems not to be affected by the substrate used, a lower noise level has been found for the ones grown on $$\text {SiO}_2$$

SiO
2

, in particular for NbReN. From this study it emerges that both NbRe and NbReN ultrathin films are of very good quality, as far as the low-temperature electrical noise and conduction are concerned, with noise levels competitive with NbN. These results may further support the proposal of using these materials in a nanowire form in the field of superconducting electronics.
Contribution of obesity and cardiometabolic risk factors in developing cardiovascular disease: a population-based cohort study
Authors: Bakhtiyari Mahmood , Kazemian Elham , Kabir Kourosh , Hadaegh Farzad , Aghajanian Sepehr , Mardi Parham , Ghahfarokhi Nooshin Taherzadeh , Ghanbari Ali , Mansournia Mohammad Ali , Azizi Freidoun
Published: January 2022

This study aims to assess the effects of central and general adiposity on development of cardiovascular diseases (CVDs) mediated by cardiometabolic risk factors and to analyze their degree of dependency for mediating their effects. To this end, data from the the Tehran Lipid and Glucose Study cohort with 6280 participants were included in this study. The hazard ratios were calculated using a 2-stage regression model in the context of a survival model. Systolic blood pressure (BP), total serum cholesterol, and fasting plasma glucose were designated as mediators. Assessing the interactions revealed that BP was the most important mediator for general ( (HRNIE: 1.11, 95% CI 1.17–1.24) and central obesity (CO) (HRNIE: 1.11, 95% CI 1.07–1.15) with 60% and 36% proportion of the effects mediated in the total population, respectively. The proportion of mediated risk for all three metabolic risk factors was 46% (95% CI 31–75%) for overweight, 66% (45–100%) for general obesity and 52% (39–87%) for central obesity. BP was the most important mediator for overweight and central obesity in men, comprising 29% and 36% of the risk, respectively. The proportion of the risk mediated through all three metabolic risk factors in women was 23% (95% CI 13–50%) for overweight, 36% (21–64%) for general obesity and 52% (39–87%) for central obesity. Based on the results of this study, cardiometabolic mediators have conciliated more than 60% of the adverse effects of high BMI on CVDs in men. Controlling the metabolic risk factors in women does not efficiently contribute to decreasing CVDs as effectively.
Aminophenol-modified gold nanoparticles kill bacteria with minimal ototoxicity
Authors: Wang Le , Zheng Wenfu , Zhong Leni , Yang Yingkun , Li Sixiang , Li Qizhen , Jiang Xingyu
Published: January 2022

We report aminophenol-modified gold nanoparticles (AGNPs) that have a potent antibacterial activity and low ototoxicity. The AGNPs are promising as novel antibiotics to replace aminoglycosides.
Synthetic chiral molecular nanographenes: the key figure of the racemization barrier
Authors: Fernández-García Jesús M. , Izquierdo-García Patricia , Buendía Manuel , Filippone Salvatore , Martín Nazario
Published: January 2022

Racemization barriers are the key! Molecular nanographenes can show a dynamic behavior which eventually controls their chiroptical and photophysical properties.
Switching photorelease to singlet oxygen generation by oxygen functionalization of phenothiazine photocages
Authors: Ojha Mamata , Banerjee Moumita , Ray Souvik , Singh Amit Kumar , Anoop Anakuthil , Singh N. D. Pradeep
Published: January 2022

Phenothiazine photoremovable protecting group (PRPG) switches its photorelease ability to singlet oxygen generation on oxygen functionalization.
Organic photoredox catalytic amino-heteroarylation of unactivated olefins to access distal amino ketones
Authors: Zhang Ji-Hua , Xiao Teng-Fei , Ji Zi-Qin , Chen Han-Nan , Yan Pen-Ji , Luo Yong-Chun , Xu Peng-Fei , Xu Guo-Qiang
Published: January 2022

A metal-free amino-heteroarylation of unactivated olefins via new organic photoredox catalysis was reported, providing a concise and efficient approach for the rapid synthesis of various δ (β, ε)-amino ketones under mild conditions. A series of mechanistic experiments and DFT calculations indicate that this transformation undergoes a photoredox catalytic sequential radical addition/functional group migration process.
Grammatical evolution-based design of SARS-CoV-2 main protease inhibitors
Authors: Frausto-Parada Francisco , Várgas-Rodríguez Ismael , Mercado-Sánchez Itzel , Bazán-Jiménez Adán , Díaz-Cervantes Erik , Sotelo-Figueroa Marco A. , García-Revilla Marco A.
Published: January 2022

A series of SARS-CoV-2 main protease (SARS-CoV-2-Mpro) inhibitors were modeled using evolutive grammar algorithms.
Ohmic heating-assisted synthesis and characterization of Zn(ii), Cu(ii) and Pd(ii) complexes of heterocyclic-fused chlorins
Authors: Moreira Maria I. F. , Almeida José , Leite Andreia , Lobo Ferreira Ana I. M. C. , Santos Luís M. N. B. F. , Silva Ana M. G. , Rangel Maria
Published: January 2022

The ohmic heating synthesis, spectroscopic properties and thermal-behaviour of Zn(ii), Cu(ii) and Pd(ii) complexes of heterocyclic-fused chlorins are described.
Sublayer-enhanced atomic sites of single atom catalysts through in situ atomization of metal oxide nanoparticles
Authors: Wu Xing , Wang Qichen , Yang Shize , Zhang Jinyang , Cheng Yi , Tang Haolin , Ma Lu , Min Xiaobo , Tang Chongjian , Jiang San Ping , Wu Feixiang , Lei Yongpeng , Ciampic Simone , Wang Shuangyin , Dai Liming
Published: January 2022

The in situ atomization of carbon supported metal oxide nanoparticles provides a novel strategy to synthesize atomic sites supported on highly graphitized carbon materials with high metal loading and controlled atomic layers.
An organometal halide perovskite supported Pt single-atom photocatalyst for H2 evolution
Authors: Wu Yaqiang , Wu Qian , Zhang Qianqian , Lou Zaizhu , Liu Kefeng , Ma Yandong , Wang Zeyan , Zheng Zhaoke , Cheng Hefeng , Liu Yuanyuan , Dai Ying , Huang Baibiao , Wang Peng
Published: January 2022

An organometal halide perovskite supported Pt single-atom photocatalyst is developed for efficient H2 evolution with a superb STH of 4.50%.
Synthesis, characterisation and carbon dioxide capture capacities of hierarchically porous Starbons®
Authors: Li Han , Li Cheng , Budarin Vitaliy L. , Clark James H. , North Michael , Wang Jinxiu , Wu Xiao
Published: January 2022

Activation of Starbons® produces hierarchically porous carbon based materials which exhibit rapid carbon dioxide adsorption with adsorption capacities of up to 20 mmol g−1 at 10 bar and 1 bar selectivities for carbon dioxide versus nitrogen of up to 64.
Boosting CO2 electroreduction over Co nanoparticles supported on N,B-co-doped graphitic carbon
Authors: Song Xinning , Guo Weiwei , Ma Xiaodong , Xu Liang , Tan Xingxing , Wu Limin , Jia Shunhan , Wu Tianbin , Ma Jun , Zhang Farao , Jia Jinchao , Sun Xiaofu , Han Buxing
Published: January 2022

Co nanoparticles supported on N,B-co-doped carbon have been synthesized and used as catalysts for CO2 electroreduction to CO. The highest faradaic efficiency can reach 97.9% with a current density of 18.8 mA cm−2, and the nanoparticles exhibit excellent stability.
The choice of ionic liquid ions to mitigate corrosion impacts: the influence of superbase cations and electron-donating carboxylate anions
Authors: Li Xin , Wang Xiaoyu , Nawaz Haq , Zhang Jiankang , Chen Xiaomei , Cheng Peng , You Tingting , Ramaswamy Shri , Xu Feng
Published: January 2022

[DBUH][CH3CH2OCH2COO] exhibited excellent corrosion inhibition for 304SS compared to imidazolium-based ILs due to the barrier effect produced by carboxylate anions containing electron-donating groups and superbase cations with a large ring.
Proton-responsive azulene-based conjugated polymer with nonvolatile memory effects
Authors: Zhao Zhizheng , Huan Weiwei , Sun Chen , El-Khouly Mohamed E. , Zhang Bin , Chen Yu
Published: January 2022

We report an azulene-based conjugated polymer, PAV, which exhibits proton-gated and electrical-gated changes in its conductivity.