bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamics of Interannual Eddy Kinetic Energy Variability in the Sulawesi Sea Revealed by OFAM3
Authors: Hao Zhanjiu , Xu Zhenhua , Feng Ming , Zhang Peiwen , Yin Baoshu
Published: August 2022

Interannual variations in eddy kinetic energy (EKE) in the Sulawesi Sea and their driving mechanisms are investigated based on the outputs of Ocean Forecasting Australia Model version 3 from 1979 to 2014. The interannual EKE variability is found to be primarily modulated by the Mindanao Current intrusion transport (MCIT). By regulating the intensity of barotropic instability of the cyclonic loop current in the Sulawesi Sea, the MCIT fluctuation leads to the downstream interannual EKE variations. Further analysis suggests that the paths of Mindanao Current (MC) and New Guinea Coastal Current and Undercurrent (NGCC/NGCUC) influence the interannual MCIT variability. During high‐EKE periods, the NGCC/NGCUC is weakened, and the MC retroflection extends to south of 5°N, which causes MCIT to increase by 0.60 Sv and strengthens the barotropic energy conversion from mean kinetic energy to EKE in the Sulawesi Sea. During low‐EKE periods, the NGCC/NGCUC is intensified whereas the MC retroflection retreats to a northernmost path, resulting in a decrease of 0.58 Sv in MCIT and thus a low EKE level. In addition, mesoscale eddies to the east of the Sulawesi Sea in the western Pacific also have an impact on the MC intrusion. This study highlights the significance of the nonlinear dynamics of western boundary currents in modulating eddy activities in the formation region of the Indonesian Throughflow.
GNSS Radio Occultation Infilling of the African Radiosonde Data Gaps Reveals Drivers of Tropopause Climate Variability
Authors: Ding Tong , Awange Joseph L. , Scherllin‐Pirscher Barbara , Kuhn Michael , Khandu  , Anyah Richard , Zerihun Ayalsew , Bui Luyen K.
Published: August 2022

Radiosonde data are important for understanding and monitoring the upper troposphere and lower stratosphere (UTLS) region. Over much of Africa, however, such data are lacking; consequently, the African UTLS is understudied, and potential proxies such as climate models and reanalysis products fail to fully capture the behavior of the UTLS. This study pioneers the use of Global Navigation Satellite System‐Radio Occultation (GNSS‐RO) data from 2001 to 2020 to address the radiosonde data gap over Africa and contributes to a better understanding of the tropopause (TP) characteristics under the influence of global and regional climate drivers over the continent. As a first step to using GNSS‐RO for infilling the radiosonde data gap over Africa, we analyzed the performance of GNSS‐RO (2001–2020) and reanalysis products (European Centre for Medium‐Range Weather Forecasts Reanalysis 5 (ERA5) and Modern‐Era Retrospective analysis for Research and Applications version 2 (MERRA‐2)) against radiosonde observations applying the Kling‐Gupta Efficiency metric. The analyses show that GNSS‐RO data from Challenging Mini‐satellite Payload, Gravity Recovery and Climate Experiment, Meteorological Operational, Constellation Observing System for Meteorology, Ionosphere, and Climate (COSMIC), and COSMIC‐2 are in good agreement with radiosonde measurements with differences being smaller than 1 K in the UTLS, thereby enabling infilling of missing radiosonde data in Africa during 2001–2020. By contrast, the smoothed vertical temperature profiles of reanalysis products lead to a warm bias of +0.8 K in ERA5 and +1.2 K in MERRA‐2 and these biases alter some vertical and temporal structure details, with possible implications on climate change detection and attribution. Furthermore, the analysis of GNSS‐RO data over Africa revealed: (a) the teleconnections of El Niño‐Southern Oscillation (ENSO), Quasi‐Biennial Oscillation (QBO), Indian Ocean Dipole (IOD), Madden‐Julian Oscillation (MJO), North Atlantic Oscillation (NAO) and Southern Annular Mode (SAM) at the tropopause boundary; (b) multiple coupled global climate drivers such as ENSO‐IOD, ENSO‐MJO, ENSO‐NAO, QBO‐IOD, and ENSO‐NAO‐MJO; (c) coupled global and regional climate drivers that influence the TP variability, for example, ENSO‐Inter Tropical Convergence Zone; and (d), the deep convection associated with the Asian Summer Monsoon and Tropical/African Easterly Jet also locally influence TP height. In conclusion, this study demonstrates the capability of GNSS‐RO to fill the vast radiosonde data gap over Africa. This opens the opportunity for further detailed studies toward a better understanding of the tropopause characteristics including localization, quantification of trends, and influences of global, regional, and coupled climate drivers.
Lower pass threshold (≥93%) for critical congenital heart disease screening at high altitude prevents repeat screening and reduces false positives
Authors: Sneeringer M. Rhonda , Vadlaputi Pranjali , Lakshminrusimha Satyan , Siefkes Heather
Published: August 2022

Objective

We evaluated first screen pass rate for two pass thresholds for critical congenital heart disease (CCHD) oxygen saturation (SpO2) screening at higher altitude.

Study design

A retrospective cohort of 948 newborns underwent CCHD screening near sea-level (n = 463) vs 6250 ft altitude (n = 485) over 3 years. Standard SpO2 pass threshold ≥95% and lower SpO2 pass threshold ≥93% (high-altitude screen) were applied to first measurements to compare pass frequencies.

Results

The median SpO2 was lower in high-altitude newborns (96% vs 99%—p < 0.001). The high-altitude newborns passed the AAP algorithm first screen less often (89.3% vs 99.6%—p < 0.001). With the high-altitude algorithm, 98% of high-altitude newborns passed the first screen.

Conclusion

Lowering the SpO2 pass threshold by 2% at >6000 ft, significantly increased first screen pass rate. Adjustments for altitude may reduce nursing time to conduct repeat measurements and prevent transfers for echocardiograms. Larger studies are necessary to assess impact on false negatives.
Continuous pressure monitoring of inpatient spinal cord injured patients: implications for pressure ulcer development
Authors: Fryer Sarah , Caggiari Silvia , Major Denise , Bader Dan L. , Worsley Peter R.
Published: August 2022

Study design

Cohort observational study.

Objectives

To examine the movement profiles of individuals with spinal cord injury (SCI) during their inpatient rehabilitative phase using continuous pressure monitoring (CPM), evaluating the trends in those with skin damage.

Setting

SCI specialist rehabilitation centre in the United Kingdom.

Methods

Individuals with SCI (n = 12) were assessed using CPM in the bed and chair over a 24–72 h. Pressure data was used as a surrogate for movement using both nursing interpretation and an intelligent algorithm. Clinical features were obtained including participants age, injury level, ASIA score, co-morbidities and prescribed support surfaces. Trends between movement profiles (frequency and intervals), SCI demographics and observed skin damage were assessed using cross-tabulation and histograms.

Results

The data revealed significant correlations (p < 0.05) between the nursing observation and algorithm for predicting movement, although the algorithm was more sensitive. Individuals with high level injuries (C1-T6) were observed to have a lower frequency of movement and larger intervals between movements when compared to low level injuries (T7-L5) during both lying and sitting periods. The individuals observed to have skin damage were predominantly those who had both a low frequency of movement and extended gaps between movements.

Conclusions

Movements for pressure relief in both the bed and chair environments were dependent on the level of injury in individuals with SCI during their inpatient rehabilitation. Distinct movement patterns corresponded with those who acquired skin damage, revealing the potential clinical applications for technologies to monitor PU risk and inform personalised care.
Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis: a cohort study in the UK Biobank
Authors: Green Harry D. , Merriel Samuel W. D. , Oram Richard A. , Ruth Katherine S. , Tyrrell Jessica , Jones Samuel E. , Thirlwell Chrissie , Weedon Michael N. , Bailey Sarah E. R.
Published: August 2022

Background

Prostate cancer is highly heritable, with >250 common variants associated in genome-wide association studies. It commonly presents with non-specific lower urinary tract symptoms that are frequently associated with benign conditions.

Methods

Cohort study using UK Biobank data linked to primary care records. Participants were men with a record showing a general practice consultation for a lower urinary tract symptom. The outcome measure was prostate cancer diagnosis within 2 years of consultation. The predictor was a genetic risk score of 269 genetic variants for prostate cancer.

Results

A genetic risk score (GRS) is associated with prostate cancer in symptomatic men (OR per SD increase = 2.12 [1.86–2.41] P = 3.5e-30). An integrated risk model including age and GRS applied to symptomatic men predicted prostate cancer (AUC 0.768 [0.739–0.796]). Prostate cancer incidence was 8.1% (6.7–9.7) in the highest risk quintile. In the lowest quintile, prostate cancer incidence was <1%.

Conclusions

This study is the first to apply GRS in primary care to improve the triage of symptomatic patients. Men with the lowest genetic risk of developing prostate cancer could safely avoid invasive investigation, whilst those identified with the greatest risk could be fast-tracked for further investigation. These results show that a GRS has potential application to improve the diagnostic pathway of symptomatic patients in primary care.
A novel long noncoding RNA SP100-AS1 induces radioresistance of colorectal cancer via sponging miR-622 and stabilizing ATG3
Authors: Zhou You , Shao Yingjie , Hu Wenwei , Zhang Jinping , Shi Yufang , Kong Xiangyin , Jiang Jingting
Published: August 2022

Although radiotherapy is an essential modality in the treatment of colorectal cancer (CRC), the incidence of radioresistance remains high clinically. Long noncoding RNAs (lncRNAs) reportedly play critical roles in CRC radioresistance by regulating genes or proteins at the transcriptional or post-translational levels. This study aimed to identify novel lncRNAs involved in radioresistance. We found that SP100-AS1 (lncRNA targeting antisense sequence of SP100 gene) was upregulated in radioresistant CRC patient tissues using RNA-seq analysis. Importantly, knockdown of SP100-AS1 significantly reduced radioresistance, cell proliferation, and tumor formation in vitro and in vivo. Mechanistically, mass spectrometry and bioinformatics analyses were used to identify the interacting proteins and microRNAs of SP100-AS1, respectively. Moreover, SP100-AS1 was found to interact with and stabilize ATG3 protein through the ubiquitination-dependent proteasome pathway. In addition, it could serve as a sponge for miR-622, which targeted ATG3 mRNA and affected autophagic activity. Thus, lncRNA SP100-AS1 could act as a radioresistance factor in CRC patients via RNA sponging and protein stabilizing mechanisms. In conclusion, the present study indicates that SP100-AS1/miR-622/ATG3 axis contributes to radioresistance and autophagic activity in CRC patients, suggesting it has huge prospects as a therapeutic target for improving CRC response to radiation therapy.
The role of immunomodulators in treatment-resistant depression: case studies
Authors: Beckett Charles W. , Niklison-Chirou Maria Victoria
Published: August 2022

Depression is a common mental disorder affecting more than 264 million people worldwide. The first-line treatment for most cases of depression are selective serotonin reuptake inhibitors (SSRIs), such as sertraline, reboxetine and fluoxetine. Recently, it has been found that one-quarter of depressed patients have excessive activation of the immune system. This potentially warrants sub-categorisation of depressed patients into inflammatory and non-inflammatory subtypes. Such a sub-category of depression already exists for those not responding to various traditional antidepressants and is known as treatment-resistant depression. Those with treatment-resistant depression are far more likely to have raised inflammatory markers relative to those whose depression is treatment-responsive. Chronic, low-level inflammation seems to trigger depression via a multitude of mechanisms. These include kynurenine pathway and microglial cell activation, resulting in a reduction in hippocampal volume. Raised inflammatory cytokines also cause perturbations in monoaminergic signalling, which perhaps explains the preponderance of treatment resistance in those patients with inflammatory depression. Therefore, if treatment-resistant depression and inflammatory depression are semi-synonymous then it should follow that anti-inflammatory drugs will display high efficacy in both sub-types. Ketamine is a drug recently approved for use in depression in the USA and displays a particularly good response rate in those patients with treatment resistance. It has been suggested that the antidepressant efficacy of ketamine results from its anti-inflammatory effects. Ketamine seems to produce anti-inflammatory effects via polarisation of monocytes to M2 macrophages. Furthermore, another anti-inflammatory drug with potential use in treatment-resistant depression is Celecoxib. Celecoxib is a long-acting, selective COX-2 inhibitor. Early clinical trials show that Celecoxib has an adjuvant effect with traditional antidepressants in treatment-resistant patients. This paper highlights the importance of classifying depressed patients into inflammatory and non-inflammatory subtypes; and how this may lead to the development of more targeted treatments for treatment-resistant depression.
Ribosomal protein L22-like1 (RPL22L1) mediates sorafenib sensitivity via ERK in hepatocellular carcinoma
Authors: Zhang Dongmei , Zhou Yunzhen , Ma Yanan , Jiang Ping , Lv Hongchao , Liu Sijia , Mu Yu , Zhou Chong , Xiao Shan , Ji Guohua , Liu Peng , Zhang Ning , Sun Donglin , Sun Haiming , Wu Nan , Jin Yan
Published: August 2022

Precision medicine in hepatocellular carcinoma (HCC) relies on validated biomarkers that help subgroup patients for targeted treatment. Here, we identified a novel candidate oncogene, ribosomal protein L22-like1 (RPL22L1), which was markedly elevated in HCC, contributed to HCC malignancy and adverse patient survival. Functional studies indicated RPL22L1 overexpression accelerated cell proliferation, migration, invasion and sorafenib resistance. Mechanism studies revealed that RPL22L1 activated ERK to induce atypical epithelial-to-mesenchymal transition (EMT) progress. Importantly, the ERK inhibitor (ERKi) could potentiate sorafenib efficiency in RPL22L1-high HCC cells. In summary, these data uncover RPL22L1 is a potential marker to guide precision therapy for utilizing ERKi to enhance the sorafenib efficacy in RPL22L1-high HCC patients.
Emergent hypernetworks in weakly coupled oscillators
Authors: Nijholt Eddie , Ocampo-Espindola Jorge Luis , Eroglu Deniz , Kiss István Z. , Pereira Tiago
Published: August 2022

Networks of weakly coupled oscillators had a profound impact on our understanding of complex systems. Studies on model reconstruction from data have shown prevalent contributions from hypernetworks with triplet and higher interactions among oscillators, in spite that such models were originally defined as oscillator networks with pairwise interactions. Here, we show that hypernetworks can spontaneously emerge even in the presence of pairwise albeit nonlinear coupling given certain triplet frequency resonance conditions. The results are demonstrated in experiments with electrochemical oscillators and in simulations with integrate-and-fire neurons. By developing a comprehensive theory, we uncover the mechanism for emergent hypernetworks by identifying appearing and forbidden frequency resonant conditions. Furthermore, it is shown that microscopic linear (difference) coupling among units results in coupled mean fields, which have sufficient nonlinearity to facilitate hypernetworks. Our findings shed light on the apparent abundance of hypernetworks and provide a constructive way to predict and engineer their emergence.
The origin and evolution of open habitats in North America inferred by Bayesian deep learning models
Authors: Andermann Tobias , Strömberg Caroline A. E. , Antonelli Alexandre , Silvestro Daniele
Published: August 2022

Some of the most extensive terrestrial biomes today consist of open vegetation, including temperate grasslands and tropical savannas. These biomes originated relatively recently in Earth’s history, likely replacing forested habitats in the second half of the Cenozoic. However, the timing of their origination and expansion remains disputed. Here, we present a Bayesian deep learning model that utilizes information from fossil evidence, geologic models, and paleoclimatic proxies to reconstruct paleovegetation, placing the emergence of open habitats in North America at around 23 million years ago. By the time of the onset of the Quaternary glacial cycles, open habitats were covering more than 30% of North America and were expanding at peak rates, to eventually become the most prominent natural vegetation type today. Our entirely data-driven approach demonstrates how deep learning can harness unexplored signals from complex data sets to provide insights into the evolution of Earth’s biomes in time and space.
AAA + ATPase Thorase inhibits mTOR signaling through the disassembly of the mTOR complex 1
Authors: Umanah George K. E. , Abalde-Atristain Leire , Khan Mohammed Repon , Mitra Jaba , Dar Mohamad Aasif , Chang Melissa , Tangella Kavya , McNamara Amy , Bennett Samuel , Chen Rong , Aggarwal Vasudha , Cortes Marisol , Worley Paul F. , Ha Taekjip , Dawson Ted M. , Dawson Valina L.
Published: August 2022

The mechanistic target of rapamycin (mTOR) signals through the mTOR complex 1 (mTORC1) and the mTOR complex 2 to maintain cellular and organismal homeostasis. Failure to finely tune mTOR activity results in metabolic dysregulation and disease. While there is substantial understanding of the molecular events leading mTORC1 activation at the lysosome, remarkably little is known about what terminates mTORC1 signaling. Here, we show that the AAA + ATPase Thorase directly binds mTOR, thereby orchestrating the disassembly and inactivation of mTORC1. Thorase disrupts the association of mTOR to Raptor at the mitochondria-lysosome interface and this action is sensitive to amino acids. Lack of Thorase causes accumulation of mTOR-Raptor complexes and altered mTORC1 disassembly/re-assembly dynamics upon changes in amino acid availability. The resulting excessive mTORC1 can be counteracted with rapamycin in vitro and in vivo. Collectively, we reveal Thorase as a key component of the mTOR pathway that disassembles and thus inhibits mTORC1.
High impact of bacterial predation on cyanobacteria in soil biocrusts
Authors: Bethany Julie , Johnson Shannon Lynn , Garcia-Pichel Ferran
Published: August 2022

Diverse bacteria lead a life as pathogens or predators of other bacteria in many environments. However, their impact on emerging ecological processes in natural settings remains to be assessed. Here we describe a novel type of obligate, intracellular predatory bacterium of widespread distribution that preys on soil cyanobacteria in biocrusts. The predator,CandidatusCyanoraptor togatus, causes localized, cm-sized epidemics that are visible to the naked eye, obliterates cyanobacterial net primary productivity, and severely impacts crucial biocrust properties like nitrogen cycling, dust trapping and moisture retention. The combined effects of high localized morbidity and areal incidence result in decreases approaching 10% of biocrust productivity at the ecosystem scale. Our findings show that bacterial predation can be an important loss factor shaping not only the structure but also the function of microbial communities.
Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly
Authors: Ratto Edoardo , Chowdhury S. Roy , Siefert Nora S. , Schneider Martin , Wittmann Marten , Helm Dominic , Palm Wilhelm
Published: August 2022

Mammalian cells can acquire exogenous amino acids through endocytosis and lysosomal catabolism of extracellular proteins. In amino acid-replete environments, nutritional utilization of extracellular proteins is suppressed by the amino acid sensor mechanistic target of rapamycin complex 1 (mTORC1) through an unknown process. Here, we show that mTORC1 blocks lysosomal degradation of extracellular proteins by suppressing V-ATPase-mediated acidification of lysosomes. When mTORC1 is active, peripheral V-ATPase V1domains reside in the cytosol where they are stabilized by association with the chaperonin TRiC. Consequently, most lysosomes display low catabolic activity. When mTORC1 activity declines, V-ATPase V1domains move to membrane-integral V-ATPase Vodomains at lysosomes to assemble active proton pumps. The resulting drop in luminal pH increases protease activity and degradation of protein contents throughout the lysosomal population. These results uncover a principle by which cells rapidly respond to changes in their nutrient environment by mobilizing the latent catabolic capacity of lysosomes.
Experimental exploration of a ribozyme neutral network using evolutionary algorithm and deep learning
Authors: Rotrattanadumrong Rachapun , Yokobayashi Yohei
Published: August 2022

A neutral network connects all genotypes with equivalent phenotypes in a fitness landscape and plays an important role in the mutational robustness and evolvability of biomolecules. In contrast to earlier theoretical works, evidence of large neutral networks has been lacking in recent experimental studies of fitness landscapes. This suggests that evolution could be constrained globally. Here, we demonstrate that a deep learning-guided evolutionary algorithm can efficiently identify neutral genotypes within the sequence space of an RNA ligase ribozyme. Furthermore, we measure the activities of all 216 variants connecting two active ribozymes that differ by 16 mutations and analyze mutational interactions (epistasis) up to the 16th order. We discover an extensive network of neutral paths linking the two genotypes and reveal that these paths might be predicted using only information from lower-order interactions. Our experimental evaluation of over 120,000 ribozyme sequences provides important empirical evidence that neutral networks can increase the accessibility and predictability of the fitness landscape.
Structural basis for proton coupled cystine transport by cystinosin
Authors: Löbel Mark , Salphati Sacha P. , El Omari Kamel , Wagner Armin , Tucker Stephen J. , Parker Joanne L. , Newstead Simon
Published: August 2022

Amino acid transporters play a key role controlling the flow of nutrients across the lysosomal membrane and regulating metabolism in the cell. Mutations in the gene encoding the transporter cystinosin result in cystinosis, an autosomal recessive metabolic disorder characterised by the accumulation of cystine crystals in the lysosome. Cystinosin is a member of the PQ-loop family of solute carrier (SLC) transporters and uses the proton gradient to drive cystine export into the cytoplasm. However, the molecular basis for cystinosin function remains elusive, hampering efforts to develop novel treatments for cystinosis and understand the mechanisms of ion driven transport in the PQ-loop family. To address these questions, we present the crystal structures of cystinosin from Arabidopsis thaliana in both apo and cystine bound states. Using a combination of in vitro and in vivo based assays, we establish a mechanism for cystine recognition and proton coupled transport. Mutational mapping and functional characterisation of human cystinosin further provide a framework for understanding the molecular impact of disease-causing mutations.
The influence of interparticle cohesion on rebounding slow impacts on rubble pile asteroids
Authors: Joeris Kolja , Schönau Laurent , Keulen Matthias , Born Philip , Kollmer Jonathan E.
Published: August 2022

The ballistic sorting effect has been proposed to be a driver behind the observed size sorting on the rubble pile asteroid Itokawa. This effect depends on the inelasticity of slow collisions with granular materials. The inelasticity of a collision with a granular material, in turn, depends on grain size. Here we argue that determining the inelasticity of such collisions in an asteroid-like environment is a nontrivial task. We show non-monotonic dependency of the coefficient of restitution (COR) on target particle size using experiments in microgravity. Employing numerical simulations, we explain these results with the growing influence of adhesion for smaller-sized particles. We conclude that there exists an optimum impactor to target particle size ratio for ballistic sorting.
Combined functional and structural imaging of brain white matter reveals stage-dependent impairment in multiple system atrophy of cerebellar type
Authors: Lin Hua , Lin Li , Xu Lyuan , Li Siran , Song Penghui , Li Muwei
Published: August 2022

Advances in fMRI of brain white matter (WM) have established the feasibility of understanding how functional signals of WM evolve with brain diseases. By combining functional signals with structural features of WM, the current study characterizes functional and structural impairments of WM in cerebelar type multiple system atrophy, with the goal to derive new mechanistic insights into the pathological progression of this disease. Our analysis of 30 well-diagnosed patients revealed pronounced decreases in functional connectivity in WM bundles of the cerebellum and brainstem, and concomitant local structural alterations that depended on the disease stage. The novel findings implicate a critical time point in the pathological evolution of the disease, which could guide optimal therapeutic interventions. Furthermore, fMRI signals of impaired WM bundles exhibited superior sensitivity in differentiating initial disease development, which demonstrates great potential of using these signals to inform disease management.
Observation of Rabi dynamics with a short-wavelength free-electron laser
Authors: Nandi Saikat , Olofsson Edvin , Bertolino Mattias , Carlström Stefanos , Zapata Felipe , Busto David , Callegari Carlo , Di Fraia Michele , Eng-Johnsson Per , Feifel Raimund , Gallician Guillaume , Gisselbrecht Mathieu , Maclot Sylvain , Neoričić Lana , Peschel Jasper , Plekan Oksana , Prince Kevin C. , Squibb Richard J. , Zhong Shiyang , Demekhin Philipp V. , Meyer Michael , Miron Catalin , Badano Laura , Danailov Miltcho B. , Giannessi Luca , Manfredda Michele , Sottocorona Filippo , Zangrando Marco , Dahlström Jan Marcus
Published: August 2022

Rabi oscillations are periodic modulations of populations in two-level systems interacting with a time-varying field1. They are ubiquitous in physics with applications in different areas such as photonics2, nano-electronics3, electron microscopy4 and quantum information5. While the theory developed by Rabi was intended for fermions in gyrating magnetic fields, Autler and Townes realized that it could also be used to describe coherent light–matter interactions within the rotating-wave approximation6. Although intense nanometre-wavelength light sources have been available for more than a decade7–9, Rabi dynamics at such short wavelengths has not been directly observed. Here we show that femtosecond extreme-ultraviolet pulses from a seeded free-electron laser10 can drive Rabi dynamics between the ground state and an excited state in helium atoms. The measured photoelectron signal reveals an Autler–Townes doublet and an avoided crossing, phenomena that are both fundamental to coherent atom–field interactions11. Using an analytical model derived from perturbation theory on top of the Rabi model, we find that the ultrafast build-up of the doublet structure carries the signature of a quantum interference effect between resonant and non-resonant photoionization pathways. Given the recent availability of intense attosecond12 and few-femtosecond13 extreme-ultraviolet pulses, our results unfold opportunities to carry out ultrafast manipulation of coherent processes at short wavelengths using free-electron lasers.
A compute-in-memory chip based on resistive random-access memory
Authors: Wan Weier , Kubendran Rajkumar , Schaefer Clemens , Eryilmaz Sukru Burc , Zhang Wenqiang , Wu Dabin , Deiss Stephen , Raina Priyanka , Qian He , Gao Bin , Joshi Siddharth , Wu Huaqiang , Wong H.-S. Philip , Cauwenberghs Gert
Published: August 2022

Realizing increasingly complex artificial intelligence (AI) functionalities directly on edge devices calls for unprecedented energy efficiency of edge hardware. Compute-in-memory (CIM) based on resistive random-access memory (RRAM)1promises to meet such demand by storing AI model weights in dense, analogue and non-volatile RRAM devices, and by performing AI computation directly within RRAM, thus eliminating power-hungry data movement between separate compute and memory2–5. Although recent studies have demonstrated in-memory matrix-vector multiplication on fully integrated RRAM-CIM hardware6–17, it remains a goal for a RRAM-CIM chip to simultaneously deliver high energy efficiency, versatility to support diverse models and software-comparable accuracy. Although efficiency, versatility and accuracy are all indispensable for broad adoption of the technology, the inter-related trade-offs among them cannot be addressed by isolated improvements on any single abstraction level of the design. Here, by co-optimizing across all hierarchies of the design from algorithms and architecture to circuits and devices, we present NeuRRAM—a RRAM-based CIM chip that simultaneously delivers versatility in reconfiguring CIM cores for diverse model architectures, energy efficiency that is two-times better than previous state-of-the-art RRAM-CIM chips across various computational bit-precisions, and inference accuracy comparable to software models quantized to four-bit weights across various AI tasks, including accuracy of 99.0 percent on MNIST18and 85.7 percent on CIFAR-1019image classification, 84.7-percent accuracy on Google speech command recognition20, and a 70-percent reduction in image-reconstruction error on a Bayesian image-recovery task.
Evidence for intrinsic charm quarks in the proton
Authors:   The NNPDF Collaboration, Ball Richard D. , Candido Alessandro , Cruz-Martinez Juan , Forte Stefano , Giani Tommaso , Hekhorn Felix , Kudashkin Kirill , Magni Giacomo , Rojo Juan
Published: August 2022

The theory of the strong force, quantum chromodynamics, describes the proton in terms of quarks and gluons. The proton is a state of two up quarks and one down quark bound by gluons, but quantum theory predicts that in addition there is an infinite number of quark–antiquark pairs. Both light and heavy quarks, whose mass is respectively smaller or bigger than the mass of the proton, are revealed inside the proton in high-energy collisions. However, it is unclear whether heavy quarks also exist as a part of the proton wavefunction, which is determined by non-perturbative dynamics and accordingly unknown: so-called intrinsic heavy quarks1. It has been argued for a long time that the proton could have a sizable intrinsic component of the lightest heavy quark, the charm quark. Innumerable efforts to establish intrinsic charm in the proton2 have remained inconclusive. Here we provide evidence for intrinsic charm by exploiting a high-precision determination of the quark–gluon content of the nucleon3 based on machine learning and a large experimental dataset. We disentangle the intrinsic charm component from charm–anticharm pairs arising from high-energy radiation4. We establish the existence of intrinsic charm at the 3-standard-deviation level, with a momentum distribution in remarkable agreement with model predictions1,5.We confirm these findings by comparing them to very recent data on Z-boson production with charm jets from the Large Hadron Collider beauty (LHCb) experiment6.
Ordered and deterministic cancer genome evolution after p53 loss
Authors: Baslan Timour , Morris John P. , Zhao Zhen , Reyes Jose , Ho Yu-Jui , Tsanov Kaloyan M. , Bermeo Jonathan , Tian Sha , Zhang Sean , Askan Gokce , Yavas Aslihan , Lecomte Nicolas , Erakky Amanda , Varghese Anna M. , Zhang Amy , Kendall Jude , Ghiban Elena , Chorbadjiev Lubomir , Wu Jie , Dimitrova Nevenka , Chadalavada Kalyani , Nanjangud Gouri J. , Bandlamudi Chaitanya , Gong Yixiao , Donoghue Mark T. A. , Socci Nicholas D. , Krasnitz Alex , Notta Faiyaz , Leach Steve D. , Iacobuzio-Donahue Christine A. , Lowe Scott W.
Published: August 2022

Although p53 inactivation promotes genomic instability1 and presents a route to malignancy for more than half of all human cancers2,3, the patterns through which heterogenous TP53 (encoding human p53) mutant genomes emerge and influence tumorigenesis remain poorly understood. Here, in a mouse model of pancreatic ductal adenocarcinoma that reports sporadic p53 loss of heterozygosity before cancer onset, we find that malignant properties enabled by p53 inactivation are acquired through a predictable pattern of genome evolution. Single-cell sequencing and in situ genotyping of cells from the point of p53 inactivation through progression to frank cancer reveal that this deterministic behaviour involves four sequential phases—Trp53 (encoding mouse p53) loss of heterozygosity, accumulation of deletions, genome doubling, and the emergence of gains and amplifications—each associated with specific histological stages across the premalignant and malignant spectrum. Despite rampant heterogeneity, the deletion events that follow p53 inactivation target functionally relevant pathways that can shape genomic evolution and remain fixed as homogenous events in diverse malignant populations. Thus, loss of p53—the ‘guardian of the genome’—is not merely a gateway to genetic chaos but, rather, can enable deterministic patterns of genome evolution that may point to new strategies for the treatment of TP53-mutant tumours.
A condensate dynamic instability orchestrates actomyosin cortex activation
Authors: Yan Victoria Tianjing , Narayanan Arjun , Wiegand Tina , Jülicher Frank , Grill Stephan W.
Published: August 2022

A key event at the onset of development is the activation of a contractile actomyosin cortex during the oocyte-to-embryo transition1–3. Here we report on the discovery that, in Caenorhabditis elegans oocytes, actomyosin cortex activation is supported by the emergence of thousands of short-lived protein condensates rich in F-actin, N-WASP and the ARP2/3 complex4–8 that form an active micro-emulsion. A phase portrait analysis of the dynamics of individual cortical condensates reveals that condensates initially grow and then transition to disassembly before dissolving completely. We find that, in contrast to condensate growth through diffusion9, the growth dynamics of cortical condensates are chemically driven. Notably, the associated chemical reactions obey mass action kinetics that govern both composition and size. We suggest that the resultant condensate dynamic instability10 suppresses coarsening of the active micro-emulsion11, ensures reaction kinetics that are independent of condensate size and prevents runaway F-actin nucleation during the formation of the first cortical actin meshwork.
In vivo single-molecule analysis reveals COOLAIR RNA structural diversity
Authors: Yang Minglei , Zhu Pan , Cheema Jitender , Bloomer Rebecca , Mikulski Pawel , Liu Qi , Zhang Yueying , Dean Caroline , Ding Yiliang
Published: August 2022

Cellular RNAs are heterogeneous with respect to their alternative processing and secondary structures, but the functional importance of this complexity is still poorly understood. A set of alternatively processed antisense non-coding transcripts, which are collectively called COOLAIR, are generated at the Arabidopsis floral-repressor locus FLOWERING LOCUS C (FLC)1. Different isoforms of COOLAIR influence FLC transcriptional output in warm and cold conditions2–7. Here, to further investigate the function of COOLAIR, we developed an RNA structure-profiling method to determine the in vivo structure of single RNA molecules rather than the RNA population average. This revealed that individual isoforms of the COOLAIR transcript adopt multiple structures with different conformational dynamics. The major distally polyadenylated COOLAIR isoform in warm conditions adopts three predominant structural conformations, the proportions and conformations of which change after cold exposure. An alternatively spliced, strongly cold-upregulated distal COOLAIR isoform6 shows high structural diversity, in contrast to proximally polyadenylated COOLAIR. A hyper-variable COOLAIR structural element was identified that was complementary to the FLC transcription start site. Mutations altering the structure of this region changed FLC expression and flowering time, consistent with an important regulatory role of the COOLAIR structure in FLC transcription. Our work demonstrates that isoforms of non-coding RNA transcripts adopt multiple distinct and functionally relevant structural conformations, which change in abundance and shape in response to external conditions.
Differential gene expression in iPSC-derived human intestinal epithelial cell layers following exposure to two concentrations of butyrate, propionate and acetate
Authors: Grouls Menno , Janssen Aafke W. F. , Duivenvoorde Loes P. M. , Hooiveld Guido J. E. J. , Bouwmeester Hans , van der Zande Meike
Published: August 2022

Intestinal epithelial cells and the intestinal microbiota are in a mutualistic relationship that is dependent on communication. This communication is multifaceted, but one aspect is communication through compounds produced by the microbiota such as the short-chain fatty acids (SCFAs) butyrate, propionate and acetate. Studying the effects of SCFAs and especially butyrate in intestinal epithelial cell lines like Caco-2 cells has been proven problematic. In contrast to the in vivo intestinal epithelium, Caco-2 cells do not use butyrate as an energy source, leading to a build-up of butyrate. Therefore, we used human induced pluripotent stem cell derived intestinal epithelial cells, grown as a cell layer, to study the effects of butyrate, propionate and acetate on whole genome gene expression in the cells. For this, cells were exposed to concentrations of 1 and 10 mM of the individual short-chain fatty acids for 24 h. Unique gene expression profiles were observed for each of the SCFAs in a concentration-dependent manner. Evaluation on both an individual gene level and pathway level showed that butyrate induced the biggest effects followed by propionate and then acetate. Several known effects of SCFAs on intestinal cells were confirmed, such as effects on metabolism and immune responses. The changes in metabolic pathways in the intestinal epithelial cell layers in this study demonstrate that there is a switch in energy homeostasis, this is likely associated with the use of SCFAs as an energy source by the induced pluripotent stem cell derived intestinal epithelial cells similar to in vivo intestinal tissues where butyrate is an important energy source.
Ultrasound-guided femoral approach for coronary angiography and interventions in the porcine model
Authors: Tsigkas Grigorios , Vasilagkos Georgios , Tousis Alexandros , Theofanis Michail , Apostolos Anastasios , Spyridonidis Ioannis , Goudas Leonidas , Karpetas Georgios , Moulias Athanasios , Katsouras Christos S. , Kitrou Panagiotis , Mplani Virginia , Moulas Anargyros N. , Karnabatidis Dimitrios , Davlouros Periklis
Published: August 2022

Coronary angiography and percutaneous coronary intervention (PCI) procedural details in swine are similar to those performed to humans, since their heart and coronary anatomy closely resembles. However, only a few detailed descriptions of the procedure are available, containing notable differences. We present a feasible and reproducible protocol for percutaneous coronary interventions in porcine experimental models, utilizing ultrasound-guided femoral approach. Nine female pigs were studied to explore the feasibility of superficial femoral arterial (SFA) access for coronary angiography and provisional PCI, as well as the most suitable guiding coronary catheters and angiographic projections for the above interventions. Experiments were performed under general anesthesia, using ultrasound-guided puncture of the SFA to gain arterial access. The Amplatzer AR1® catheter, and the Right Coronary Bypass® catheter were used for the selective engagement of the right and the left coronary artery, respectively. Successful arterial access and subsequent cardiac catheterization were performed in all pigs. Only one animal required a second puncture for femoral artery access. None of the 9 animals presented any significant tachycardia or hypotensive episode. One animal developed an access site-related complication following the first catheterization procedure. During follow-up, 100% success of SFA catheterization was achieved using the same ultrasound-guided technique. The ultrasound-guided superficial femoral artery access for coronary angiography and provisional interventions in porcine models is a quick and safe alternative to the carotid artery approach. The RCB and AR1 catheters may be the best choice for the quick and easy selective coronary engagement of the right and left ostia, respectively.
Use of InSAR data for measuring land subsidence induced by groundwater withdrawal and climate change in Ardabil Plain, Iran
Authors: Ghorbani Zahra , Khosravi Ali , Maghsoudi Yasser , Mojtahedi Farid Fazel , Javadnia Eslam , Nazari Ali
Published: August 2022

The Ardabil plain, with an approximate area of 1097.2 km2in northwestern Iran, has experienced land subsidence due to intensive groundwater withdrawal and long seasons of drought in recent years. Different techniques have been used to investigate and evaluate subsidence in this region including: Global Positioning Systems (GPS), Levelling, and Geotechnical methods. These methods are typically expensive, time-consuming, and identify only a small fraction of the areas prone to subsidence. This study employs an Interferometric Synthetic Aperture Radar (InSAR) technique to measure the long-term subsidence of the plain. An open-source SAR interferometry time series analysis package, LiCSBAS, that integrates with the automated Sentinel-1 InSAR processor (COMET-LiCSAR) is used to analyze Sentinel-1 satellite images from October 2014 to January 2021. Processing of Sentinel-1 images shows that the Ardabil plain has been facing rapid subsidence due to groundwater pumping and reduced rainfall, especially between May 2018 to January 2019. The maximum subsidence rate was 45 mm/yr, measured at the southeastern part of the plain. While providing significant advantages (less processing time and disk space) over other InSAR processing packages, implementation of the LiCSBAS processing package and its accuracy for land subsidence measurements at different scales needs further evaluation. This study provides a procedure for evaluating its efficiency and accuracy for land subsidence measurements by comparing its measurements with the results of the GMTSAR and geotechnical numerical modeling. The results of geotechnical numerical modeling showed land subsidence with an average annual rate of 38 mm between 2006 and 2020, which was close to measurements using the InSAR technique. Comparison of the subsidence measurements of the Ardabil plain using the LiCSBAS package with results obtained from other techniques shows that LiCSBAS is able to accurately detect land deformation at large scales (~ km). However, they may not be optimized for more local deformations such as infrastructure monitoring.
Large scale screening of CRISPR guide RNAs using an optimized high throughput robotics system
Authors: Spangler J. R. , Leski T. A. , Schultzhaus Z. , Wang Z. , Stenger D. A.
Published: August 2022

All CRISPR/CAS systems utilize CRISPR guide RNAs (crRNAs), the design of which depend on the type of CAS protein, genetic target and the environment/matrix. While machine learning approaches have recently been developed to optimize some crRNA designs, candidate crRNAs must still be screened for efficacy under relevant conditions. Here, we demonstrate a high-throughput method to screen hundreds of candidate crRNAs for activation of Cas13a collateral RNA cleavage. Entire regions of a model gene transcript (Y. pestislcrV gene) were tiled to produce overlapping crRNA sets. We tested for possible effects that included crRNA/target sequence, size and secondary structures, and the commercial source of DNA oligomers used to generate crRNAs. Detection of a 981 nt target RNA was initially successful with 271 out of 296 tested guide RNAs, and that was improved to 287 out of 296 (97%) after protocol optimizations. For this specific example, we determined that crRNA efficacy did not strongly depend on the target region or crRNA physical properties, but was dependent on the source of DNA oligomers used for RNA preparation. Our high-throughput methods for screening crRNAs has general applicability to the optimization of Cas12 and Cas13 guide RNA designs.
Wearable adjunct ozone and antibiotic therapy system for treatment of Gram-negative dermal bacterial infection
Authors: Roth Alexander , Maruthamuthu Murali Kannan , Nejati Sina , Krishnakumar Akshay , Selvamani Vidhya , Sedaghat Sotoudeh , Nguyen Juliane , Seleem Mohamed N. , Rahimi Rahim
Published: August 2022

The problematic combination of a rising prevalence of skin and soft tissue infections and the growing rate of life-threatening antibiotic resistant infections presents an urgent, unmet need for the healthcare industry. These evolutionary resistances originate from mutations in the bacterial cell walls which prevent effective diffusion of antibiotics. Gram-negative bacteria are of special consideration due to the natural resistance to many common antibiotics due to the unique bilayer structure of the cell wall. The system developed here provides one solution to this problem through a wearable therapy that delivers and utilizes gaseous ozone as an adjunct therapy with topical antibiotics through a novel dressing with drug-eluting nanofibers (NFs). This technology drastically increases the sensitivity of Gram-negative bacteria to common antibiotics by using oxidative ozone to bypass resistances created by the bacterial cell wall. To enable simple and effective application of adjunct therapy, ozone delivery and topical antibiotics have been integrated into a single application patch. The drug delivery NFs are generated via electrospinning in a fast-dissolve PVA mat without inducing decreasing gas permeability of the dressing. A systematic study found ozone generation at 4 mg/h provided optimal ozone levels for high antimicrobial performance with minimal cytotoxicity. This ozone treatment was used with adjunct therapy delivered by the system in vitro. Results showed complete eradication of Gram-negative bacteria with ozone and antibiotics typically used only for Gram-positive bacteria, which showed the strength of ozone as an enabling adjunct treatment option to sensitize bacteria strains to otherwise ineffective antibiotics. Furthermore, the treatment is shown through biocompatibility testing to exhibit no cytotoxic effect on human fibroblast cells.