bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Homozygous Variant in the MCOLN1 Gene Associated With Severe Oromandibular Dystonia and Parkinsonism
Authors: Ghasemi Aida , Eslami Ardakani Mahdieh , Togha Mansoureh , Yazdi Narges , Lang Anthony E. , Amini Elahe , Rohani Mohammad , Alavi Afagh
Published: March 2024

Background:

Mucolipidosis type IV (MLIV) is a rare, progressive lysosomal storage disorder characterized by severe intellectual disability, delayed motor milestones and ophthalmologic abnormalities. MLIV is an autosomal recessive disease caused by mutations in the MCOLN1 gene, encoding mucolipin-1 which is responsible for maintaining lysosomal function.

Objectives and Methods:

Here, we report a family of four Iranian siblings with cognitive decline, progressive visual and pyramidal disturbances, and abnormal movements manifested by severe oromandibular dystonia and parkinsonism. MRI scans of the brain demonstrated signal abnormalities in the white matter and thinning of the corpus callosum.

Results and Conclusions:

Whole-exome sequencing identified a novel homozygous variant, c.362C > T:p. Thr121Met in the MCOLN1 gene consistent with a diagnosis of MLIV. The presentation of MLIV may overlap with a variety of other neurological diseases, and genetic analysis is an important strategy to clarify the diagnosis. This is an important point that clinicians should be familiar with. The novel variant c.362C > T:p. Thr121Met herein described may be related to a comparatively older age at onset. Our study also expands the clinical spectrum of MLIV associated with the MCOLN1 variants and introduces a novel likely pathogenic variant for testing in MLIV cases that remain unresolved.
A spectrum of physics-informed Gaussian processes for regression in engineering
Authors: Cross Elizabeth J. , Rogers Timothy J. , Pitchforth Daniel J. , Gibson Samuel J. , Zhang Sikai , Jones Matthew R.
Published: March 2024

Despite the growing availability of sensing and data in general, we remain unable to fully characterize many in-service engineering systems and structures from a purely data-driven approach. The vast data and resources available to capture human activity are unmatched in our engineered world, and, even in cases where data could be referred to as “big,” they will rarely hold information across operational windows or life spans. This paper pursues the combination of machine learning technology and physics-based reasoning to enhance our ability to make predictive models with limited data. By explicitly linking the physics-based view of stochastic processes with a data-based regression approach, a derivation path for a spectrum of possible Gaussian process models is introduced and used to highlight how and where different levels of expert knowledge of a system is likely best exploited. Each of the models highlighted in the spectrum have been explored in different ways across communities; novel examples in a structural assessment context here demonstrate how these approaches can significantly reduce reliance on expensive data collection. The increased interpretability of the models shown is another important consideration and benefit in this context.
Processed food consumption and risk of non-communicable diseases (NCDs) in South Africa: evidence from Demographic and Health Survey (DHS) VII
Authors: Godbharle Swapnil , Kesa Hema , Jeyakumar Angeline
Published: March 2024

We aimed to analyse the association between processed food consumption and the risk of non-communicable diseases (NCDs) in South Africa. In this empirical study, we analysed nationally representative secondary data obtained from the South African Demographic and Health Survey (SADHS) VII. The survey included 13,288 occupied households, of which 11,083 were interviewed. In the interviewed households, 12,717 eligible adults aged 15 and older were identified and 10,336 were successfully interviewed. The study included four processed food groups (i.e. fried foods, takeaway foods/fast foods, salty snacks/packed chips, and processed meats) and eight NCDs (i.e. hypertension, cardiac arrest, cancer, stroke, hypercholesterolaemia, diabetes, chronic bronchitis, and asthma). As per the logistic regression results following adjustment, none of the disease states showed association with all four processed food groups. However, at least three processed food groups showed a significant positive association with hypertension, cardiac arrest, and diabetes. Two processed food groups showed significant positive association with stroke, and chronic bronchitis; one with hypercholesterolaemia and asthma; and cancer was not associated with any food groups. Processed meat and salted snacks/packed chips were each associated with five chronic conditions. In summary, we found that the consumption of any of the processed food groups increased the risk of NCDs in the South African population. Enabling policy and regulatory efforts in the production and distribution of processed foods, combined with improved awareness among the population need to be prioritised for immediate action. Facilitating the populations to choose traditional healthy diets would be a sustainable strategy for the prevention of NCDs.
“The state is something that disappoints”: legal consciousness amid institutional dissatisfaction
Authors: Feddersen Mayra , Wilenmann Javier , Cavieres Julia , Gambardella Maite
Published: March 2024

Through the lens of legal consciousness, this paper analyzes institutional dissatisfaction within the backdrop of profound skepticism directed at formal institutions, particularly within the context of post-October 2019 Chilean society. It aims at inquiring into the relationship between the expression of deep state antipathy and the stance that individuals manifest regarding legality. The paper reports on the findings derived from 12 focus groups, categorized by age, gender and location. We find that despite prevalent negative sentiments harbored by individuals toward these establishments, interviewees continue to use the language of law, expressing their dissatisfaction as frustrated formal entitlements or a lack of enforcement of the law regarding corrupt elites. We conclude that the existence of a gap between normative expectations and the acute rejection of the fulfillment of those expectations by institutional actors points to a structure of opportunities conducive to the emergence of more authoritative forms of state power.
Effects of multi-dimensionality and energy exchange on electrostatic current-driven plasma instabilities and turbulence
Authors: Chan Wai Hong Ronald , Hara Kentaro , Boyd Iain D.
Published: March 2024

Large-amplitude current-driven plasma instabilities, which can transition to the Buneman instability, were observed in one-dimensional simulations to generate high-energy back-streaming ions. We investigate the saturation of multi-dimensional plasma instabilities and its effects on energetic ion formation. Such ions directly impact spacecraft thruster lifetimes and are associated with magnetic reconnection and cosmic ray inception. An Eulerian Vlasov–Poisson solver employing the grid-based direct kinetic method is used to study the growth and saturation of 2D2V collisionless, electrostatic current-driven instabilities spanning two dimensions each in the configuration (D) and velocity (V) spaces supporting ion and electron phase-space transport. Four stages characterise the electric potential evolution in such instabilities: linear modal growth, harmonic growth, accelerated growth via quasi-linear mechanisms alongside nonlinear fill-in and saturated turbulence. Its transition and isotropisation process bears considerable similarities to the development of hydrodynamic turbulence. While a tendency to isotropy is observed in the plasma waves, followed by electron and then ion phase spaces after several ion-acoustic periods, the formation of energetic back-streaming ions is more limited in the 2D2V than in the 1D1V simulations. Plasma waves formed by two-dimensional electrostatic kinetic instabilities can propagate in the direction perpendicular to the net electron drift. Thus, large-amplitude multi-dimensional waves generate high-energy transverse-streaming ions and eventually limit energetic backward-streaming ions along the longitudinal direction. The multi-dimensional study sheds light on interactions between longitudinal and transverse electrostatic plasma instabilities, as well as fundamental characteristics of the inception and sustenance of unmagnetised plasma turbulence.
N6-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model
Authors: Present Cassandra , Girão Roberson Donola , Lin Cai , Caljon Guy , Van Calenbergh Serge , Moreira Otacilio , Ruivo Leonardo Alexandre de Souza , Batista Marcos Meuser , Azevedo Raquel , Batista Denise da Gama Jaen , Soeiro Maria de Nazaré Correia
Published: March 2024

Leishmania is a trypanosomatid parasite that causes skin lesions in its cutaneous form. Current therapies rely on old and expensive drugs, against which the parasites have acquired considerable resistance. Trypanosomatids are unable to synthesize purines relying on salvaging from the host, and nucleoside analogues have emerged as attractive antiparasitic drug candidates. 4-Methyl-7-β-D-ribofuranosyl-7H-pyrrolo[2,3-d]pyrimidine (CL5564), an analogue of tubercidin in which the amine has been replaced by a methyl group, demonstrates activity against Trypanosoma cruzi and Leishmania infantum. Herein, we investigated its in vitro and in vivo activity against L. amazonensis. CL5564 was 6.5-fold (P = 0.0002) more potent than milteforan™ (ML) against intracellular forms in peritoneal mouse macrophages, and highly selective, while combination with ML gave an additive effect. These results stimulated us to study the activity of CL5564 in mouse model of cutaneous Leishmania infection. BALB/c female and male mice infected by L. amazonensis treated with CL5564 (10 mg kg−1, intralesional route for five days) presented a >93% reduction of paw lesion size likely ML given orally at 40 mg kg−1, while the combination (10 + 40 mg kg−1 of CL5564 and ML, respectively) caused >96% reduction. The qPCR confirmed the suppression of parasite load, but only the combination approach reached 66% of parasitological cure. These results support additional studies with nucleoside derivatives.
Performance evaluation and dimensional optimization design of planar 6R redundant actuation parallel mechanism
Authors: Han Ming , Che Jiajin , Liu Jinyue , Yang Dong
Published: March 2024

Aiming at the problems of small good workspace, many singular configurations, and limited carrying capacity of non-redundant parallel mechanisms, a full-redundant drive parallel mechanism is designed and developed, and its performance evaluation, good workspace identification, and scale optimization design are studied. First, the kinematics analysis of the planar 6R parallel mechanism is completed. Then, the motion/force transmission performance evaluation index of the mechanism is established, and the singularity analysis of the mechanism is completed. Based on this, the fully redundant driving mode of the mechanism is determined, and the good transmission workspace of the mechanism in this mode is identified. Then, the mapping relationship between the performance and scale of the mechanism is established by using the space model theory, and the scale optimization of the mechanism is completed. Finally, the robot prototype is made according to the optimal scale, and the performance verification is carried out based on the research of dynamics and control strategy. The results show that the fully redundant actuation parallel mechanism obtained by design optimization has high precision and large bearing capacity. The position repeatability and position accuracy are 0.053 mm and 0.635 mm, respectively, and the load weight ratio can reach 15.83%. The research results of this paper complement and improve the performance evaluation and scale optimization system of redundantly actuated parallel mechanisms.
Effect of dietary selenium intake on CVD: a retrospective cohort study based on China Health and Nutrition Survey (CHNS) data
Authors: Wen Yaqi , Zhang Laixi , Li Shengping , Wang Tiankun , Jiang Ke , Zhao Lingxi , Zhu Yuzhao , Zhao Wen , Lei Xun , Sharma Manoj , Zhao Yong , Shi Zumin , Yuan Jun
Published: March 2024

Objective:

We aimed to examine the association between dietary Se intake and CVD risk in Chinese adults.

Design:

This prospective cohort study included adults above 20 years old in the China Health and Nutrition Survey (CHNS), and they were followed up from 1997 to 2015 (n 16 030). Dietary data were retrieved from CHNS, and a 3-d, 24-h recall of food intake was used to assess the cumulative average intake of dietary Se, which was divided into quartiles. The Cox proportional hazards model was adopted to analyse the association between dietary Se intake and incident CVD risk.

Setting:

CHNS (1991, 1993, 1997, 2000, 2004, 2006, 2009, 2011 and 2015)

Results:

A total of 663 respondents developed CVD after being followed up for a mean of 9·9 years (median 9 years). The incidence of CVD was 4·3, 3·7, 4·6 and 4·0 per 1000 person-years across the quartiles of cumulative Se intake. After adjusting all potential factors, no significant associations were found between cumulative Se intake and CVD risk. No interactions were found between Se intake and income, urbanisation, sex, region, weight, hypertension and CVD risk.

Conclusion:

We found no association between dietary Se and CVD.
Knowledge, perceptions and practices towards diabetes risk in sub-Saharan Africa: a mixed-methods scoping review
Authors: Manyara Anthony Muchai , Mwaniki Elizabeth , Gill Jason MR , Gray Cindy M
Published: March 2024

Objective:

To synthesise current evidence on knowledge, perceptions and practices towards type 2 diabetes risk in sub-Saharan Africa

Design:

Mixed-methods scoping review, which included 101 studies (seventy-three quantitative, twenty qualitative and eight mixed methods) from seven electronic databases.

Setting:

Sub-Saharan Africa, 2000–2023.

Participants:

Men and women without diabetes with mean ages ranging from 20 to 63 years.

Results:

The majority of participants in most studies knew the three main diabetes modifiable risk factors – excess weight, unhealthy diet and physical inactivity. However, most people with excess weight in almost all studies underestimated their weight. Further, the self-described ideal body weight was between midpoint of normal weight and the upper limits of overweight in most quantitative studies and was described as not too skinny but not too fat in qualitative studies. In the majority of studies, participants reported low engagement in weight control, high regular sugar intake, and low regular fruit and vegetable intake but moderate to high engagement in physical activity. Barriers to reducing diabetes risk were social (e.g. societal perceptions promoting weight gain) and environmental (e.g. limited affordability of healthy foods, high accessibility of Western diets and lack of physical activity facilities).

Conclusion:

There is a need for multicomponent type 2 diabetes prevention interventions that increase knowledge of identifying diabetes risk (e.g. what constitutes excess weight) and create social and physical environments that support healthy lifestyles (e.g. societal perceptions that promote healthy living, increased availability and affordability of healthy foods and physical activity facilities).
Time living with food insecurity and socio-demographic factors: longitudinal analysis in a city in the semi-arid region of Northeast Brazil
Authors: Santos Ana Beatriz Macêdo Venâncio dos , Palmeira Poliana de Araújo , Roncalli da Costa Oliveira Angelo Giuseppe
Published: March 2024

Objective:

Food insecurity (FI) is the lack of daily access for everyone to quality food in sufficient quantity. In many populations, it presents as a chronic and persistent condition. This study analysed the association between the length of time living with FI and socio-demographic conditions in households in a semi-arid municipality in the Brazilian Northeast between 2011 and 2019.

Design:

This is a population-based cohort study among families in the municipality in Northeast Brazil (2011, 2014 and 2019). FI was estimated through the Escala Brasileira de Insegurança Alimentar (EBIA, Brazilian Household Food Insecurity Measurement Scale), and the longitudinal category of time of living with FI was adopted to classify them according to the time they remained in FI during the cohort. The association with the socio-demographic profiles of the population was verified through multinomial logistic regression.

Setting:

Households in semi-arid, Northeast of Brazil.

Participants:

Household respondents interviewed in 2011, 2014 and 2019 (n 274).

Results:

Sixty-seven percentage (67 %) of families lived in FI in this period. Rural residence, low monthly per capita income and low schooling of the household reference person increased the chances of these families living longer in FI. These overlapping conditions increased the odds of FI in the household.

Conclusions:

Coping with FI requires intersectoral intervention that improves the socio-demographic conditions of the population.
Contrasting Approaches to Managing the Debate on Same-Sex Blessing and Same-Sex Marriage in New Zealand and Australia: Applying Insights from Jungian Psychological Type Theory
Authors: McKenna Ursula , Francis Leslie J. , Village Andrew
Published: March 2024

In October 2022 the Church of England commissioned an examination of the impact of the debate on same-sex blessing and same-sex marriage within other Anglican Churches. The examination involved a literature search, an original survey among key informers and a general internet search. This paper draws on the general internet search to contrast the impacts in New Zealand and Australia. Drawing on Jungian psychological type theory, this analysis employs the contrasting decision-making functions of feeling (concerned with subjective interpersonal values) and thinking (concerned with objective logical analysis). The data suggest that the feeling approach dominant in New Zealand, which prioritized offering space and time for those of differing opinions to meet together, reported more positive outcomes than the thinking approach dominant in Australia, which gave greater priority to adversarial debate.
GoldDigger and Checkers, computational developments in cryo-scanning transmission electron tomography to improve the quality of reconstructed volumes
Authors: Buckley Genevieve , Ramm Georg , Trépout Sylvain
Published: March 2024

In this work, we present a pair of tools to improve the fiducial tracking and reconstruction quality of cryo-scanning transmission electron tomography (STET) datasets. We then demonstrate the effectiveness of these two tools on experimental cryo-STET data. The first tool, GoldDigger, improves the tracking of fiducials in cryo-STET by accommodating the changed appearance of highly defocussed fiducial markers. Since defocus effects are much stronger in scanning transmission electron microscopy than in conventional transmission electron microscopy, existing alignment tools do not perform well without manual intervention. The second tool, Checkers, combines image inpainting and unsupervised deep learning for denoising tomograms. Existing tools for denoising cryo-tomography often rely on paired noisy image frames, which are unavailable in cryo-STET datasets, necessitating a new approach. Finally, we make the two software tools freely available for the cryo-STET community.
The Importance of Riverine Nutrient Supply for the Marine Silica Pump of Arctic Shelves: Evidence From the Laptev Sea
Authors: Debyser M. C. F. , Pichevin L. , Tuerena R. E. , Doncila A. , Semiletov I. , Ganeshram R. S.
Published: March 2024

Arctic shelves receive a large load of nutrients from Arctic rivers, which play a major role in the biogeochemical cycles of the Arctic Ocean. In this study, we present measurements of dissolved silicon isotopes (δ30Si(OH)4) around the Laptev Sea and surface waters of the Eurasian shelves collected in October 2018 to document terrestrial silicon modifications on shelves and their contribution to the Arctic basin. Nitrogen was found to be depleted in surface waters and the limiting nutrient to primary production in the Laptev Sea, allowing excess silicon export to the central Arctic Ocean. Heavy δ30Si(OH)4 in the water column was linked to the strong biological removal of DSi on shelves, enabled by vigorous N recycling. From isotopically constrained processes, we estimate that >50% of the silicon from riverine inputs is removed within the Lena River delta and on the Laptev Sea shelf. Extrapolating this to major Siberian rivers, this leads to an export of 2.5 ± 0.8 kmol/s of riverine silicon through the Transpolar Drift. An updated isotopic budget of the Arctic Ocean reproduces the observed δ30Si(OH)4 signatures out of the Arctic Ocean and underlines the importance of biological processes in modulating silicon export. Given that opal burial fluxes on Artic shelves are controlled by denitrification and N‐limitation, these processes are sensitive to ongoing climate change. As a consequence of higher riverine DSi inputs and shelf denitrification responding to productivity, it is inferred that silicon export from the Arctic Ocean could increase in the future, accompanied by lighter δ30Si(OH)4 signatures.
Overwinter and Spring Thaw Nitrous Oxide Fluxes in a Northern Prairie Cropland Are Limited but a Significant Proportion of Annual Emissions
Authors: Wagner‐Riddle Claudia , Congreves Kate A. , Brown Shannon E. , Helgason Warren D. , Farrell Richard E.
Published: March 2024

Croplands that experience seasonal soil freezing and thawing have been shown to be significant sources of N2O emissions. Yet, there is a paucity of year‐round N2O emission data for one of the most significant crop production regions that seasonally freeze, the Prairies. Here, we present micrometeorological N2O fluxes measured over 4 years in Saskatchewan, Canada, to evaluate the magnitude of freeze‐thaw N2O emissions and investigate its driving factors. Significant thaw related emissions occurred in 2 of the 4 years and were associated with relatively higher fall nitrate levels and a more gradual soil thawing period. Overall, fall soil nitrate levels were a strong explanatory variable for the differences in non‐growing season (NGS) N2O emission (r2 = 0.485). Measured cumulative N2O emissions for the NGS were 123–938 g N ha−1 and were much smaller than those obtained at other cold climate sites but amounted to 52% of annual totals on average. The November to April period contributed 30% of the annual total emissions in years without major thaw events, but 70% in years with significant thaws. NGS N2O emissions were not explained by cumulative freezing degree days unlike most other cold climate sites. We propose that NGS N2O emissions are more strongly influenced by thaw dynamics during freezing‐thawing conditions in dry regions, whereas freezing intensity is the dominant factor for wetter regions. Our results indicate that even for a semi‐arid region freeze‐thaw is an important source of N2O emissions and must be considered for more accurate reporting and development of mitigation strategies.
Environment‐Modulated Glacial Seismicity Near Dålk Glacier in East Antarctica Revealed by Deep Clustering
Authors: Hu Yanlan , Li Zefeng , Fu Lei , Liu Xuying
Published: March 2024

Over the past decades, seismic monitoring has been increasingly used to track glacial activities associated with ice loss. Many seismological studies focus on West Antarctica, whereas glacial seismicity in East Antarctica is much less studied. Here, we apply unsupervised deep learning to a dense nodal seismic array near Dålk Glacier, East Antarctica, operating from 6 December 2019 to 2 January 2020. An autoencoder is used to automatically extract event features, which are then input into a Gaussian mixture model for clustering. We divide the data into 50 clusters and merge them according to their temporal and spectral characteristics. The results reveal five main types of seismic signals: two groups with monochromatic and high frequencies, two groups with broadband frequency and short duration, and a group with mainly low frequency and long duration. By comparing the environmental conditions (wind, temperature and tides), we infer that the two monochromatic groups are wind‐induced vibrations of the near‐station flag markers and topography; the two broadband groups are likely thermal contractions on the blue ice surface and stick‐slip events at the ice base; and the low‐frequency events are water‐filled basal crevassing and iceberg calving. In particular, we observe one type of low‐frequency event preceded by high‐frequency onset, which is likely basal crevassing near the grounding line of Dålk Glacier and predominantly occurred during rising tides. Our findings show that deep clustering is effective in identifying a wide range of glacial seismic events and can contribute to the rapid growth of passive glacier seismic monitoring.
ATG or post-transplant cyclophosphamide to prevent GVHD in matched unrelated stem cell transplantation?
Authors: Penack Olaf , Abouqateb Mouad , Peczynski Christophe , Boreland William , Kröger Nicolaus , Stelljes Matthias , Gedde-Dahl Tobias , Blau Igor Wolfgang , Schroeder Thomas , Salmenniemi Urpu , Kulagin Alexander , Peffault de Latour Régis , Mielke Stephan , Zeiser Robert , Moiseev Ivan , Schoemans Hélène , Koenecke Christian , Peric Zinaida
Published: March 2024

There is a high risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) from unrelated donors. Prophylaxis with rabbit anti-thymocyte globulin (rATG) is standard in Europe but post-transplantation Cyclophosphamide (PTCy) is an emerging alternative. We analyzed outcomes of rATG (n = 7725) vs. PTCy (n = 1039) prophylaxis in adult patients with hematologic malignancies undergoing peripheral blood alloSCT from 10/10 antigen-matched unrelated donors (MUD) between January 2018 and June 2021 in the EBMT database. The provided P-values and hazard ratios (HR) are derived from multivariate analysis. Two years after alloSCT, NRM in the PTCy group was 12.1% vs. 16.4% in the rATG group; p = 0.016; HR 0.72. Relapse was less frequent after PTCy vs. rATG (22.8% vs. 26.6%; p = 0.046; HR 0.87). Overall survival after PTCy was higher (73.1% vs. 65.9%; p = 0.001, HR 0.82). Progression free survival was better after PTCy vs. rATG (64.9% vs. 57.2%; p < 0.001, HR 0.83). The incidence of chronic GVHD was lower after PTCy (28.4% vs. rATG 31.4%; p = 0.012; HR 0.77), whereas the incidence and severity of acute GVHD were not significantly different. GVHD-free relapse-free survival was significantly higher in the PTCy arm compared to the rATG arm (2 y incidence: 51% vs. 45%; HR: 0.86 [95% CI 0.75–0.99], p = 0.035). In the absence of evidence from randomized controlled trials, our findings support a preference for the use of PTCy in adult recipients of peripheral blood alloSCTs from MUD.
RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy
Authors: Liu Wei-Wei , Zheng Si-Qing , Li Tian , Fei Yun-Fei , Wang Chen , Zhang Shuang , Wang Fei , Jiang Guan-Min , Wang Hao
Published: March 2024

Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding of pathophysiology, and inspiring development of therapeutics. As a crucial component of epigenetics at post-transcription level, RNA modification significantly determines RNA fates, further affecting various biological processes and cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts. In this review, we characterize the distribution features, modifying mechanisms and biological functions of 8 RNA modifications, including N6-methyladenosine (m6A), N6,2′-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively the most studied types. Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described, categorized as glucose, lipid, amino acid, and mitochondrial metabolism. And we highlight the regulation of RNA modifications on immunometabolism, further influencing immune responses. Above all, we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy, progression of RNA modification-targeted agents, and its potential in RNA-targeted therapeutics. Eventually, we give legitimate perspectives for future researches in this field from methodological requirements, mechanistic insights, to therapeutic applications.
Melatonin alleviates chronic stress-induced hippocampal microglia pyroptosis and subsequent depression-like behaviors by inhibiting Cathepsin B/NLRP3 signaling pathway in rats
Authors: Gao Zhicheng , Luo Kangxin , Hu Yulin , Niu Yunqian , Zhu Xinchao , Li Shoujun , Zhang Haiyang
Published: March 2024

Melatonin improves chronic stress-induced hippocampal damage and depression-like behaviors, but the mechanism needs further study. This study was to explore the mechanism of melatonin inhibiting microglia pyroptosis. In virtro experiments, melatonin improved corticosterone-induced the ultrastructure and microstructure damage of HAPI cells by inhibiting pyroptosis, thereby increasing cell survival rate. Protein-protein interaction network and molecular autodocking predicted that Cathespin B might be the target of melatonin inhibition of NLRP3-mediated pyroptosis. Melatonin inhibited corticosterone-induced Cathespin B expression. Both Cathepsin B inhibitor CA-074Me and NLRP3 knockout inhibited the HAPI cells pyroptosis. Similarly, melatonin inhibited Cathepsin B agonist Pazopanib-induced activation of Cathepsin B/NLRP3 signaling pathway and HAPI cells pyroptosis. In vivo studies, melatonin inhibited chronic restraint stress (CRS)-induced activation of Cathepsin B/NLRP3 signaling pathway and alleviated hippocampal microglia pyroptosis in rats. Inhibition of microglia pyroptosis improved CRS-induced depression-like behaviors of rats. In addition, inhibition of Cathepsin B and NLRP3 alleviated hippocampal pyroptosis. Melatonin inhibited Pazopanib-induced activation of Cathepsin B/NLRP3 signaling pathway and hippocampal pyroptosis. These results demonstrated that melatonin could alleviate CRS-induced hippocampal microglia pyroptosis by inhibiting Cathepsin B/NLRP3 signaling pathway, thereby improving depression-like behaviors in rats. This study reveals the molecular mechanism of melatonin in the prevention and treatment of chronic stress-related encephalopathy.
NAP1L1 regulates BIRC2 ubiquitination modification via E3 ubiquitin ligase UBR4 and hence determines hepatocellular carcinoma progression
Authors: Zhang Shi-Long , Zhang Shen-Jie , Li Lian , Zhang Ye-Wei , Wang Zhi , Wang Long , Lu Jie-Yu , Chen Teng-Xiang , Zuo Shi
Published: March 2024

We have previously shown that nucleosome assembly protein 1-like 1 (NAP1L1) plays an important role in the abnormal proliferation of hepatocellular carcinoma (HCC) cells. However, the effects of NAP1L1 on the malignant behaviour of HCC cells, including cell migration, invasion and apoptosis, remain unclear. Baculoviral IAP repeat-containing 2 (BIRC2) plays a key role in initiating the abnormal proliferation, apoptotic escape and multidrug resistance of HCC cells; however, the mechanisms through which its stability is regulated in HCC remain elusive. Here, we found that knockdown of NAP1L1 inhibited the proliferation of HCC cells and activated apoptotic pathways but did not remarkably affect the migratory and invasive abilities of HCC cells. In addition, knockdown of NAP1L1 did not alter the expression of BIRC2 at the transcriptional level but substantially reduced its expression at the translational level, suggesting that NAP1L1 is involved in the post-translational modification (such as ubiquitination) of BIRC2. Furthermore, BIRC2 was highly expressed in human HCC tissues and promoted the proliferation and apoptotic escape of HCC cells. Co-immunoprecipitation (Co-IP) assay and mass spectrometry revealed that NAP1L1 and BIRC2 did not bind to each other; however, ubiquitin protein ligase E3 component n-recognin 4 (UBR4) was identified as an intermediate molecule associating NAP1L1 with BIRC2. Knockdown of NAP1L1 promoted the ubiquitin-mediated degradation of BIRC2 through the ubiquitin–protein junction of UBR4, which in turn inhibited the proliferation and apoptotic escape of HCC cells and exerted anti-tumour effects. In conclusion, this study reveals a novel mechanism through which NAP1L1 regulates the ubiquitination of BIRC2 through UBR4, thereby determining the progression of HCC. Based on this mechanism, suppression of NAP1L1 may inhibit tumour progression in patients with HCC with high protein expression of NAP1L1 or BIRC2.
The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease
Authors: Manuello Jordi , Min Joosung , McCarthy Paul , Alfaro-Almagro Fidel , Lee Soojin , Smith Stephen , Elliott Lloyd T. , Winkler Anderson M. , Douaud Gwenaëlle
Published: March 2024

We have previously identified a network of higher-order brain regions particularly vulnerable to the ageing process, schizophrenia and Alzheimer’s disease. However, it remains unknown what the genetic influences on this fragile brain network are, and whether it can be altered by the most common modifiable risk factors for dementia. Here, in ~40,000 UK Biobank participants, we first show significant genome-wide associations between this brain network and seven genetic clusters implicated in cardiovascular deaths, schizophrenia, Alzheimer’s and Parkinson’s disease, and with the two antigens of the XG blood group located in the pseudoautosomal region of the sex chromosomes. We further reveal that the most deleterious modifiable risk factors for this vulnerable brain network are diabetes, nitrogen dioxide – a proxy for traffic-related air pollution – and alcohol intake frequency. The extent of these associations was uncovered by examining these modifiable risk factors in a single model to assess the unique contribution of each on the vulnerable brain network, above and beyond the dominating effects of age and sex. These results provide a comprehensive picture of the role played by genetic and modifiable risk factors on these fragile parts of the brain.
CMOS plus stochastic nanomagnets enabling heterogeneous computers for probabilistic inference and learning
Authors: Singh Nihal Sanjay , Kobayashi Keito , Cao Qixuan , Selcuk Kemal , Hu Tianrui , Niazi Shaila , Aadit Navid Anjum , Kanai Shun , Ohno Hideo , Fukami Shunsuke , Camsari Kerem Y.
Published: March 2024

Extending Moore’s law by augmenting complementary-metal-oxide semiconductor (CMOS) transistors with emerging nanotechnologies (X) has become increasingly important. One important class of problems involve sampling-based Monte Carlo algorithms used in probabilistic machine learning, optimization, and quantum simulation. Here, we combine stochastic magnetic tunnel junction (sMTJ)-based probabilistic bits (p-bits) with Field Programmable Gate Arrays (FPGA) to create an energy-efficient CMOS + X (X = sMTJ) prototype. This setup shows how asynchronously driven CMOS circuits controlled by sMTJs can perform probabilistic inference and learning by leveraging the algorithmic update-order-invariance of Gibbs sampling. We show how the stochasticity of sMTJs can augment low-quality random number generators (RNG). Detailed transistor-level comparisons reveal that sMTJ-based p-bits can replace up to 10,000 CMOS transistors while dissipating two orders of magnitude less energy. Integrated versions of our approach can advance probabilistic computing involving deep Boltzmann machines and other energy-based learning algorithms with extremely high throughput and energy efficiency.
iNOS is necessary for GBP-mediated T. gondii clearance in murine macrophages via vacuole nitration and intravacuolar network collapse
Authors: Zhao Xiao-Yu , Lempke Samantha L. , Urbán Arroyo Jan C. , Brown Isabel G. , Yin Bocheng , Magaj Magdalena M. , Holness Nadia K. , Smiley Jamison , Redemann Stefanie , Ewald Sarah E.
Published: March 2024

Toxoplasma gondii is an obligate intracellular parasite of rodents and humans. Interferon-inducible guanylate binding proteins (GBPs) are mediators of T. gondii clearance, however, this mechanism is incomplete. Here, using automated spatially targeted optical micro proteomics we demonstrate that inducible nitric oxide synthetase (iNOS) is highly enriched at GBP2+ parasitophorous vacuoles (PV) in murine macrophages. iNOS expression in macrophages is necessary to limit T. gondii load in vivo and in vitro. Although iNOS activity is dispensable for GBP2 recruitment and PV membrane ruffling; parasites can replicate, egress and shed GBP2 when iNOS is inhibited. T. gondii clearance by iNOS requires nitric oxide, leading to nitration of the PV and collapse of the intravacuolar network of membranes in a chromosome 3 GBP-dependent manner. We conclude that reactive nitrogen species generated by iNOS cooperate with GBPs to target distinct structures in the PV that are necessary for optimal parasite clearance in macrophages.
Strongly interacting Rydberg atoms in synthetic dimensions with a magnetic flux
Authors: Chen Tao , Huang Chenxi , Velkovsky Ivan , Hazzard Kaden R. A. , Covey Jacob P. , Gadway Bryce
Published: March 2024

Synthetic dimensions, wherein dynamics occurs in a set of internal states, have found great success in recent years in exploring topological effects in cold atoms and photonics. However, the phenomena thus far explored have largely been restricted to the non-interacting or weakly interacting regimes. Here, we extend the synthetic dimensions playbook to strongly interacting systems of Rydberg atoms prepared in optical tweezer arrays. We use precise control over driving microwave fields to introduce a tunable U(1) flux in a four-site lattice of coupled Rydberg levels. We find highly coherent dynamics, in good agreement with theory. Single atoms show oscillatory dynamics controllable by the gauge field. Small arrays of interacting atoms exhibit behavior suggestive of the emergence of ergodic and arrested dynamics in the regimes of intermediate and strong interactions, respectively. These demonstrations pave the way for future explorations of strongly interacting dynamics and many-body phases in Rydberg synthetic lattices.
One-photon three-dimensional printed fused silica glass with sub-micron features
Authors: Li Ziyong , Jia Yanwen , Duan Ke , Xiao Ran , Qiao Jingyu , Liang Shuyu , Wang Shixiang , Chen Juzheng , Wu Hao , Lu Yang , Wen Xiewen
Published: March 2024

The applications of silica-based glass have evolved alongside human civilization for thousands of years. High-precision manufacturing of three-dimensional (3D) fused silica glass objects is required in various industries, ranging from everyday life to cutting-edge fields. Advanced 3D printing technologies have emerged as a potent tool for fabricating arbitrary glass objects with ultimate freedom and precision. Stereolithography and femtosecond laser direct writing respectively achieved their resolutions of ~50 μm and ~100 nm. However, fabricating glass structures with centimeter dimensions and sub-micron features remains challenging. Presented here, our study effectively bridges the gap through engineering suitable materials and utilizing one-photon micro-stereolithography (OμSL)-based 3D printing, which flexibly creates transparent and high-performance fused silica glass components with complex, 3D sub-micron architectures. Comprehensive characterizations confirm that the final material is stoichiometrically pure silica with high quality, defect-free morphology, and excellent optical properties. Homogeneous volumetric shrinkage further facilitates the smallest voxel, reducing the size from 2.0 × 2.0 × 1.0 μm3 to 0.8 × 0.8 × 0.5 μm3. This approach can be used to produce fused silica glass components with various 3D geometries featuring sub-micron details and millimetric dimensions. This showcases promising prospects in diverse fields, including micro-optics, microfluidics, mechanical metamaterials, and engineered surfaces.
Intermediate soil acidification induces highest nitrous oxide emissions
Authors: Qiu Yunpeng , Zhang Yi , Zhang Kangcheng , Xu Xinyu , Zhao Yunfeng , Bai Tongshuo , Zhao Yexin , Wang Hao , Sheng Xiongjie , Bloszies Sean , Gillespie Christopher J. , He Tangqing , Wang Yang , Chen Huaihai , Guo Lijin , Song He , Ye Chenglong , Wang Yi , Woodley Alex , Guo Jingheng , Cheng Lei , Bai Yongfei , Zhu Yongguan , Hallin Sara , Firestone Mary K. , Hu Shuijin
Published: March 2024

Global potent greenhouse gas nitrous oxide (N2O) emissions from soil are accelerating, with increases in the proportion of reactive nitrogen emitted as N2O, i.e., N2O emission factor (EF). Yet, the primary controls and underlying mechanisms of EFs remain unresolved. Based on two independent but complementary global syntheses, and three field studies determining effects of acidity on N2O EFs and soil denitrifying microorganisms, we show that soil pH predominantly controls N2O EFs and emissions by affecting the denitrifier community composition. Analysis of 5438 paired data points of N2O emission fluxes revealed a hump-shaped relationship between soil pH and EFs, with the highest EFs occurring in moderately acidic soils that favored N2O-producing over N2O-consuming microorganisms, and induced high N2O emissions. Our results illustrate that soil pH has a unimodal relationship with soil denitrifiers and EFs, and the net N2O emission depends on both the N2O/(N2O + N2) ratio and overall denitrification rate. These findings can inform strategies to predict and mitigate soil N2O emissions under future nitrogen input scenarios.
Real-time monitoring of replication errors’ fate reveals the origin and dynamics of spontaneous mutations
Authors: Enrico Bena Chiara , Ollion Jean , De Paepe Marianne , Ventroux Magali , Robert Lydia , Elez Marina
Published: March 2024

The efficiency of replication error repair is a critical factor governing the emergence of mutations. However, it has so far been impossible to study this efficiency at the level of individual cells and to investigate if it varies within isogenic cell populations. In addition, why some errors escape repair remains unknown. Here we apply a combination of fluorescent labelling of the Escherichia coli Mismatch Repair (MMR) complex, microfluidics, and time-lapse microscopy, to monitor in real-time the fate of >20000 replication errors. We show that i) many mutations result from errors that are detected by MMR but inefficiently repaired ii) this limited repair efficiency is due to a temporal constraint imposed by the transient nature of the DNA strand discrimination signal, a constraint that is likely conserved across organisms, and iii) repair capacity varies from cell to cell, resulting in a subpopulation of cells with higher mutation rate. Such variations could influence the fitness and adaptability of populations, accelerating for instance the emergence of antibiotic resistance.
Collective incentives reduce over-exploitation of social information in unconstrained human groups
Authors: Deffner Dominik , Mezey David , Kahl Benjamin , Schakowski Alexander , Romanczuk Pawel , Wu Charley M. , Kurvers Ralf H. J. M.
Published: March 2024

Collective dynamics emerge from countless individual decisions. Yet, we poorly understand the processes governing dynamically-interacting individuals in human collectives under realistic conditions. We present a naturalistic immersive-reality experiment where groups of participants searched for rewards in different environments, studying how individuals weigh personal and social information and how this shapes individual and collective outcomes. Capturing high-resolution visual-spatial data, behavioral analyses revealed individual-level gains—but group-level losses—of high social information use and spatial proximity in environments with concentrated (vs. distributed) resources. Incentivizing participants at the group (vs. individual) level facilitated adaptation to concentrated environments, buffering apparently excessive scrounging. To infer discrete choices from unconstrained interactions and uncover the underlying decision mechanisms, we developed an unsupervised Social Hidden Markov Decision model. Computational results showed that participants were more sensitive to social information in concentrated environments frequently switching to a social relocation state where they approach successful group members. Group-level incentives reduced participants’ overall responsiveness to social information and promoted higher selectivity over time. Finally, mapping group-level spatio-temporal dynamics through time-lagged regressions revealed a collective exploration-exploitation trade-off across different timescales. Our study unravels the processes linking individual-level strategies to emerging collective dynamics, and provides tools to investigate decision-making in freely-interacting collectives.
In situ detection of spatial distribution information of temperature-pH-strain of sandstone cultural relics
Authors: Xu Changyuan , Li Linyang , Hu Rong , Wu Huihua , Kong Lingnan , Zhong Nianbing , Wan Bo , Wu Lei , Lai Dong , He Yuanyuan , Liu Yang , Peng Xiaoling , Zhao Mingfu , Xie Quanhua
Published: March 2024

To monitor in situ the temperature, pH, and micro-strain change information of sandstone artifacts in the process of oxalic acid corrosion, the temperature, pH, and micro-strain fiber Bragg grating (FBG) sensors are developed. A theoretical model of the sensors is established. The surface morphology, material composition, pore structure, temperature, pH, and micro-strain of sandstone corroded by oxalic acid solutions of different concentrations are investigated. The experimental results show that the higher the concentration of oxalic acid, the stronger the corrosiveness of the sandstone. Ferrous oxalate and calcium oxalate produced by corrosion continuously precipitate from the inside of the rock, and the dual reaction of crystallization and dissolution occurs, reducing the proportion of fine pores in the rock pore suction and gravity. The oxalic acid solution is transported to the middle of the sandstone (3 cm) and undergoes the strongest chemical reaction with ore particles and debris, resulting in the maximum wavelength drift of the temperature, pH, and micro-strain sensors. The results of this study provide important support for analyzing the acid dissolution mechanism of stone cultural relics and the preventive protection of cultural relics.