bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of a community-based primary healthcare programme on childhood diphtheria-tetanus-pertussis (DPT3) immunisation coverage in rural northern Ghana
Authors: Kanmiki Edmund Wedam , Mamun Abdullah A. , Phillips James F. , O’Flaherty Martin
Published: December 2023

Background

Child healthcare services such as diphtheria-tetanus-pertussis (DPT3) vaccination are known to reduce childhood mortality and morbidity. However, inequalities in access to these services in developing countries continue to constrain global efforts aimed at improving child health. This study examines the impact and equity effect of a community-based primary healthcare programme known as the Ghana Essential Health Intervention Programme (GEHIP) on improving the uptake of childhood DPT3 immunisation coverage in a remote rural region of Ghana.

Methods

Using baseline and end-line household survey data collected from mothers, the effect of GEHIP’s community-based healthcare programme on DPT3 immunisation coverage is evaluated using difference-in-differences multivariate logistic regression models. Household wealth index and maternal educational attainment were used as equity measures.

Results

At end-line, both intervention and comparison districts recorded increases in DPT3 immunisation coverage although intervention districts had a relatively higher coverage than comparison districts (90% versus 88%). While children resident in intervention areas had slightly higher rates than children resident in comparison areas, regression results show that this difference was not statistically significant (DiD = 0.038, p-value = 0.102). There were also no significant equity disparities in the coverage of DPT3 vaccination for both household wealth index and maternal educational attainment.

Conclusion

DPT3 vaccination coverage in both study arms met the global vaccine action plan targets. However, because estimated effects are not significantly higher among treatment area children than among comparison districts counterparts, no equity/inequity effects of the community-based healthcare programme on DPT 3 coverage is evident.
Physicochemical characteristics and seasonal variations of PM2.5 in urban, industrial, and suburban areas in South Korea
Authors: Hwang Kyucheol , Kim Jeongho , Lee Jae Young , Park Jong-Sung , Park Sechan , Lee Gahye , Kim Chang Hyeok , Kim Pilho , Shin Su Hyun , Lee Kwang Yul , An Joon-Young , Park Jungmin , Kim Jong Bum
Published: December 2023

Among countries that are a part of the Organization for Economic Co-operation and Development, South Korea is the most exposed to PM2.5. Despite the country having implemented various strategies to limit PM2.5 emissions, its concentrations are still high enough to pose serious environmental and health concerns. Herein, we monitored various physiochemical properties of PM2.5 across different regions in South Korea from January 1 to December 31, 2021. Specifically, the study area consisted of the city center, industrial complexes, and suburban areas. Before analyzing dynamics of emissions specific to each site, the Clean Air Policy Support System data for the three areas were compared to elucidate their respective primary emission sources. The particle concentrations for the three areas were 21.8–26.44 µg/m3, with the highest concentrations being observed in March. All the three areas exhibited high ratios of NO3− across all seasons. The particle number concentrations in the three sites were 1.3–1.5 × 107, and the peak points of the concentrations were different in every site: city center (40 nm), industrial complexes (60 nm), and suburban areas (80 nm). We also conducted potential source contribution function and conditional bivariate probability function analyses. These analyses were conducted to determine the inflow direction of the pollution sources for high PM2.5 episodes. For the episodes that occurred in spring and winter, there were no differences in the PM2.5 concentrations between the three sites. Overall, the insights gained from this study offer a framework for developing air-quality management policies in South Korea, specifically in the context of PM2.5 emissions.
Sensitivity analysis for causality in observational studies for regulatory science
Authors: Díaz Iván , Lee Hana , Kıcıman Emre , Schenck Edward J. , Akacha Mouna , Follman Dean , Ghosh Debashis
Published: December 2023

Objective:

The United States Congress passed the 21st Century Cures Act mandating the development of Food and Drug Administration guidance on regulatory use of real-world evidence. The Forum on the Integration of Observational and Randomized Data conducted a meeting with various stakeholder groups to build consensus around best practices for the use of real-world data (RWD) to support regulatory science. Our companion paper describes in detail the context and discussion of the meeting, which includes a recommendation to use a causal roadmap for study designs using RWD. This article discusses one step of the roadmap: the specification of a sensitivity analysis for testing robustness to violations of causal model assumptions.

Methods:

We present an example of a sensitivity analysis from a RWD study on the effectiveness of Nifurtimox in treating Chagas disease, and an overview of various methods, emphasizing practical considerations on their use for regulatory purposes.

Results:

Sensitivity analyses must be accompanied by careful design of other aspects of the causal roadmap. Their prespecification is crucial to avoid wrong conclusions due to researcher degrees of freedom. Sensitivity analysis methods require auxiliary information to produce meaningful conclusions; it is important that they have at least two properties: the validity of the conclusions does not rely on unverifiable assumptions, and the auxiliary information required by the method is learnable from the corpus of current scientific knowledge.

Conclusions:

Prespecified and assumption-lean sensitivity analyses are a crucial tool that can strengthen the validity and trustworthiness of effectiveness conclusions for regulatory science.
Comparison constructions in two Northern Talyshi dialects
Authors: Avchyan Hakob
Published: December 2023

This article examines the comparison constructions in two Northern Talyshi varieties: in Anbarāni, used in the Islamic Republic of Iran; and the Northern Talyshi dialects spoken in the Republic of Azerbaijan. These constructions have been poorly studied in previous research dealing with this North-western Iranian language and this article aims to fill that gap. In contrast with a number of Western Iranian languages, Northern Talyshi (and the Talyshi language in general) does not have special morphological markers for expressing the degrees of comparison. The comparative grades are marked syntactically using various adpositions and function words. Having long been under the influence of neighbouring languages such as Persian and Azerbaijani, both Anbarāni and the Talyshi dialects spoken in the present-day Republic of Azerbaijan have been affected by these languages at some level in the ways to make comparison.
The prevalence of vegetarians, vegans and other dietary patterns that exclude some animal-source foods in a representative sample of New Zealand adults
Authors: Greenwell James , Grant Megan , Young Leanne , Mackay Sally , Bradbury Kathryn Erica
Published: December 2023

Objective:

This study aimed to estimate the prevalence of vegetarians, vegans and other dietary patterns that exclude some animal-source foods in New Zealand adults. We also examined socio-demographic and lifestyle correlates of these dietary patterns.

Design:

The New Zealand Health Survey is a representative rolling cross-sectional survey of New Zealanders; data from the 2018/19 and 2019/20 waves were used for this analysis. Participants were asked if they completely excluded red meat, poultry, fish/shellfish, eggs or dairy products from their diet.

Setting:

New Zealand.

Participants:

Adults, aged ≥ 15 years (n 23 292).

Results:

The prevalence of red-meat excluders (2·89 %), pescatarians (1·40 %), vegetarians (2·04 %) and vegans (0·74 %) was low. After adjustment for socio-demographic and lifestyle factors, women (OR = 1·54, 95 % CI: 1·22, 1·95), Asian people (OR = 2·56, 95 % CI: 1·96, 4·45), people with tertiary education (OR = 1·71, 95 % CI: 1·18, 2·48) and physically active people (OR = 1·36, 95 % CI: 1·04, 1·76) were more likely to be vegetarian/vegan. Those aged ≥ 75 years (OR = 0·28, 95 % CI: 0·14, 0·53) and current smokers (OR = 0·42, 95 % CI: 0·23, 0·76) were less likely to be vegetarian/vegan. Similar associations were seen between socio-demographic and lifestyle factors and the odds of being a red-meat excluder/pescatarian.

Conclusions:

Approximately 93 % of New Zealand adults eat red meat and a very small number exclude all animal products from their diets. The Eating and Activity Guidelines for New Zealand adults recommend a plant-based diet with moderate amounts of animal-source foods. A comprehensive national nutrition survey would provide detailed information on the amount of red meat and other animal-source foods that the New Zealand population currently consumes.
Higher adherence to the Mediterranean Diet is associated with lower micronutrient inadequacy in children: the SENDO project
Authors: Oliver Olid Asier , Fabios Elise , García-Blanco Lorena , Moreno-Villares Jose Manuel , Martínez-González Miguel Ángel , Martín-Calvo Nerea
Published: December 2023

Objective:

To assess whether the Mediterranean Diet (MedDiet) is associated with lower micronutrients inadequacy in a sample of Spanish preschoolers.

Design:

We conducted a cross-sectional study with 4–5-year-old children participating in the SENDO project. Information was gathered through an online questionnaire completed by parents. Dietary information was collected with a previously validated semi-quantitative FFQ. The estimated average requirements or adequate intake levels as proposed by the Institute of Medicine were used as cut-off point to define inadequate intake.

Statistical analyses:

Crude and multivariable adjusted estimates were calculated with generalised estimated equations to account for intra-cluster correlation between siblings.

Participants:

We used baseline information of 1153 participants enrolled in the SENDO project between January 2015 and June 2022.

Main outcomes measures:

OR and 95 % CI of presenting an inadequate intake of ≥ 3 micronutrients associated with the MedDiet.

Results:

The adjusted proportion of children with inadequate intake of ≥ 3 micronutrients was 27·2 %, 13·5 % and 8·1 % in the categories of low, medium and high adherence to the MedDiet, respectively. After adjusting for all potential confounders, children who had a low adherence to the MedDiet showed a significant lower odds of inadequate intake of ≥ 3 micronutrients compared to those with a high adherence (OR 9·85; 95 % CI 3·33, 29·09).

Conclusion:

Lower adherence to the MedDiet is associated with higher odds of nutritional inadequacy.
Rethinking AI for Science: An Evolution From Data‐Driven to Data‐Centric Framework
Authors: Maskey Manil
Published: December 2023

The rapid advancements in Artificial Intelligence (AI) have found applications across a multitude of disciplines, including the scientific domain. Yet, the dominant focus on model‐centric AI often overlooks the critical role that data plays, thereby limiting its effectiveness in scientific investigations. This paper advocates for a transition to a data‐centric viewpoint, especially within the framework of AI applied to scientific advancements. The paper outlines the contrasting philosophies of model‐centric and data‐centric AI, highlighting the latter's commitment to data strategies. It explores a range of techniques that bolster the data‐centric framework. Furthermore, the paper presents an overview of key milestones in AI technology, the significance and the changing role of data‐centric AI, and the current state of research in this emerging field.
Monitoring of over-the-counter (OTC) and COVID-19 treatment drugs complement wastewater surveillance of SARS-CoV-2
Authors: Lee Cheng-Shiuan , Wang Mian , Nanjappa Deepak , Lu Yi-Ta , Meliker Jaymie , Clouston Sean , Gobler Christopher J. , Venkatesan Arjun K.
Published: December 2023

Background

The application of wastewater-based epidemiology to track the outbreak and prevalence of coronavirus disease (COVID-19) in communities has been tested and validated by several researchers across the globe. However, the RNA-based surveillance has its inherent limitations and uncertainties.

Objective

This study aims to complement the ongoing wastewater surveillance efforts by analyzing other chemical biomarkers in wastewater to help assess community response (hospitalization and treatment) during the pandemic (2020–2021).

Methods

Wastewater samples (n = 183) were collected from the largest wastewater treatment facility in Suffolk County, NY, USA and analyzed for COVID-19 treatment drugs (remdesivir, chloroquine, and hydroxychloroquine (HCQ)) and their human metabolites. We additionally monitored 26 pharmaceuticals including common over-the-counter (OTC) drugs. Lastly, we developed a Bayesian model that uses viral RNA, COVID-19 treatment drugs, and pharmaceuticals data to predict the confirmed COVID-19 cases within the catchment area.

Results

The viral RNA levels in wastewater tracked the actual COVID-19 case numbers well as expected. COVID-19 treatment drugs were detected with varying frequency (9–100%) partly due to their instability in wastewater. We observed a significant correlation (R = 0.30, p < 0.01) between the SARS-CoV-2 genes and desethylhydroxychloroquine (DHCQ, metabolite of HCQ). Remdesivir levels peaked immediately after the Emergency Use Authorization approved by the FDA. Although, 13 out of 26 pharmaceuticals assessed were consistently detected (DF = 100%, n = 111), only acetaminophen was significantly correlated with viral loads, especially when the Omicron variant was dominant. The Bayesian models were capable of reproducing the temporal trend of the confirmed cases.

Impact

In this study, for the first time, we measured COVID-19 treatment and pharmaceutical drugs and their metabolites in wastewater to complement ongoing COVID-19 viral RNA surveillance efforts. Our results highlighted that, although the COVID-19 treatment drugs were not very stable in wastewater, their detection matched with usage trends in the community. Acetaminophen, an OTC drug, was significantly correlated with viral loads and confirmed cases, especially when the Omicron variant was dominant. A Bayesian model was developed which could predict COVID-19 cases more accurately when incorporating other drugs data along with viral RNA levels in wastewater.
Oxytocin activity in the paraventricular and supramammillary nuclei of the hypothalamus is essential for social recognition memory in rats
Authors: Thirtamara Rajamani Keerthi , Barbier Marie , Lefevre Arthur , Niblo Kristi , Cordero Nicholas , Netser Shai , Grinevich Valery , Wagner Shlomo , Harony-Nicolas Hala
Published: December 2023

Oxytocin plays an important role in modulating social recognition memory. However, the direct implication of oxytocin neurons of the paraventricular nucleus of the hypothalamus (PVH) and their downstream hypothalamic targets in regulating short- and long-term forms of social recognition memory has not been fully investigated. In this study, we employed a chemogenetic approach to target the activity of PVH oxytocin neurons in male rats and found that specific silencing of this neuronal population led to an impairment in short- and long-term social recognition memory. We combined viral-mediated fluorescent labeling of oxytocin neurons with immunohistochemical techniques and identified the supramammillary nucleus (SuM) of the hypothalamus as a target of PVH oxytocinergic axonal projections in rats. We used multiplex fluorescence in situ hybridization to label oxytocin receptors in the SuM and determined that they are predominantly expressed in glutamatergic neurons, including those that project to the CA2 region of the hippocampus. Finally, we used a highly selective oxytocin receptor antagonist in the SuM to examine the involvement of oxytocin signaling in modulating short- and long-term social recognition memory and found that it is necessary for the formation of both. This study discovered a previously undescribed role for the SuM in regulating social recognition memory via oxytocin signaling and reinforced the specific role of PVH oxytocin neurons in regulating this form of memory.
Geraniol reverses obesity by improving conversion of WAT to BAT in high fat diet induced obese rats by inhibiting HMGCoA reductase
Authors: Chand Shushmita , Tripathi Alok Shiomurti , Hasan Tabinda , Ganesh Kavitha , Cordero Mary Anne W. , Yasir Mohammad , Zaki Magdi E. A. , Tripathi Pankaj , Mohapatra Lucy , Maurya Rahul Kumar
Published: December 2023

Objectives

Present report evaluates the protective effect of geraniol on high fat diet (HFD) induced obesity in rats and also determines the molecular mechanism of it.

Methods

Rats were induced with obesity with administration of HFD for four weeks and geraniol 200 and 400 mg/kg p.o. was administered for the next four week in the respective groups. Blood glucose and oral glucose tolerance test (OGTT), lipid profile was estimated in the geraniol treated HFD induced obesity in rats. Moreover, docking study was performed to determine the specific mechanism of geraniol by targeting HMG-CoE A reductase (in silico).

Results

There was significant increase in body weight and amelioration in altered serum glucose and lipid profile were observed in the geraniol treated group than negative control group. Weight of organs and adipose tissue isolated from different regions of the body was reduced in geraniol treated group than negative control. Moreover, geraniol interact with HMG-CoA reductase having binding energy −5.13.

Conclusions

In conclusion, data of the report reveals that geraniol reduces obesity by promoting the conversion of white adipose tissue (WAT) to brown adipose tissue (BAT), as it interacts with HMG-CoA reductase in HFD induced obesity in rats.
RPLP2 activates TLR4 in an autocrine manner and promotes HIF-1α-induced metabolic reprogramming in hepatocellular carcinoma
Authors: Yang Qingqing , Meng Xiangrui , Chen Jin , Li Xiangsu , Huang Yang , Xiao Xueyi , Li Rongqing , Wu Xudong
Published: December 2023

Metabolic reprogramming is a major feature of cancer, and aerobic glycolysis is one of the most widely studied metabolic reprogramming processes. Acidic ribosome protein P2 (RPLP2) is associated with both tumorigenesis and endoplasmic reticulum stress. However, limited knowledge exists regarding the role of RPLP2 in hepatocellular carcinoma (HCC) progression. In the present study, we observed a significant upregulation of RPLP2 in HCC tissues. Moreover, RPLP2 expression is closely correlated with patient prognosis and survival. The subsequent experimental validation demonstrated that RPLP2 exerted a regulatory effect on the expression of glycolytic enzymes and lactate production, thereby facilitating HCC cell proliferation. Mechanistically, the PI3K/AKT signalling pathway was found to play an important role in the regulation of hypoxia-inducible factor-1α (HIF-1α)-mediated aerobic glycolysis and cell growth. RPLP2 activates TLR4 on the surface of HCC cells and the downstream PI3K/AKT pathway through autocrine signalling. This activation then facilitates the entry of HIF-1α into the nucleus, enabling it to fulfil its transcriptional function. In conclusion, our findings suggested that RPLP2 induces a metabolic shift towards aerobic glycolysis and facilitates the progression of HCC through TLR4-dependent activation of the PI3K/AKT/HIF-1α pathway. Our study revealed the novel mechanism by which the ribosomal protein RPLP2 regulates glycolysis to promote HCC progression. These findings may offer a potential therapeutic target for HCC treatment.
Investigation of monoclonal antibody CSX-1004 for fentanyl overdose
Authors: Bremer Paul T. , Burke Emily L. , Barrett Andrew C. , Desai Rajeev I.
Published: December 2023

The opioid crisis in the United States is primarily driven by the highly potent synthetic opioid fentanyl leading to >70,000 overdose deaths annually; thus, new therapies for fentanyl overdose are urgently needed. Here, we present the first clinic-ready, fully human monoclonal antibody CSX-1004 with picomolar affinity for fentanyl and related analogs. In mice CSX-1004 reverses fentanyl antinociception and the intractable respiratory depression caused by the ultrapotent opioid carfentanil. Moreover, toxicokinetic evaluation in a repeat-dose rat study and human tissue cross-reactivity study reveals a favorable pharmacokinetic profile of CSX-1004 with no safety-related issues. Using a highly translational non-human primate (NHP) model of respiratory depression, we demonstrate CSX-1004-mediated protection from repeated fentanyl challenges for 3-4 weeks. Furthermore, treatment with CSX-1004 produces up to a 15-fold potency reduction of fentanyl in NHP respiration, antinociception and operant responding assays without affecting non-fentanyl opioids like oxycodone. Taken together, our data establish the feasibility of CSX-1004 as a promising candidate medication for preventing and reversing fentanyl-induced overdose.
Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells
Authors: Maimaitili Muyesier , Chen Muwan , Febbraro Fabia , Ucuncu Ekin , Kelly Rachel , Niclis Jonathan Christos , Christiansen Josefine Rågård , Mermet-Joret Noëmie , Niculescu Dragos , Lauritsen Johanne , Iannielli Angelo , Klæstrup Ida H. , Jensen Uffe Birk , Qvist Per , Nabavi Sadegh , Broccoli Vania , Nykjær Anders , Romero-Ramos Marina , Denham Mark
Published: December 2023

Current differentiation protocols for generating mesencephalic dopaminergic (mesDA) neurons from human pluripotent stem cells result in grafts containing only a small proportion of mesDA neurons when transplanted in vivo. In this study, we develop lineage-restricted undifferentiated stem cells (LR-USCs) from pluripotent stem cells, which enhances their potential for differentiating into caudal midbrain floor plate progenitors and mesDA neurons. Using a ventral midbrain protocol, 69% of LR-USCs become bona fide caudal midbrain floor plate progenitors, compared to only 25% of human embryonic stem cells (hESCs). Importantly, LR-USCs generate significantly more mesDA neurons under midbrain and hindbrain conditions in vitro and in vivo. We demonstrate that midbrain-patterned LR-USC progenitors transplanted into 6-hydroxydopamine-lesioned rats restore function in a clinically relevant non-pharmacological behavioral test, whereas midbrain-patterned hESC-derived progenitors do not. This strategy demonstrates how lineage restriction can prevent the development of undesirable lineages and enhance the conditions necessary for mesDA neuron generation.
Evolution of high-molecular-mass hyaluronic acid is associated with subterranean lifestyle
Authors: Zhao Yang , Zheng Zhizhong , Zhang Zhihui , Xu Yandong , Hillpot Eric , Lin Yifei S. , Zakusilo Frances T. , Lu J. Yuyang , Ablaeva Julia , Biashad Seyed Ali , Miller Richard A. , Nevo Eviatar , Seluanov Andrei , Gorbunova Vera
Published: December 2023

Hyaluronic acid is a major component of extracellular matrix which plays an important role in development, cellular response to injury and inflammation, cell migration, and cancer. The naked mole-rat (Heterocephalus glaber) contains abundant high-molecular-mass hyaluronic acid in its tissues, which contributes to this species’ cancer resistance and possibly to its longevity. Here we report that abundant high-molecular-mass hyaluronic acid is found in a wide range of subterranean mammalian species, but not in phylogenetically related aboveground species. These subterranean mammalian species accumulate abundant high-molecular-mass hyaluronic acid by regulating the expression of genes involved in hyaluronic acid degradation and synthesis and contain unique mutations in these genes. The abundant high-molecular-mass hyaluronic acid may benefit the adaptation to subterranean environment by increasing skin elasticity and protecting from oxidative stress due to hypoxic conditions. Our work suggests that high-molecular-mass hyaluronic acid has evolved with subterranean lifestyle.
Prostate cancer genetic risk and associated aggressive disease in men of African ancestry
Authors: Soh Pamela X. Y. , Mmekwa Naledi , Petersen Desiree C. , Gheybi Kazzem , van Zyl Smit , Jiang Jue , Patrick Sean M. , Campbell Raymond , Jaratlerdseri Weerachai , Mutambirwa Shingai B. A. , Bornman M. S. Riana , Hayes Vanessa M.
Published: December 2023

African ancestry is a significant risk factor for prostate cancer and advanced disease. Yet, genetic studies have largely been conducted outside the context of Sub-Saharan Africa, identifying 278 common risk variants contributing to a multiethnic polygenic risk score, with rare variants focused on a panel of roughly 20 pathogenic genes. Based on this knowledge, we are unable to determine polygenic risk or differentiate prostate cancer status interrogating whole genome data for 113 Black South African men. To further assess for potentially functional common and rare variant associations, here we interrogate 247,780 exomic variants for 798 Black South African men using a case versus control or aggressive versus non-aggressive study design. Notable genes of interest include HCP5, RFX6 and H3C1 for risk, and MKI67 and KLF5 for aggressive disease. Our study highlights the need for further inclusion across the African diaspora to establish African-relevant risk models aimed at reducing prostate cancer health disparities.
Leukemia-intrinsic determinants of CAR-T response revealed by iterative in vivo genome-wide CRISPR screening
Authors: Ramos Azucena , Koch Catherine E. , Liu-Lupo Yunpeng , Hellinger Riley D. , Kyung Taeyoon , Abbott Keene L. , Fröse Julia , Goulet Daniel , Gordon Khloe S. , Eidell Keith P. , Leclerc Paul , Whittaker Charles A. , Larson Rebecca C. , Muscato Audrey J. , Yates Kathleen B. , Dubrot Juan , Doench John G. , Regev Aviv , Vander Heiden Matthew G. , Maus Marcela V. , Manguso Robert T. , Birnbaum Michael E. , Hemann Michael T.
Published: December 2023

CAR-T therapy is a promising, novel treatment modality for B-cell malignancies and yet many patients relapse through a variety of means, including loss of CAR-T cells and antigen escape. To investigate leukemia-intrinsic CAR-T resistance mechanisms, we performed genome-wide CRISPR-Cas9 loss-of-function screens in an immunocompetent murine model of B-cell acute lymphoblastic leukemia (B-ALL) utilizing a modular guide RNA library. We identified IFNγR/JAK/STAT signaling and components of antigen processing and presentation pathway as key mediators of resistance to CAR-T therapy in vivo; intriguingly, loss of this pathway yielded the opposite effect in vitro (sensitized leukemia to CAR-T cells). Transcriptional characterization of this model demonstrated upregulation of these pathways in tumors relapsed after CAR-T treatment, and functional studies showed a surprising role for natural killer (NK) cells in engaging this resistance program. Finally, examination of data from B-ALL patients treated with CAR-T revealed an association between poor outcomes and increased expression of JAK/STAT and MHC-I in leukemia cells. Overall, our data identify an unexpected mechanism of resistance to CAR-T therapy in which tumor cell interaction with the in vivo tumor microenvironment, including NK cells, induces expression of an adaptive, therapy-induced, T-cell resistance program in tumor cells.
Transition between distinct hybrid skyrmion textures through their hexagonal-to-square crystal transformation in a polar magnet
Authors: Singh Deepak , Fujishiro Yukako , Hayami Satoru , Moody Samuel H. , Nomoto Takuya , Baral Priya R. , Ukleev Victor , Cubitt Robert , Steinke Nina-Juliane , Gawryluk Dariusz J. , Pomjakushina Ekaterina , Ōnuki Yoshichika , Arita Ryotaro , Tokura Yoshinori , Kanazawa Naoya , White Jonathan S.
Published: December 2023

Magnetic skyrmions, topological vortex-like spin textures, garner significant interest due to their unique properties and potential applications in nanotechnology. While they typically form a hexagonal crystal with distinct internal magnetisation textures known as Bloch- or Néel-type, recent theories suggest the possibility for direct transitions between skyrmion crystals of different lattice structures and internal textures. To date however, experimental evidence for these potentially useful phenomena have remained scarce. Here, we discover the polar tetragonal magnet EuNiGe3 to host two hybrid skyrmion phases, each with distinct internal textures characterised by anisotropic combinations of Bloch- and Néel-type windings. Variation of the magnetic field drives a direct transition between the two phases, with the modification of the hybrid texture concomitant with a hexagonal-to-square skyrmion crystal transformation. We explain these observations with a theory that includes the key ingredients of momentum-resolved Ruderman–Kittel–Kasuya–Yosida and Dzyaloshinskii-Moriya interactions that compete at the observed low symmetry magnetic skyrmion crystal wavevectors. Our findings underscore the potential of polar magnets with rich interaction schemes as promising for discovering new topological magnetic phases.
Sub-50 nm perovskite-type tantalum-based oxynitride single crystals with enhanced photoactivity for water splitting
Authors: Xiao Jiadong , Nakabayashi Mamiko , Hisatomi Takashi , Vequizo Junie Jhon M. , Li Wenpeng , Chen Kaihong , Tao Xiaoping , Yamakata Akira , Shibata Naoya , Takata Tsuyoshi , Inoue Yasunobu , Domen Kazunari
Published: December 2023

A long-standing trade-off exists between improving crystallinity and minimizing particle size in the synthesis of perovskite-type transition-metal oxynitride photocatalysts via the thermal nitridation of commonly used metal oxide and carbonate precursors. Here, we overcome this limitation to fabricate ATaO2N (A = Sr, Ca, Ba) single nanocrystals with particle sizes of several tens of nanometers, excellent crystallinity and tunable long-wavelength response via thermal nitridation of mixtures of tantalum disulfide, metal hydroxides (A(OH)2), and molten-salt fluxes (e.g., SrCl2) as precursors. The SrTaO2N nanocrystals modified with a tailored Ir–Pt alloy@Cr2O3 cocatalyst evolved H2 around two orders of magnitude more efficiently than the previously reported SrTaO2N photocatalysts, with a record solar-to-hydrogen energy conversion efficiency of 0.15% for SrTaO2N in Z-scheme water splitting. Our findings enable the synthesis of perovskite-type transition-metal oxynitride nanocrystals by thermal nitridation and pave the way for manufacturing advanced long-wavelength-responsive particulate photocatalysts for efficient solar energy conversion.
ANCA: artificial nucleic acid circuit with argonaute protein for one-step isothermal detection of antibiotic-resistant bacteria
Authors: Jang Hyowon , Song Jayeon , Kim Sunjoo , Byun Jung-Hyun , Lee Kyoung G. , Park Kwang-Hyun , Woo Euijeon , Lim Eun-Kyung , Jung Juyeon , Kang Taejoon
Published: December 2023

Endonucleases have recently widely used in molecular diagnostics. Here, we report a strategy to exploit the properties of Argonaute (Ago) proteins for molecular diagnostics by introducing an artificial nucleic acid circuit with Ago protein (ANCA) method. The ANCA is designed to perform a continuous autocatalytic reaction through cross-catalytic cleavage of the Ago protein, enabling one-step, amplification-free, and isothermal DNA detection. Using the ANCA method, carbapenemase-producing Klebsiella pneumoniae (CPKP) are successfully detected without DNA extraction and amplification steps. In addition, we demonstrate the detection of carbapenem-resistant bacteria in human urine and blood samples using the method. We also demonstrate the direct identification of CPKP swabbed from surfaces using the ANCA method in conjunction with a three-dimensional nanopillar structure. Finally, the ANCA method is applied to detect CPKP in rectal swab specimens from infected patients, achieving sensitivity and specificity of 100% and 100%, respectively. The developed method can contribute to simple, rapid and accurate diagnosis of CPKP, which can help prevent nosocomial infections.
SAM, SAH and C. elegans longevity: insights from a partial AHCY deficiency model
Authors: Thapa Pankaj , Olek Katarzyna , Kowalska Agata , Serwa Remigiusz A. , Pokrzywa Wojciech
Published: December 2023

Supplementation with S-adenosylhomocysteine (SAH) extends the lifespan of model organisms. To explore the impact of SAH on aging, we generated a Caenorhabditis elegans model by introducing the S-adenosylhomocysteine hydrolase (AHCY-1) variant Y145C, corresponding to the human AHCY Y143C pathogenic mutation. This mutation is anticipated to impair SAH hydrolysis, resulting in its increased levels. Our findings revealed that animals with this endogenous mutation exhibited delayed aging, accompanied by decreased S-adenosylmethionine (SAM) and moderately increased SAH levels. The extended lifespan of these worms depends on the AMP-activated protein kinase (AMPK), its activator Vaccinia virus–related kinase (VRK-1), and the DAF-16 transcription factor. The results underline the complex nature of SAH’s influence on aging, proposing that the balance between SAM and SAH might play a pivotal role in defining the lifespan of C. elegans. Moreover, our partial AHCY-1 deficiency model offers a tool for studying the intersection of methionine metabolism and aging.
Trompe L’oeil Ferromagnetism—magnetic point group analysis
Authors: Cheong Sang-Wook , Huang Fei-Ting
Published: December 2023

Ferromagnetism can be characterized by various distinct phenomena such as non-zero magnetization (inducing magnetic attraction/repulsion), diagonal piezomagnetism, nonreciprocal circular dichroism (such as Faraday effect), odd-order (including linear) anomalous Hall effect, and magneto-optical Kerr effect. We identify all broken symmetries requiring each of the above phenomena, and also the relevant magnetic point groups (MPGs) with those broken symmetries. All ferromagnetic point groups, relevant for ferromagnets, ferrimagnets, and weak ferromagnets, can certainly exhibit all these phenomena, including non-zero magnetization. Some of the true antiferromagnets, which are defined as magnets with MPGs that do not belong to ferromagnetic point groups, can display these phenomena through magnetization induced by external perturbations such as applied current, light illumination, and uniaxial stress, which preserve the combined symmetry of spatial inversion together with time reversal. Such MPGs are identified for each external perturbation. Since high-density and ultrafast spintronic technologies can be enabled by antiferromagnets, our findings will be essential guidance for future magnetism-related science as well as technology.
Revealing emergent magnetic charge in an antiferromagnet with diamond quantum magnetometry
Authors: Tan Anthony K. C. , Jani Hariom , Högen Michael , Stefan Lucio , Castelnovo Claudio , Braund Daniel , Geim Alexandra , Mechnich Annika , Feuer Matthew S. G. , Knowles Helena S. , Ariando Ariando , Radaelli Paolo G. , Atatüre Mete
Published: December 2023

Whirling topological textures play a key role in exotic phases of magnetic materials and are promising for logic and memory applications. In antiferromagnets, these textures exhibit enhanced stability and faster dynamics with respect to their ferromagnetic counterparts, but they are also difficult to study due to their vanishing net magnetic moment. One technique that meets the demand of highly sensitive vectorial magnetic field sensing with negligible backaction is diamond quantum magnetometry. Here we show that an archetypal antiferromagnet—haematite—hosts a rich tapestry of monopolar, dipolar and quadrupolar emergent magnetic charge distributions. The direct read-out of the previously inaccessible vorticity of an antiferromagnetic spin texture provides the crucial connection to its magnetic charge through a duality relation. Our work defines a paradigmatic class of magnetic systems to explore two-dimensional monopolar physics, and highlights the transformative role that diamond quantum magnetometry could play in exploring emergent phenomena in quantum materials.
Reverse metabolomics for the discovery of chemical structures from humans
Authors: Gentry Emily C. , Collins Stephanie L. , Panitchpakdi Morgan , Belda-Ferre Pedro , Stewart Allison K. , Carrillo Terrazas Marvic , Lu Hsueh-han , Zuffa Simone , Yan Tingting , Avila-Pacheco Julian , Plichta Damian R. , Aron Allegra T. , Wang Mingxun , Jarmusch Alan K. , Hao Fuhua , Syrkin-Nikolau Mashette , Vlamakis Hera , Ananthakrishnan Ashwin N. , Boland Brigid S. , Hemperly Amy , Vande Casteele Niels , Gonzalez Frank J. , Clish Clary B. , Xavier Ramnik J. , Chu Hiutung , Baker Erin S. , Patterson Andrew D. , Knight Rob , Siegel Dionicio , Dorrestein Pieter C.
Published: December 2023

Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn’s disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4+ T cells3 and agonism of the pregnane X receptor4. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.
Balance between solitude and socializing: everyday solitude time both benefits and harms well-being
Authors: Weinstein Netta , Vuorre Matti , Adams Mark , Nguyen Thuy-vy
Published: December 2023

Two literatures argue that time alone is harmful (i.e., isolation) and valuable (i.e., positive solitude). We explored whether people benefit from a balance between their daily solitude and social time, such that having ‘right’ quantities of both maximizes well-being. Participants (n = 178) completed a 21-day diary study, which quantified solitude time in hours through reconstructing daily events. This procedure minimized retrospective bias and tested natural variations across time. There was no evidence for a one-size-fits-all ‘optimal balance’ between solitude and social time. Linear effects suggested that people were lonelier and less satisfied on days in which they spent more hours in solitude. These detrimental relations were nullified or reduced when daily solitude was autonomous (choiceful) and did not accumulate across days; those who were generally alone more were not, on the whole, lonelier. On days in which people spent more time alone they felt less stress and greater autonomy satisfaction (volitional, authentic, and free from pressure). These benefits were cumulative; those who spent more time alone across the span of the study were less stressed and more autonomy satisfied overall. Solitude time risks lowering well-being on some metrics but may hold key advantages to other aspects of well-being.

Protocol registration

The stage 1 protocol for this Registered Report was accepted in principle on June 1, 2022. The protocol, as accepted by the journal, can be found at: https://doi.org/10.17605/OSF.IO/5KXQ3.
Maternal suboptimal selenium intake and low-level lead exposure affect offspring’s microglial immune profile and its reactivity to a subsequent inflammatory hit
Authors: De Simone R. , Ajmone-Cat M. A. , Tartaglione A. M. , Calamandrei G. , Minghetti L.
Published: December 2023

Micronutrients such as selenium (Se) are essentials since prenatal life to support brain and cognitive development. Se deficiency, which affects up to 1 billion people worldwide, can interact with common adverse environmental challenges including (Pb), exacerbating their toxic effects. Exploiting our recently validated rat model of maternal Se restriction and developmental low Pb exposure, our aims were to investigate: (i) the early consequences of suboptimal Se intake and low-Pb exposure on neuroinflammation in neonates’ whole brains; (ii) the potential priming effect of suboptimal Se and low-Pb exposure on offspring’s glial reactivity to a further inflammatory hit. To these aims female rats were fed with suboptimal (0.04 mg/kg; Subopt) and optimal (0.15 mg/kg; Opt) Se dietary levels throughout pregnancy and lactation and exposed or not to environmentally relevant Pb dose in drinking water (12.5 µg/mL) since 4 weeks pre-mating. We found an overall higher basal expression of inflammatory markers in neonatal brains, as well as in purified microglia and organotypic hippocampal slice cultures, from the Subopt Se offspring. Subopt/Pb cultures were highly activated than Subopt cultures and showed a higher susceptibility to the inflammatory challenge lipopolysaccharide than cultures from the Opt groups. We demonstrate that even a mild Se deficiency and low-Pb exposure during brain development can influence the neuroinflammatory tone of microglia, exacerbate the toxic effects of Pb and prime microglial reactivity to subsequent inflammatory stimuli. These neuroinflammatory changes may be responsible, at least in part, for adverse neurodevelopmental outcomes.
Differential roles of eNOS in late effects of VEGF-A on hyperpermeability in different types of endothelial cells
Authors: Bosma Esmeralda K. , Darwesh Shahan , Habani Yasmin I. , Cammeraat Maxime , Serrano Martinez Paola , van Breest Smallenburg Mathilda E. , Zheng Jia Y. , Vogels Ilse M. C. , van Noorden Cornelis J. F. , Schlingemann Reinier O. , Klaassen Ingeborg
Published: December 2023

Vascular endothelial growth factor (VEGF)-A induces endothelial hyperpermeability, but the molecular pathways remain incompletely understood. Endothelial nitric oxide synthase (eNOS) regulates acute effects of VEGF-A on permeability of endothelial cells (ECs), but it remains unknown whether and how eNOS regulates late effects of VEGF-A-induced hyperpermeability. Here we show that VEGF-A induces hyperpermeability via eNOS-dependent and eNOS-independent mechanisms at 2 days after VEGF-A stimulation. Silencing of expression of the eNOS gene (NOS3) reduced VEGF-A-induced permeability for dextran (70 kDa) and 766 Da-tracer in human dermal microvascular ECs (HDMVECs), but not in human retinal microvascular ECs (HRECs) and human umbilical vein ECs (HUVECs). However, silencing of NOS3 expression in HRECs increased permeability to dextran, BSA and 766 Da-tracer in the absence of VEGF-A stimulation, suggesting a barrier-protective function of eNOS. We also investigated how silencing of NOS3 expression regulates the expression of permeability-related transcripts, and found that NOS3 silencing downregulates the expression of PLVAP, a molecule associated with trans-endothelial transport via caveolae, in HDMVECs and HUVECs, but not in HRECs. Our findings underscore the complexity of VEGF-A-induced permeability pathways in ECs and the role of eNOS therein, and demonstrate that different pathways are activated depending on the EC phenotype.
Metformin ameliorates valve interstitial cell calcification by promoting autophagic flux
Authors: Phadwal K. , Tan X. , Koo E. , Zhu D. , MacRae V. E.
Published: December 2023

Calcific aortic valve disease (CAVD) is the most common heart disease of the developed world. It has previously been established that metformin administration reduces arterial calcification via autophagy; however, whether metformin directly regulates CAVD has yet to be elucidated. In the present study we investigated whether metformin alleviates valvular calcification through the autophagy-mediated recycling of Runx2. Calcification was reduced in rat valve interstitial cells (RVICs) by metformin treatment (0.5–1.5 mM) (P < 0.01), with a marked decrease in Runx2 protein expression compared to control cells (P < 0.05). Additionally, upregulated expression of Atg3 and Atg7 (key proteins required for autophagosome formation), was observed following metformin treatment (1 mM). Blocking autophagic flux using Bafilomycin-A1 revealed colocalisation of Runx2 with LC3 puncta in metformin treated RVICs (P < 0.001). Comparable Runx2 accumulation was seen in LC3 positive autolysosomes present within cells that had been treated with both metformin and hydroxychloroquine in combination (P < 0.001). Mechanistic studies employing three-way co-immunoprecipitation with Runx2, p62 and LC3 suggested that Runx2 binds to LC3-II upon metformin treatment in VICs. Together these studies suggest that the utilisation of metformin may represent a novel strategy for the treatment of CAVD.
Dynamical analysis for the motion of a 2DOF spring pendulum on a Lissajous curve
Authors: Amer Asmaa , Amer T. S. , El-Kafly H. F.
Published: December 2023

This study examines the motion of a spring pendulum with two degrees-of-freedom (DOF) in a plane as a vibrating system, in which its pivot point is constrained to move along a Lissajous curve. In light of the system’s coordinates, the governing equations of motion (EOM) are obtained utilizing the equations of Lagrange’s. The novelty of this work is to use the approach of multiple scales (AMS), as a traditional method, to obtain novel approximate solutions (AS) of the EOM with a higher degree of approximation. These solutions have been compared with the numerical ones that have been obtained using the fourth-order Runge–Kutta algorithm (4RKA) to reveal the accuracy of the analytic solutions. According to the requirements of solvability, the emergent resonance cases are grouped and the modulation equations (ME) are established. Therefore, the solutions at the steady-state case are confirmed. The stability/instability regions are inspected using Routh–Hurwitz criteria (RHC), and examined in accordance with the steady-state solutions. The achieved outcomes, resonance responses, and stability areas are demonstrated and graphically displayed, to evaluate the positive effects of different values of the physical parameters on the behavior of the examined system. Investigating zones of stability/instability reveals that the system’s behavior is stable for a significant portion of its parameters. A better knowledge of the vibrational movements that are closely related to resonance is crucial in many engineering applications because it enables the avoidance of on-going exposure to potentially harmful occurrences.