bluuebunny/crossref_metadata_2025 huggingface dataset:
Current updates on arrhythmia within Timothy syndrome: genetics, mechanisms and therapeutics
Authors: Jiang Congshan , Zhang Yanmin
Published: May 2023

Timothy syndrome (TS), characterised by multiple system malfunction especially the prolonged corrected QT interval and synchronised appearance of hand/foot syndactyly, is an extremely rare disease affecting early life with devastating arrhythmia. In this work, firstly, the various mutations in causative geneCACNA1Cencoding cardiac L-type voltage-gated calcium channel (LTCC), regard with the genetic pathogeny and nomenclature of TS are reviewed. Secondly, the expression profile and function ofCACNA1Cgene encoding Cav1.2 proteins, and its gain-of-function mutation in TS leading to multiple organ disease phenotypes especially arrhythmia are discussed. More importantly, we focus on the altered molecular mechanism underlying arrhythmia in TS, and discuss about how LTCC malfunction in TS can cause disorganised calcium handling with excessive intracellular calcium and its triggered dysregulated excitation–transcription coupling. In addition, current therapeutics for TS cardiac phenotypes including LTCC blockers, beta-adrenergic blocking agents, sodium channel blocker, multichannel inhibitors and pacemakers are summarised. Eventually, the research strategy using patient-specific induced pluripotent stem cells is recommended as one of the promising future directions for developing therapeutic approaches. This review updates our understanding on the research progress and future avenues to study the genetics and molecular mechanism underlying the pathogenesis of devastating arrhythmia within TS, and provides novel insights for developing therapeutic measures.
Exploring the Throughput Legitimacy of European Union Policy Evaluation: Challenges to Transparency and Inclusiveness in the European Commission’s Consultation Procedures and the Implications for Risk Regulation
Authors: Stephenson Paul
Published: May 2023

In its evaluation cycle, the European Commission emphasises the importance of good data and the systematic involvement of a plurality of policy stakeholders, including citizens. Findings from European Union policy evaluation should inform further law-making, encourage learning and provide accountability. Transparent and inclusive formal procedures and tools are seen as essential for securing citizen participation in risk regulation; however, the Commission faces numerous challenges in securing engagement, particularly concerning the complexity of policy issues and the formal procedures for institutionalised consultations. Considering the Commission’s work from a proceduralist perspective, the article engages with Vivien Schmidt’s notion of “throughput legitimacy” to explore recent procedural innovations emerging since the Better Regulation agenda that have sought to enhance accountability, transparency, inclusiveness and openness, ensuring fairer and more balanced input on EU policy performance. The article argues in favour of greater throughput legitimacy in ex post policy evaluation but recognises challenges to the promotion of evaluation tools and their use by citizens.
Proper extensions of the 2-sphere’s conformal group present entropy and are 4-transitive
Authors: LAKATOS ULISSES , TAL FÁBIO
Published: May 2023

In this paper, we prove using elementary techniques that any group of diffeomorphisms acting on the 2-sphere and properly extending the conformal group of Möbius transformations must be at least 4-transitive or, more precisely, arc 4-transitive. As an important consequence, we derive that any such group must always contain an element of positive topological entropy. We also provide a self-contained characterization, in terms of transitivity, of the Möbius transformations within the full group of sphere diffeomorphisms.
Īhām, or the Technique of Double Meaning in Literature: Its Theory and Practice in the Twelfth Century
Authors: Khanjari Shahrouz
Published: May 2023

This article examines the chapter on īhām (literary amphiboly) in Ḥadāʾiq al-Siḥr by Rashīd Vaṭvāṭ (d. 1182). Ḥadāʾiq, a treatise on stylistics with Persian and Arabic examples, is the oldest extant document to define īhām. Vaṭvāṭ's definition of īhām sheds light on the mechanism and function of this literary technique. This article argues that īhām, according to Vaṭvāṭ, operates through the creation of semantic fields and defamiliarization. Previous scholars who examined this chapter of Ḥadāʾiq, oblivious to this point, have made a number of misinterpretations. However, by analyzing the name he prefers for this figure of speech, the definition he gives, and the examples he cites to explain it, this article demonstrates that Vaṭvāṭ had this function of defamiliarization in mind.
Poiseuille and thermal transpiration flows of a dense gas between two parallel plates
Authors: Hattori Masanari
Published: May 2023

The Poiseuille and thermal transpiration flows of a dense gas between two parallel plates are investigated on the basis of the Enskog kinetic equation under the diffuse reflection boundary condition. In contrast to the case of an ideal gas, the density and the gradients of pressure and the normal stress component in the flow direction are not uniform in the direction normal to the plates for a dense gas. The non-uniform normal stress gradient contributes also to the acceleration or deceleration of the thermal transpiration flow for small Knudsen numbers. The profiles of mass and heat flows as well as the net mass flows are obtained for various Knudsen numbers and ratios of the molecular diameter to the distance of plates. In the analysis of the Poiseuille flow, most characteristics of a force-driven flow with a small force are recovered. However, for the case of a dense gas, differences between the force-driven and the present pressure-driven flows are observed even within the linearized regime for small force and pressure gradient, especially at the microscopic level. The behaviour of the velocity distribution functions, in particular, the way in which they approach the ones for the Boltzmann equation as the molecular diameter becomes smaller, is clarified.
Intestinal absorption of D-fructose isomers, D-allulose, D-sorbose and D-tagatose, via glucose transporter type 5 (GLUT5) but not sodium-dependent glucose cotransporter 1 (SGLT1) in rats
Authors: Kishida Kunihiro , Iida Tetsuo , Yamada Takako , Toyoda Yukiyasu
Published: May 2023

D-allulose, D-sorbose and D-tagatose are D-fructose isomers that are called rare sugars. These rare sugars have been studied intensively in terms of biological production and food application as well as physiological effects. There are limited papers with regard to the transporters mediating the intestinal absorption of these rare sugars. We examined whether these rare sugars are absorbed via sodium-dependent glucose cotransporter 1 (SGLT1) as well as via GLUT type 5 (GLUT5) using rats. High-fructose diet fed rats, which express more intestinal GLUT5, exhibited significantly higher peripheral concentrations, Cmax and AUC0–180 min when D-allulose, D-sorbose and D-tagatose were orally administrated. KGA-2727, a selective SGLT1 inhibitor, did not affect the peripheral and portal vein concentrations and pharmacokinetic parameters of these rare sugars. The results suggest that D-allulose, D-sorbose and D-tagatose are likely transported via GLUT5 but not SGLT1 in rat small intestine.
NEW ROBUST INFERENCE FOR PREDICTIVE REGRESSIONS
Authors: Ibragimov Rustam , Kim Jihyun , Skrobotov Anton
Published: May 2023

We propose a robust inference method for predictive regression models under heterogeneously persistent volatility as well as endogeneity, persistence, or heavy-tailedness of regressors. This approach relies on two methodologies, nonlinear instrumental variable estimation and volatility correction, which are used to deal with the aforementioned characteristics of regressors and volatility, respectively. Our method is simple to implement and is applicable both in the case of continuous and discrete time models. According to our simulation study, the proposed method performs well compared with widely used alternative inference procedures in terms of its finite sample properties in various dependence and persistence settings observed in real-world financial and economic markets.
Inequalities Among Political Scientists: Race and Gender Relations During the COVID-19 Pandemic
Authors: Candido Marcia Rangel , Catelano Otávio Zilioli , Chaguri Mariana Miggiolaro , Marques Danusa , Elias de Oliveira Vanessa , Biroli Flávia
Published: May 2023

This study examines the division of labor among political scientists during different periods of the COVID-19 pandemic. The article explores the hypothesis that the pandemic increased inequalities, especially by exacerbating the burden of housework and care responsibilities for women. We ground our analysis on the results of two surveys conducted in Brazil: one shortly after the onset of the pandemic in June 2020; and the other, more recently, from March 2022, after the ending of social-distancing measures. Brazil is a relevant case study because it was an epicenter of the virus for many months. This public health crisis occurred while a denialist and authoritarian government was in power. Considering gender and race variables, the data show a transformation of the dynamics of time organization during the period. At the beginning of the pandemic, men—primarily white men—devoted more time to academic work; in 2022, the most substantive difference was one of race. We observed a greater convergence among white people, as opposed to Black people, about household chores, with the latter group more overloaded than the former group. Traditional class and race inequalities concerning the Brazilian population can contribute to the explanation for this. When in-person work returned, white political scientists began to outsource domestic care more than their nonwhite counterparts.
The prevalence of mental disorders among incarcerated adult men convicted of child sexual exploitation material offences
Authors: Seiser Alexander , Eher Reinhard , Turner Daniel , Rettenberger Martin
Published: May 2023

Objective

Despite the growing body of research on individuals convicted of child sexual exploitation material (CSEM), relatively little is known about the prevalence of mental disorders in this population. The aim of the present study was to describe the prevalence of mental disorders among individuals convicted of CSEM offenses.

Methods

This cross-sectional study examined data from 66 individuals serving a sentence for CSEM offenses in the Austrian prison system who underwent a clinical assessment between 2002 and 2020. Diagnoses were based on the German version of the Structured Clinical Interview for Axis I and Axis II disorders.

Results

In the total sample, n = 53 individuals (80.3%) were diagnosed with a mental disorder. Twenty-seven individuals (40.9%) had an Axis I disorder and n = 47 (71.2%) had an Axis II disorder. More than two-thirds of the sample, n = 47 (71.2%), had a personality disorder diagnosis, with cluster B personality disorders being the most frequent mental disorders. More than half of the sample, n = 43 (65.2%), had a diagnosis of pedophilic disorder, of which n = 9 (13.6%) were of the exclusive type. Twenty-eight persons (42.4%) showed evidence of a hypersexual disorder.

Conclusions

In line with previous research, the present sample of convicted CSEM offenders showed a comparatively high prevalence of personality disorders and paraphilic disorders, particularly pedophilic disorders. Additionally, the rate of hypersexual disorder symptoms was considerably high. These findings should be considered for the development of successful risk management strategies for this population.
Weak regulations threaten the safety of consumers from harmful weight-loss supplements globally: results from a pilot global policy scan
Authors: Okoya Funmbi T , Santoso Monique , Raffoul Amanda , Atallah Maya Azar , Bryn Austin S
Published: May 2023

Objective:

To pilot a global policy scan assessing how governments worldwide regulate weight-loss supplements (WLS).

Design:

Experts on WLS policies from thirty countries that varied by World Bank income classification, with five from each of the six WHO regions, completed an online survey on WLS regulation in their country. The survey covered six domains: legal frameworks; pre-market requirements; claims, labelling, and advertisements; product availability; adverse events reporting; and monitoring and enforcement. Percentages were calculated for presence or absence of a type of regulation.

Setting:

Experts were recruited through websites of regulatory bodies and professional LinkedIn networks and scientific article searches on Google Scholar.

Participants:

Thirty experts, one from each country (i.e. researchers, regulators, other experts in food and drug regulation).

Results:

WLS regulations varied widely across countries, and a number of gaps were identified. One country (Nigeria) has a minimum legal age to purchase WLS. Thirteen countries reported independently evaluating the safety of a new WLS product sample. Two countries have limitations on where WLS can be sold. In eleven countries, reports on adverse events related to WLS are publicly available. In eighteen countries, safety of new WLS is to be established through scientific criteria. Penalties for WLS non-compliance with pre-market regulations exist in twelve countries and labelling requirements in sixteen countries.

Conclusions:

Results of this pilot study document wide variability in national WLS regulations globally, exposing many gaps in important components of consumer protection regulatory frameworks for WLS, which likely put consumer health at risk.
Francoism, Urban Displacement, and Nostalgia in Flamenco Dance from Seville
Authors: VAN TONGEREN CARLOS
Published: May 2023

While it is often assumed that flamenco is strongly oriented towards the past, thus far, few scholars have explored the roles of flamenco in voicing memories of the Franco dictatorship (1939–75). During the second half of the dictatorship, a series of natural disasters, combined with new economic and political developments, led to the forced displacement of a number of flamenco artists and their wider communities in various Spanish cities. This article will explore how memories of this episode have impacted the flamenco dance repertoire associated with the Triana neighbourhood in Seville, focusing on three interrelated case studies: the performance and documentary film Triana pura y pura, and recent productions by the flamenco dancers Pastora Galván and Israel Galván. By analysing these performances alongside their historical, social, and institutional contexts, this article conceptualizes the intersections between dance, nostalgia, and festivity as a meaningful scenario of embodied memory in post-Franco Spain.
Variations in Spring Atmospheric Circulation on the Southwestern Tibetan Plateau During Holocene Linked to High‐ and Low‐Latitude Forcing
Authors: Ma Qingfeng , Zhu Liping , Wang Junbo , Ju Jianting , Wang Yong
Published: May 2023

Recent climate and environment over the Tibetan Plateau (TP) have undergone significant changes, dominated by variations in the Westerlies and the Indian summer monsoon. However, long‐term shifts in atmospheric circulation during the transitional seasons are still lacking. Here we investigate the modern distribution of Tsuga pollen over the central‐western TP and confirm it as an indicator of variable atmospheric circulation in spring. By combining our Tsuga record from Taro Co with existing records in the Tsuga pollen source area, we suggest that a potential particle transport pathway from the southern slope of the Himalayas to the interior of the plateau appeared in the spring of the late Holocene. Our results show that the springtime atmospheric circulation over the southwestern TP during the early and late Holocene is closely related to the substantial remnants of ice sheets at northern high latitudes and the frequency of El Niño events, respectively.
The Io, Europa, and Ganymede Auroral Footprints at Jupiter in the Ultraviolet: Positions and Equatorial Lead Angles
Authors: Hue V. , Gladstone G. R. , Louis C. K. , Greathouse T. K. , Bonfond B. , Szalay J. R. , Moirano A. , Giles R. S. , Kammer J. A. , Imai M. , Mura A. , Versteeg M. H. , Clark G. , Gérard J.‐C. , Grodent D. C. , Rabia J. , Sulaiman A. H. , Bolton S. J. , Connerney J. E. P.
Published: May 2023

Jupiter's satellite auroral footprints are a consequence of the interaction between the Jovian magnetic field with co‐rotating iogenic plasma and the Galilean moons. The disturbances created near the moons propagate as Alfvén waves along the magnetic field lines. The position of the moons is therefore “Alfvénically” connected to their respective auroral footprint. The angular separation from the instantaneous magnetic footprint can be estimated by the so‐called lead angle. That lead angle varies periodically as a function of orbital longitude, since the time for the Alfvén waves to reach the Jovian ionosphere varies accordingly. Using spectral images of the Main Alfvén Wing auroral spots collected by Juno‐UVS during the first 43 orbits, this work provides the first empirical model of the Io, Europa, and Ganymede equatorial lead angles for the northern and southern hemispheres. Alfvén travel times between the three innermost Galilean moons to Jupiter's northern and southern hemispheres are estimated from the lead angle measurements. We also demonstrate the accuracy of the mapping from the Juno magnetic field reference model (JRM33) at the completion of the prime mission for M‐shells extending to at least 15 RJ. Finally, we shows how the added knowledge of the lead angle can improve the interpretation of the moon‐induced decametric emissions.
The Ultraviolet Martian Dayglow Observed With NOMAD/UVIS on ExoMars Trace Gas Orbiter
Authors: Soret L. , Gérard J.‐C. , Hubert B. , Vandaele A. C. , Thomas I. R. , Ristic B. , Willame Y. , Schneider N. , Jain S. , Gupta S. , Mason J. P. , Patel M. R.
Published: May 2023

The Trace Gas Orbiter has been orbiting Mars since 2016 with the Nadir and Occultation for MArs Discovery (NOMAD) UltraViolet and Visible Spectrometer (UVIS) instrument on board. Focusing on limb observations recorded in the ultraviolet (UV) part of the NOMAD/UVIS spectra, we describe here the CO Cameron bands, UV doublet and Fox‐Duffendach‐Barker (FDB) bands and [OI] UV emissions. Averaged limb profiles are presented, showing that the strongest brightness and the highest peak altitudes are reached near perihelion. Ratios between the UV emissions are also estimated and compared with previous observations from Mariner and Mars Express. NOMAD/UVIS is the first instrument able to simultaneously acquire data both in the UV and the visible in the Mars atmosphere so that the oxygen green line at 557.7 nm and its UV counterpart at 297.2 nm, both originating from the same O(1S) upper state level, may be directly compared. A mean ratio of 15.8 is derived, in close agreement with ab initio calculations. The spectral composition of the FDB system that has not been observed entirely since the Mariner missions in the 1970s is analyzed. According to the spectral composition of the FDB bands, we show that this emission is produced at ∼70% by photoionization of CO2 (which populates the shorter wavelengths of the spectrum) and ∼30% by resonance scattering of solar radiation (which populates longer wavelengths). No evidence of a change with altitude in the FDB spectral composition is observed in the NOMAD/UVIS spectra.
Primary cells from patients with adult T cell leukemia/lymphoma depend on HTLV-1 Tax expression for NF-κB activation and survival
Authors: Hleihel Rita , Skayneh Hala , de Thé Hugues , Hermine Olivier , Bazarbachi Ali
Published: May 2023

Adult T cell leukemia/lymphoma (ATL) is an aggressive malignancy secondary to chronic infection with human T cell leukemia virus type 1 (HTLV-1). The viral oncoprotein Tax initiates T cell transformation through activation of critical cellular pathways, including NF-κB. Unexpectedly, Tax protein is not detectable in most ATL cells, in contrast to the HTLV-1 HBZ protein which antagonizes Tax effects. Here, we demonstrate that primary ATL cells from patients with acute or chronic ATL express very low levels of Tax mRNA and protein. Critically, survival of these primary ATL cells is dependent on continued Tax expression. Mechanistically, Tax extinction results in reversal of NF-κB activation, P53/PML activation and apoptosis. Tax drives interleukin-10 (IL-10) expression and recombinant IL-10 rescues the survival of tax-depleted primary ATL cells. These results demonstrate the critical role of continued Tax and IL-10 expression for the survival of primary ATL cells, highlighting their relevance as therapeutic targets.
Impact of clonal plasma cells in autografts on outcomes in high-risk multiple myeloma patients
Authors: Pasvolsky Oren , Milton Denái R. , Rauf Mikael , Ghanem Sassine , Masood Adeel , Mohamedi Ali H. , Tanner Mark R. , Bashir Qaiser , Srour Samer , Saini Neeraj , Lin Paul , Ramdial Jeremy , Nieto Yago , Tang Guilin , Lee Hans C. , Patel Krina K. , Kebriaei Partow , Thomas Sheeba K. , Weber Donna M. , Orlowski Robert Z. , Rezvani Katy , Champlin Richard , Shpall Elizabeth J. , Lin Pei , Qazilbash Muzaffar H.
Published: May 2023

Most patients with multiple myeloma (MM) undergoing autologous hematopoietic stem cell transplantation (autoHCT) eventually relapse, perhaps due to the presence of clonal plasma cells (CPC) in the autograft. We conducted a retrospective analysis to evaluate the impact of CPC in the autograft on the outcomes of high-risk chromosomal abnormalities (HRMM) patients undergoing autoHCT between 2008 and 2018. Patients were divided into CPC+ or CPC− in the autograft by next-generation flow cytometry (NGF). There were 75 CPC + autografts (18%) and 341 CPC− (82%). The CPC + group was less likely to achieve MRD-negative complete remission post-transplant (11% vs. 42%; p < 0.001). Median progression free survival (PFS) and overall survival (OS) were (12.8 vs. 32.1 months) and (36.4 vs. 81.2 months) in the CPC + and CPC− groups, respectively (both p < 0.001). Also in the subset of patients with MRD-negative ≥VGPR prior to autoHCT, those with CPC + autografts had inferior PFS (HR 4.21, p = 0.006) and OS (HR 7.04, p = 0.002) compared to CPC-. In multivariable analysis, the degree of CPC positivity in the autograft was independently predictive of worse PFS (HR 1.50, p = 0.001) and OS (HR 1.37, p = 0.001). In conclusion, both the presence and degree of CPC in the autograft were highly predictive of inferior PFS and OS.
Inequalities in cancer screening participation between adults with and without severe mental illness: results from a cross-sectional analysis of primary care data on English Screening Programmes
Authors: Kerrison Robert Stephen , Jones Alex , Peng Jianhe , Price Gabriele , Verne Julia , Barley Elizabeth Alexandra , Lugton Cam
Published: May 2023

Background

People with severe mental illness (SMI) are 2.5 times more likely to die prematurely from cancer in England. Lower participation in screening may be a contributing factor.

Methods

Clinical Practice Research Datalink data for 1.71 million, 1.34 million and 2.50 million adults were assessed (using multivariate logistic regression) for possible associations between SMI and participation in bowel, breast and cervical screening, respectively.

Results

Screening participation was lower among adults with SMI, than without, for bowel (42.11% vs. 58.89%), breast (48.33% vs. 60.44%) and cervical screening (64.15% vs. 69.72%; all p < 0.001). Participation was lowest in those with schizophrenia (bowel, breast, cervical: 33.50%, 42.02%, 54.88%), then other psychoses (41.97%, 45.57%, 61.98%), then bipolar disorder (49.94%, 54.35%, 69.69%; all p-values < 0.001, except cervical screening in bipolar disorder; p-value > 0.05). Participation was lowest among people with SMI who live in the most deprived quintile of areas (bowel, breast, cervical: 36.17%, 40.23%, 61.47%), or are of a Black ethnicity (34.68%, 38.68%, 64.80%). Higher levels of deprivation and diversity, associated with SMI, did not explain the lower participation in screening.

Conclusions

In England, participation in cancer screening is low among people with SMI. Support should be targeted to ethnically diverse and socioeconomically deprived areas, where SMI prevalence is greatest.
NK cell activity and methylated HOXA9 ctDNA as prognostic biomarkers in patients with non-small cell lung cancer treated with PD-1/PD-L1 inhibitors
Authors: Wen Sara Witting Christensen , Nederby Line , Andersen Rikke Fredslund , Hansen Torben Schjødt , Nyhus Christa Haugaard , Hilberg Ole , Jakobsen Anders , Hansen Torben Frøstrup
Published: May 2023

Background

PD-1/PD-L1 inhibitors have improved survival for patients with non-small cell lung cancer (NSCLC). We evaluated natural killer cell activity (NKA) and methylated HOXA9 circulating tumor DNA (ctDNA) as prognostic biomarkers in NSCLC patients treated with PD-1/PD-L1 inhibitors.

Methods

Plasma was prospectively collected from 71 NSCLC patients before treatment with PD-1/PD-L1 inhibitors and before cycles 2–4. We used the NK Vue® assay to measure the level of interferon gamma (IFNγ) as a surrogate for NKA. Methylated HOXA9 was measured by droplet digital PCR.

Results

A score combining NKA and ctDNA status measured after one treatment cycle had a strong prognostic impact. Group 1 had IFNγ < 250 pg/ml and detectable ctDNA (n = 27), group 2 consisted of patients with either low levels of IFNγ and undetectable ctDNA or high levels of IFNγ and detectable ctDNA (n = 29), group 3 had IFNγ ≥250 pg/ml and undetectable ctDNA (n = 15). Median OS was 221 days (95% CI 121–539 days), 419 days (95% CI 235–650 days), and 1158 days (95% CI 250 days—not reached), respectively (P = 0.002). Group 1 had a poor prognosis with a hazard ratio of 5.560 (95% CI 2.359–13.101, n = 71, P < 0.001) adjusting for PD-L1 status, histology, and performance status.

Conclusions

Combining NKA and ctDNA status after one cycle of treatment was prognostic in patients with NSCLC treated with PD-1/PD-L1 inhibitors.
Downregulated liver-elevated long intergenic noncoding RNA (LINC02428) is a tumor suppressor that blocks KDM5B/IGF2BP1 positive feedback loop in hepatocellular carcinoma
Authors: Du Xuanlong , Zhou Pengcheng , Zhang Haidong , Peng Hao , Mao Xinyu , Liu Shiwei , Xu Wenjing , Feng Kun , Zhang Yewei
Published: May 2023

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognoses worldwide. Many studies have reported that long noncoding RNAs (lncRNAs) are related to the progression and prognosis of HCC. However, the functions of downregulated liver-elevated (LE) lncRNAs in HCC remain elusive. Here we report the roles and mechanisms of downregulated LE LINC02428 in HCC. Downregulated LE lncRNAs played significant roles in HCC genesis and development. LINC02428 was upregulated in liver tissues compared with other normal tissues and showed low expression in HCC. The low expression of LINC02428 was attributed to poor HCC prognosis. Overexpressed LINC02428 suppressed the proliferation and metastasis of HCC in vitro and in vivo. LINC02428 was predominantly located in the cytoplasm and bound to insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) to prevent it from binding to lysine demethylase 5B (KDM5B) mRNA, which decreased the stability of KDM5B mRNA. KDM5B was found to preferentially bind to the promoter region of IGF2BP1 to upregulate its transcription. Therefore, LINC02428 interrupts the KDM5B/IGF2BP1 positive feedback loops to inhibit HCC progression. The KDM5B/IGF2BP1 positive feedback loop is involved in tumorigenesis and progression of HCC.
Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss
Authors: Rüland Laura , Andreatta Francesco , Massalini Simone , Chuva de Sousa Lopes Susana , Clevers Hans , Hendriks Delilah , Artegiani Benedetta
Published: May 2023

Fibrolamellar carcinoma (FLC) is a lethal primary liver cancer, affecting young patients in absence of chronic liver disease. Molecular understanding of FLC tumorigenesis is limited, partly due to the scarcity of experimental models. Here, we CRISPR-engineer human hepatocyte organoids to recreate different FLC backgrounds, including the predominant genetic alteration, the DNAJB1-PRKACA fusion, as well as a recently reported background of FLC-like tumors, encompassing inactivating mutations of BAP1 and PRKAR2A. Phenotypic characterizations and comparisons with primary FLC tumor samples revealed mutant organoid-tumor similarities. All FLC mutations caused hepatocyte dedifferentiation, yet only combined loss of BAP1 and PRKAR2A resulted in hepatocyte transdifferentiation into liver ductal/progenitor-like cells that could exclusively grow in a ductal cell environment. BAP1-mutant hepatocytes represent primed cells attempting to proliferate in this cAMP-stimulating environment, but require concomitant PRKAR2A loss to overcome cell cycle arrest. In all analyses, DNAJB1-PRKACAfus organoids presented with milder phenotypes, suggesting differences between FLC genetic backgrounds, or for example the need for additional mutations, interactions with niche cells, or a different cell-of-origin. These engineered human organoid models facilitate the study of FLC.
N-Formimidoylation/-iminoacetylation modification in aminoglycosides requires FAD-dependent and ligand-protein NOS bridge dual chemistry
Authors: Wang Yung-Lin , Chang Chin-Yuan , Hsu Ning-Shian , Lo I-Wen , Lin Kuan-Hung , Chen Chun-Liang , Chang Chi-Fon , Wang Zhe-Chong , Ogasawara Yasushi , Dairi Tohru , Maruyama Chitose , Hamano Yoshimitsu , Li Tsung-Lin
Published: May 2023

Oxidized cysteine residues are highly reactive and can form functional covalent conjugates, of which the allosteric redox switch formed by the lysine-cysteine NOS bridge is an example. Here, we report a noncanonical FAD-dependent enzyme Orf1 that adds a glycine-derived N-formimidoyl group to glycinothricin to form the antibiotic BD-12. X-ray crystallography was used to investigate this complex enzymatic process, which showed Orf1 has two substrate-binding sites that sit 13.5 Å apart unlike canonical FAD-dependent oxidoreductases. One site could accommodate glycine and the other glycinothricin or glycylthricin. Moreover, an intermediate-enzyme adduct with a NOS-covalent linkage was observed in the later site, where it acts as a two-scissile-bond linkage facilitating nucleophilic addition and cofactor-free decarboxylation. The chain length of nucleophilic acceptors vies with bond cleavage sites at either N–O or O–S accounting for N-formimidoylation or N-iminoacetylation. The resultant product is no longer sensitive to aminoglycoside-modifying enzymes, a strategy that antibiotic-producing species employ to counter drug resistance in competing species.
Surface plasmon-enhanced photo-driven CO2 hydrogenation by hydroxy-terminated nickel nitride nanosheets
Authors: Singh Saideep , Verma Rishi , Kaul Nidhi , Sa Jacinto , Punjal Ajinkya , Prabhu Shriganesh , Polshettiwar Vivek
Published: May 2023

The majority of visible light-active plasmonic catalysts are often limited to Au, Ag, Cu, Al, etc., which have considerations in terms of costs, accessibility, and instability. Here, we show hydroxy-terminated nickel nitride (Ni3N) nanosheets as an alternative to these metals. The Ni3N nanosheets catalyze CO2 hydrogenation with a high CO production rate (1212 mmol g−1 h−1) and selectivity (99%) using visible light. Reaction rate shows super-linear power law dependence on the light intensity, while quantum efficiencies increase with an increase in light intensity and reaction temperature. The transient absorption experiments reveal that the hydroxyl groups increase the number of hot electrons available for photocatalysis. The in situ diffuse reflectance infrared Fourier transform spectroscopy shows that the CO2 hydrogenation proceeds via the direct dissociation pathway. The excellent photocatalytic performance of these Ni3N nanosheets (without co-catalysts or sacrificial agents) is suggestive of the use of metal nitrides instead of conventional plasmonic metal nanoparticles.
Detergent modulates the conformational equilibrium of SARS-CoV-2 Spike during cryo-EM structural determination
Authors: Egri Shawn B. , Wang Xue , Díaz-Salinas Marco A. , Luban Jeremy , Dudkina Natalya V. , Munro James B. , Shen Kuang
Published: May 2023

The Spike glycoprotein of SARS-CoV-2 mediates viral entry into the host cell via the interaction between its receptor binding domain (RBD) and human angiotensin-converting enzyme 2 (ACE2). Spike RBD has been reported to adopt two primary conformations, a closed conformation in which the binding site is shielded and unable to interact with ACE2, and an open conformation that is capable of binding ACE2. Many structural studies have probed the conformational space of the homotrimeric Spike from SARS-CoV-2. However, how sample buffer conditions used during structural determination influence the Spike conformation is currently unclear. Here, we systematically explored the impact of commonly used detergents on the conformational space of Spike. We show that in the presence of detergent, the Spike glycoprotein predominantly occupies a closed conformational state during cryo-EM structural determination. However, in the absence of detergent, such conformational compaction was neither observed by cryo-EM, nor by single-molecule FRET designed to visualize the movement of RBD in solution in real-time. Our results highlight the highly sensitive nature of the Spike conformational space to buffer composition during cryo-EM structural determination, and emphasize the importance of orthogonal biophysical approaches to validate the structural models obtained.
Antibodies to variable surface antigens induce antigenic variation in the intestinal parasite Giardia lamblia
Authors: Tenaglia Albano H. , Luján Lucas A. , Ríos Diego N. , Molina Cecilia R. , Midlej Victor , Iribarren Paula A. , Berazategui María A. , Torri Alessandro , Saura Alicia , Peralta Damián O. , Rodríguez-Walker Macarena , Fernández Elmer A. , Petiti Juan P. , Serradell Marianela C. , Gargantini Pablo R. , Sparwasser Tim , Alvarez Vanina E. , de Souza Wanderley , Luján Hugo D.
Published: May 2023

The genomes of most protozoa encode families of variant surface antigens. In some parasitic microorganisms, it has been demonstrated that mutually exclusive changes in the expression of these antigens allow parasites to evade the host’s immune response. It is widely assumed that antigenic variation in protozoan parasites is accomplished by the spontaneous appearance within the population of cells expressing antigenic variants that escape antibody-mediated cytotoxicity. Here we show, both in vitro and in animal infections, that antibodies to Variant-specific Surface Proteins (VSPs) of the intestinal parasite Giardia lamblia are not cytotoxic, inducing instead VSP clustering into liquid-ordered phase membrane microdomains that trigger a massive release of microvesicles carrying the original VSP and switch in expression to different VSPs by a calcium-dependent mechanism. This novel mechanism of surface antigen clearance throughout its release into microvesicles coupled to the stochastic induction of new phenotypic variants not only changes current paradigms of antigenic switching but also provides a new framework for understanding the course of protozoan infections as a host/parasite adaptive process.
Investigating the rationale for COPD maintenance therapy prescription across Europe, findings from a multi-country study
Authors: Kocks Janwillem , Ferreira António Jorge , Bakke Per , van Schayck Onno C. P. , Ekroos Heikki , Tzanakis Nikolaos , Soulard Stéphane , Haaksma-Herczegh Monika , Mestres-Simon Montserrat , Águila-Fuentes Malena , Cataldo Didier
Published: May 2023

This study aims to understand healthcare professionals’ thoughts and motivations about optimal management and treatment of patients with chronic obstructive pulmonary disease (COPD). We conducted a DELPHI survey through an online questionnaire distributed to 220 panellists from six European countries and a discrete choice experiment to describe the relationship between selected clinical criteria and the initial COPD treatment of choice. One hundred twenty-seven panellists (general practitioners [GPs] and pulmonologists) completed the survey. Despite the familiarity and use (89.8%) of the GOLD classification for initial treatment selection, a frequent use of LAMA/LABA/ICS was noted. In fact, panellists agreed that inhaled corticosteroids (ICS) are over-prescribed in the primary care setting. Our study showed that GPs felt less confident than pulmonologists with ICS withdrawal. This mismatch observed between best practice and behaviour indicates the need to increase awareness and efforts to improve the adherence to guidelines in clinical practice.
Photo-induced high-temperature ferromagnetism in YTiO3
Authors: Disa A. S. , Curtis J. , Fechner M. , Liu A. , von Hoegen A. , Först M. , Nova T. F. , Narang P. , Maljuk A. , Boris A. V. , Keimer B. , Cavalleri A.
Published: May 2023

In quantum materials, degeneracies and frustrated interactions can have a profound impact on the emergence of long-range order, often driving strong fluctuations that suppress functionally relevant electronic or magnetic phases1–7. Engineering the atomic structure in the bulk or at heterointerfaces has been an important research strategy to lift these degeneracies, but these equilibrium methods are limited by thermodynamic, elastic and chemical constraints8. Here we show that all-optical, mode-selective manipulation of the crystal lattice can be used to enhance and stabilize high-temperature ferromagnetism in YTiO3, a material that shows only partial orbital polarization, an unsaturated low-temperature magnetic moment and a suppressed Curie temperature, Tc = 27 K (refs. 9–13). The enhancement is largest when exciting a 9 THz oxygen rotation mode, for which complete magnetic saturation is achieved at low temperatures and transient ferromagnetism is realized up to Tneq > 80 K, nearly three times the thermodynamic transition temperature. We interpret these effects as a consequence of the light-induced dynamical changes to the quasi-degenerate Ti t2g orbitals, which affect the magnetic phase competition and fluctuations found in the equilibrium state14–20. Notably, the light-induced high-temperature ferromagnetism discovered in our work is metastable over many nanoseconds, underscoring the ability to dynamically engineer practically useful non-equilibrium functionalities.
Electrically driven amplified spontaneous emission from colloidal quantum dots
Authors: Ahn Namyoung , Livache Clément , Pinchetti Valerio , Jung Heeyoung , Jin Ho , Hahm Donghyo , Park Young-Shin , Klimov Victor I.
Published: May 2023

Colloidal quantum dots (QDs) are attractive materials for realizing solution-processable laser diodes that could benefit from size-controlled emission wavelengths, low optical-gain thresholds and ease of integration with photonic and electronic circuits1–7. However, the implementation of such devices has been hampered by fast Auger recombination of gain-active multicarrier states1,8, poor stability of QD films at high current densities9,10 and the difficulty to obtain net optical gain in a complex device stack wherein a thin electroluminescent QD layer is combined with optically lossy charge-conducting layers11–13. Here we resolve these challenges and achieve amplified spontaneous emission (ASE) from electrically pumped colloidal QDs. The developed devices use compact, continuously graded QDs with suppressed Auger recombination incorporated into a pulsed, high-current-density charge-injection structure supplemented by a low-loss photonic waveguide. These colloidal QD ASE diodes exhibit strong, broadband optical gain and demonstrate bright edge emission with instantaneous power of up to 170 μW.
The electron–proton bottleneck of photosynthetic oxygen evolution
Authors: Greife Paul , Schönborn Matthias , Capone Matteo , Assunção Ricardo , Narzi Daniele , Guidoni Leonardo , Dau Holger
Published: May 2023

Photosynthesis fuels life on Earth by storing solar energy in chemical form. Today’s oxygen-rich atmosphere has resulted from the splitting of water at the protein-bound manganese cluster of photosystem II during photosynthesis. Formation of molecular oxygen starts from a state with four accumulated electron holes, the S4 state—which was postulated half a century ago1 and remains largely uncharacterized. Here we resolve this key stage of photosynthetic O2 formation and its crucial mechanistic role. We tracked 230,000 excitation cycles of dark-adapted photosystems with microsecond infrared spectroscopy. Combining these results with computational chemistry reveals that a crucial proton vacancy is initally created through gated sidechain deprotonation. Subsequently, a reactive oxygen radical is formed in a single-electron, multi-proton transfer event. This is the slowest step in photosynthetic O2 formation, with a moderate energetic barrier and marked entropic slowdown. We identify the S4 state as the oxygen-radical state; its formation is followed by fast O–O bonding and O2 release. In conjunction with previous breakthroughs in experimental and computational investigations, a compelling atomistic picture of photosynthetic O2 formation emerges. Our results provide insights into a biological process that is likely to have occurred unchanged for the past three billion years, which we expect to support the knowledge-based design of artificial water-splitting systems.
Structural atlas of a human gut crassvirus
Authors: Bayfield Oliver W. , Shkoporov Andrey N. , Yutin Natalya , Khokhlova Ekaterina V. , Smith Jake L. R. , Hawkins Dorothy E. D. P. , Koonin Eugene V. , Hill Colin , Antson Alfred A.
Published: May 2023

CrAssphage and related viruses of the order Crassvirales (hereafter referred to as crassviruses) were originally discovered by cross-assembly of metagenomic sequences. They are the most abundant viruses in the human gut, are found in the majority of individual gut viromes, and account for up to 95% of the viral sequences in some individuals1–4. Crassviruses are likely to have major roles in shaping the composition and functionality of the human microbiome, but the structures and roles of most of the virally encoded proteins are unknown, with only generic predictions resulting from bioinformatic analyses4,5. Here we present a cryo-electron microscopy reconstruction of Bacteroides intestinalis virus ΦcrAss0016, providing the structural basis for the functional assignment of most of its virion proteins. The muzzle protein forms an assembly about 1 MDa in size at the end of the tail and exhibits a previously unknown fold that we designate the ‘crass fold’, that is likely to serve as a gatekeeper that controls the ejection of cargos. In addition to packing the approximately 103 kb of virus DNA, the ΦcrAss001 virion has extensive storage space for virally encoded cargo proteins in the capsid and, unusually, within the tail. One of the cargo proteins is present in both the capsid and the tail, suggesting a general mechanism for protein ejection, which involves partial unfolding of proteins during their extrusion through the tail. These findings provide a structural basis for understanding the mechanisms of assembly and infection of these highly abundant crassviruses.
Learnable latent embeddings for joint behavioural and neural analysis
Authors: Schneider Steffen , Lee Jin Hwa , Mathis Mackenzie Weygandt
Published: May 2023

Mapping behavioural actions to neural activity is a fundamental goal of neuroscience. As our ability to record large neural and behavioural data increases, there is growing interest in modelling neural dynamics during adaptive behaviours to probe neural representations1–3. In particular, although neural latent embeddings can reveal underlying correlates of behaviour, we lack nonlinear techniques that can explicitly and flexibly leverage joint behaviour and neural data to uncover neural dynamics3–5. Here, we fill this gap with a new encoding method, CEBRA, that jointly uses behavioural and neural data in a (supervised) hypothesis- or (self-supervised) discovery-driven manner to produce both consistent and high-performance latent spaces. We show that consistency can be used as a metric for uncovering meaningful differences, and the inferred latents can be used for decoding. We validate its accuracy and demonstrate our tool’s utility for both calcium and electrophysiology datasets, across sensory and motor tasks and in simple or complex behaviours across species. It allows leverage of single- and multi-session datasets for hypothesis testing or can be used label free. Lastly, we show that CEBRA can be used for the mapping of space, uncovering complex kinematic features, for the production of consistent latent spaces across two-photon and Neuropixels data, and can provide rapid, high-accuracy decoding of natural videos from visual cortex.
Ancient human DNA recovered from a Palaeolithic pendant
Authors: Essel Elena , Zavala Elena I. , Schulz-Kornas Ellen , Kozlikin Maxim B. , Fewlass Helen , Vernot Benjamin , Shunkov Michael V. , Derevianko Anatoly P. , Douka Katerina , Barnes Ian , Soulier Marie-Cécile , Schmidt Anna , Szymanski Merlin , Tsanova Tsenka , Sirakov Nikolay , Endarova Elena , McPherron Shannon P. , Hublin Jean-Jacques , Kelso Janet , Pääbo Svante , Hajdinjak Mateja , Soressi Marie , Meyer Matthias
Published: May 2023

Artefacts made from stones, bones and teeth are fundamental to our understanding of human subsistence strategies, behaviour and culture in the Pleistocene. Although these resources are plentiful, it is impossible to associate artefacts to specific human individuals1 who can be morphologically or genetically characterized, unless they are found within burials, which are rare in this time period. Thus, our ability to discern the societal roles of Pleistocene individuals based on their biological sex or genetic ancestry is limited2–5. Here we report the development of a non-destructive method for the gradual release of DNA trapped in ancient bone and tooth artefacts. Application of the method to an Upper Palaeolithic deer tooth pendant from Denisova Cave, Russia, resulted in the recovery of ancient human and deer mitochondrial genomes, which allowed us to estimate the age of the pendant at approximately 19,000–25,000 years. Nuclear DNA analysis identifies the presumed maker or wearer of the pendant as a female individual with strong genetic affinities to a group of Ancient North Eurasian individuals who lived around the same time but were previously found only further east in Siberia. Our work redefines how cultural and genetic records can be linked in prehistoric archaeology.