bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring of Thick Vadose Zone Water Dynamics Under Irrigation Using a 48 m Deep Caisson at the Luancheng Critical Zone Observatory
Authors: Wu Lin , Min Leilei , Liu Meiying , Zhang Yucui , Pei Hongwei , Li Hongjun , Zhang Guanglu , Wang Shiqin , Shen Yanjun
Published: May 2023

Understanding soil water dynamics in the deep vadose zone (DVZ, below the root zone) of irrigated farmland is critical for estimating groundwater recharge and assessing the impacts of agricultural activities on groundwater quality. However, the state and movement of soil water in the DVZ remain poorly understood owing to the lack of in‐situ observations. Here, based on a 48‐m deep caisson (Critical Zone Observatory, CZO) established in a typical irrigated farmland in the piedmont region of the North China Plain, we extended the monitoring of soil water content and matric potential across the entire vadose zone profile. We found that a high soil water content and matric potential (close to or slightly higher than the field capacity) was maintained in the DVZ of typical irrigated cropland. The response of soil water in the DVZ to the water inputs at the ground surface was predominantly sequentially delayed with an increase in depth in the DVZ. As a result, the wetting front propagated into the soil layer to a depth of 38 m within 228 days. Moreover, high soil moisture contents and matric potentials in the DVZ resulted in a dramatic but explicable difference between the estimated average pore water velocity (0.73 m year−1) and the wetting front propagation rate (0.16 m day−1). This study demonstrates the unreported rapid response of soil water in the DVZ to water input at the ground surface under intensively irrigated cropland and could promote a better understanding of groundwater recharge processes with a thick unsaturated zone.
Wave Activities Throughout a Low‐Mach Number Quasi‐Parallel Shock: 2‐D Hybrid Simulations
Authors: Hao Yufei , Lu Quanming , Wu Dejin , Xiang Liang
Published: May 2023

In this paper, two‐dimensional hybrid simulations are used to study wave excitation and evolution throughout a low‐Mach number quasi‐parallel shock. Simulation results show that quasi‐parallel fast magnetosonic waves, ion Bernstein waves with harmonics and possible Alfven/ion cyclotron waves can be excited in the upstream region, and their small phase velocities compared to injected flow velocity results in the convection to the shock front where they are mode converted into several groups of downstream waves, including Alfven waves along the directions parallel to downstream average magnetic fields and perpendicular to the shock normal, the quasi‐perpendicular kinetic slow waves and possible kinetic Alfven waves. We suggest that downstream Alfven waves originate from the mode conversion of upstream quasi‐parallel fast magnetosonic waves with left‐hand polarization in the downstream rest frame under helicity conservation, while the downstream left‐hand polarized kinetic slow waves and right‐hand polarized kinetic Alfven waves can be from the upstream quasi‐perpendicular ion Bernstein waves.
Life course BMI trajectories from childhood to mid-adulthood are differentially associated with anxiety and depression outcomes in middle age
Authors: Gallagher Claire , Pirkis Jane , Lambert Katrina A. , Perret Jennifer L. , Ali Gulshan B. , Lodge Caroline J. , Bowatte Gayan , Hamilton Garun S. , Matheson Melanie C. , Bui Dinh S. , Abramson Michael J. , Walters E. Haydn , Dharmage Shyamali C. , Erbas Bircan
Published: May 2023

Background/Objective

Obesity is a risk factor for multimorbidity, including depression and possibly anxiety. However, it is currently unclear how patterns of change in BMI over the life course differentially influence the magnitude in risk of depression and anxiety in mid-adulthood. We aimed to examine associations between BMI trajectories from childhood to adulthood and the risk of depression and anxiety in middle age.

Methods

In the Tasmanian Longitudinal Health Study (n = 2416), five distinct BMI trajectories were previously defined from age 5 to 45 years using group-based modelling. At age 53, current depression and anxiety were assessed using the Patient Health Questionnaire and the Generalized Anxiety Disorder scale, respectively. Logistic regression models adjusted for potential confounders estimated associations between BMI trajectories and these outcomes.

Results

Those belonging to the child average-increasing (OR = 2.24; 95%CI: 1.24, 4.06) and persistently high (OR = 2.64; 1.26, 5.52) trajectories were more likely to have depression in middle age, compared to the persistently average trajectory. However, the odds of experiencing greater severity of depressive symptoms was highest in the child average-increasing group (OR = 2.36; 1.59, 3.49). Despite finding no evidence of association between BMI trajectories and current anxiety, we observed less severe symptoms in the child high-decreasing trajectory (OR = 0.68; 0.51, 0.91).

Conclusion

We found an increased risk of depression in middle age among individuals with a persistently high BMI from childhood to mid-adulthood and individuals with an average BMI in childhood which then increased consistently throughout adulthood. Encouragingly, resolving childhood adiposity by adulthood was associated with lesser anxiety symptoms. Taken together, these findings highlight the need to target mental health screening and treatment towards high-risk BMI trajectory groups and the importance of early interventions to prevent and resolve excess weight.
Mast cell deficiency prevents BCR::ABL1 induced splenomegaly and cytokine elevation in a CML mouse model
Authors: Langhammer Melanie , Schöpf Julia , Jaquet Timo , Horn Katharina , Angel Moritz , Spohr Corinna , Christen Daniel , Uhl Franziska Maria , Maié Tiago , Jacobi Henrike , Feyerabend Thorsten B. , Huber Julia , Panning Marcus , Sitaru Cassian , Costa Ivan , Zeiser Robert , Aumann Konrad , Becker Heiko , Braunschweig Till , Koschmieder Steffen , Shoumariyeh Khalid , Huber Michael , Schemionek-Reinders Mirle , Brummer Tilman , Halbach Sebastian
Published: May 2023

The persistence of leukemic stem cells (LSCs) represents a problem in the therapy of chronic myeloid leukemia (CML). Hence, it is of utmost importance to explore the underlying mechanisms to develop new therapeutic approaches to cure CML. Using the genetically engineered ScltTA/TRE-BCR::ABL1 mouse model for chronic phase CML, we previously demonstrated that the loss of the docking protein GAB2 counteracts the infiltration of mast cells (MCs) in the bone marrow (BM) of BCR::ABL1 positive mice. Here, we show for the first time that BCR::ABL1 drives the cytokine independent expansion of BM derived MCs and sensitizes them for FcεRI triggered degranulation. Importantly, we demonstrate that genetic mast cell deficiency conferred by the Cpa3Cre allele prevents BCR::ABL1 induced splenomegaly and impairs the production of pro-inflammatory cytokines. Furthermore, we show in CML patients that splenomegaly is associated with high BM MC counts and that upregulation of pro-inflammatory cytokines in patient serum samples correlates with tryptase levels. Finally, MC-associated transcripts were elevated in human CML BM samples. Thus, our study identifies MCs as essential contributors to disease progression and suggests considering them as an additional target in CML therapy.
Signaling pathways in cancer metabolism: mechanisms and therapeutic targets
Authors: You Mengshu , Xie Zhuolin , Zhang Nan , Zhang Yixuan , Xiao Desheng , Liu Shuang , Zhuang Wei , Li Lili , Tao Yongguang
Published: May 2023

A wide spectrum of metabolites (mainly, the three major nutrients and their derivatives) can be sensed by specific sensors, then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics, which is called metabolite sensing. Life body regulates metabolism, immunity, and inflammation by metabolite sensing, coordinating the pathophysiology of the host to achieve balance with the external environment. Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell, including cell proliferation, migration, invasion, angiogenesis, etc. Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer, thus forming a vicious circle. At the same time, exogenous metabolites can also affect the biological behavior of tumors. Here, we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives, as well as their abnormalities in the development of various cancers, and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.
Effect of psilocybin on marble burying in ICR mice: role of 5-HT1A receptors and implications for the treatment of obsessive-compulsive disorder
Authors: Singh Sandeep , Botvinnik Alexander , Shahar Orr , Wolf Gilly , Yakobi Corel , Saban Michal , Salama Adham , Lotan Amit , Lerer Bernard , Lifschytz Tzuri
Published: May 2023

Preliminary clinical findings, supported by preclinical studies employing behavioral paradigms such as marble burying, suggest that psilocybin may be effective in treating obsessive-compulsive disorder. However, the receptor mechanisms implicated in the putative anti-obsessional effect are not clear. On this background, we set out to explore (1) the role of serotonin 2A (5-HT2A) and serotonin 1A (5-HT1A) receptors in the effect of psilocybin on marble burying; (2) the effect of staggered versus bolus psilocybin administration and persistence of the effect; (3) the effect of the 5-HT1A partial agonist, buspirone, on marble-burying and the head twitch response (HTR) induced by psilocybin, a rodent correlate of psychedelic effects. Male ICR mice were administered psilocybin 4.4 mg/kg, escitalopram 5 mg/kg, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) 2 mg/kg, M100907 2 mg/kg, buspirone 5 mg/kg, WAY100635 2 mg/kg or combinations, intraperitoneally, and were tested on the marble burying test. HTR was examined in a magnetometer-based assay. The results show that (1) Psilocybin and escitalopram significantly reduced marble burying. The effect of psilocybin was not attenuated by the 5-HT2A antagonist, M100907. The 5-HT1A agonist, 8-OH-DPAT, reduced marble burying as did the 5-HT1A partial agonist, buspirone. The effect of 8-OH-DPAT was additive to that of psilocybin, but that of buspirone was not. The 5-HT1A antagonist, WAY100635, attenuated the effect of 8-OH-DPAT and buspirone but not the effect of psilocybin. (2) Psilocybin injections over 3.5 h had no effect on marble burying and the effect of bolus injection was not persistent. (3) Co-administration of buspirone with psilocybin blocked its effect on HTR. These data suggest that neither 5-HT2A nor 5-HT1A receptors are pivotally implicated in the effect of psilocybin on marble burying. Co-administration with buspirone may block the psychedelic effects of psilocybin without impeding its anti-obsessional effects.
Prenatal programming of environmental sensitivity
Authors: Hartman Sarah , Belsky Jay , Pluess Michael
Published: May 2023

According to several theories, people differ in their sensitivity to environmental influences with some more susceptible than others to both supportive and adverse contextual conditions. Such differences in environmental sensitivity have a genetic basis but are also shaped by environmental factors. Herein we narratively build on our previous work proposing that prenatal experiences contribute to the development of environmental sensitivity. This hypothesis of prenatal programming of postnatal plasticity has considerable empirical support. After presenting illustrative animal and human evidence consistent with this claim, we discuss a range of biological mechanisms likely involved in the pathway from prenatal stress exposure to postnatal environmental sensitivity. We also consider work suggesting that genetic differences, gender, as well as the timing, duration and intensity of prenatal exposures may moderate the effects of prenatal programming on postnatal environmental susceptibility or sensitivity. Before concluding, we highlight “unknowns in the prenatal programming of environmental sensitivity” and their practical implications. Ultimately, we conclude that prenatal stress does not necessarily predispose individuals to problematical development, but rather increases sensitivity to both adverse and supportive postnatal contexts. Thus, prenatal stress may actually foster positive development if paired with supportive and caring postnatal environments.
Biological factors influencing depression in later life: role of aging processes and treatment implications
Authors: Szymkowicz Sarah M. , Gerlach Andrew R. , Homiack Damek , Taylor Warren D.
Published: May 2023

Late-life depression occurring in older adults is common, recurrent, and malignant. It is characterized by affective symptoms, but also cognitive decline, medical comorbidity, and physical disability. This behavioral and cognitive presentation results from altered function of discrete functional brain networks and circuits. A wide range of factors across the lifespan contributes to fragility and vulnerability of those networks to dysfunction. In many cases, these factors occur earlier in life and contribute to adolescent or earlier adulthood depressive episodes, where the onset was related to adverse childhood events, maladaptive personality traits, reproductive events, or other factors. Other individuals exhibit a later-life onset characterized by medical comorbidity, pro-inflammatory processes, cerebrovascular disease, or developing neurodegenerative processes. These later-life processes may not only lead to vulnerability to the affective symptoms, but also contribute to the comorbid cognitive and physical symptoms. Importantly, repeated depressive episodes themselves may accelerate the aging process by shifting allostatic processes to dysfunctional states and increasing allostatic load through the hypothalamic–pituitary–adrenal axis and inflammatory processes. Over time, this may accelerate the path of biological aging, leading to greater brain atrophy, cognitive decline, and the development of physical decline and frailty. It is unclear whether successful treatment of depression and avoidance of recurrent episodes would shift biological aging processes back towards a more normative trajectory. However, current antidepressant treatments exhibit good efficacy for older adults, including pharmacotherapy, neuromodulation, and psychotherapy, with recent work in these areas providing new guidance on optimal treatment approaches. Moreover, there is a host of nonpharmacological treatment approaches being examined that take advantage of resiliency factors and decrease vulnerability to depression. Thus, while late-life depression is a recurrent yet highly heterogeneous disorder, better phenotypic characterization provides opportunities to better utilize a range of nonspecific and targeted interventions that can promote recovery, resilience, and maintenance of remission.
Intraoral occlusal adjustment time and volume required for CAD/CAM crowns fabricated with different virtual mounting methods (A randomized crossover trial)
Authors: Elkady Aly Ayman Mohamed , Ameen Shereen Adel , Sami Rasha Nabil
Published: May 2023

Objective

To measure the required clinical time and volume of occlusal adjustment when the maxillary cast is positioned in a virtual articulator using one of three methods: digitization of a facebow-mounted mechanical articulator (group A), virtual Bonwill triangle (group B) or a 3D face scan (group F).

Materials and methods

In this randomized, triple-blind, crossover trial; 11 participants were enrolled. Every participant had one molar indicated for a single crown restoration. Three crowns were designed and milled for every participant molar totaling 33 crowns. Each of the three crowns was fabricated with the participant’s casts virtually mounted utilizing a different method. An impression was taken of the crown in place before occlusal adjustment. The occlusal adjustment was then performed and timed with the three crowns in the different groups. After the occlusal adjustment, an impression of the adjusted crown was taken. The pre-adjustment and post-adjustment impressions were digitally superimposed and the volume difference was measured. The Kruskal-Wallis test was used to compare the groups.

Results

Group A showed the shortest mean adjustment time (3:44.59 ± 3:39.07) followed by group F (4:30.09 ± 2:01.50) and group B (4:35.30 ± 2:32.33). The mean adjustment volume for group A was (28 ± 19.1 mm3) followed by group F (30.5 ± 18.8 mm3) and group B (40.6 ± 29.5 mm3). Different virtual mounting methods had no statistically significant effect on adjustment time (P-value = 0.538) or adjustment volume (P-value = 0.490).

Conclusions

A simplified approach in virtual articulator mounting appears to be justified in the construction of a single full-coverage prosthesis. Added labor, time and cost of more elaborate virtual mounting methods seem to be counterproductive.
Dynamic frailty risk assessment among older adults with multiple myeloma: A population-based cohort study
Authors: Mian Hira , Wildes Tanya M. , Vij Ravi , Pianko Matthew J. , Major Ajay , Fiala Mark A.
Published: May 2023

Multiple myeloma (MM) is a cancer of older adults and those who are more frail are at high risk of poor outcomes. Current tools for identifying and categorizing frail patients are often static and measured only at the time of diagnosis. The concept of dynamic frailty (i.e. frailty changing over time) is largely unexplored in MM. In our study, adults with newly-diagnosed MM who received novel drugs between the years 2007–2014 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Using a previously published cumulative deficit approach, a frailty index score was calculated at diagnosis and each landmark interval (1-yr, 2-yr, 3-yr post diagnosis). The association of frailty with overall survival (OS) both at baseline and at each landmark interval as well as factors associated with worsening frailty status over time were evaluated. Overall, 4617 patients were included. At baseline, 39% of the patients were categorized as moderately frail or severely frail. Among those who had 3 years of follow-up, frailty categorization changed post diagnosis in 93% of the cohort (78% improved and 72% deteriorated at least at one time point during the follow up period). In a landmark analysis, the predictive ability of frailty at the time of diagnosis decreased over time for OS (Harrell’s C Statistic 0.65 at diagnosis, 0.63 at 1-yr, 0.62 at 2-yr, and 0.60 at 3-yr) and was inferior compared to current frailty status at each landmark interval. Our study is one of the first to demonstrate the dynamic nature of frailty among older adults with MM. Frailty may improve or deteriorate over time. Current frailty status is a better predictor of outcomes than frailty status at time of diagnosis, indicating the need for re-measurement in this high-risk patient population.
Canonical and truncated transglutaminase-2 regulate mucin-1 expression and androgen independency in prostate cancer cell lines
Authors: Atobatele Adeola Grace , Tonoli Elisa , Vadakekolathu Jayakumar , Savoca Maria Pia , Barr Melissa , Kataria Yukti , Rossanese Marta , Burhan Izhar , McArdle Stephanie , Caccamo Daniela , Verderio Elisabetta A. M.
Published: May 2023

Androgen independency is associated with poor prostate cancer (PCa) survival. Here we report that silencing of transglutaminase-2 (TG2) expression by CRISPR-Cas9 is associated with upregulation of androgen receptor (AR) transcription in PCa cell lines. Knockout of TG2 reversed the migratory potential and anchorage independency of PC3 and DU145 cells and revealed a reduced level of mucin-1 (MUC1) RNA transcript through unbiased multi-omics profiling, which was restored by selective add-back of the truncated TG2 isoform (TGM2_v2). Silencing of AR resulted into increased MUC1 in TG2KO PC3 cells showing that TG2 affects transcriptional regulation of MUC1 via repressing AR expression. Treatment of PC3 WT cell line with TG2 inhibitor ZDON led to a significant increase in AR expression and decrease in MUC1. ZDON also blocked the formation of MUC1-multimers labelled with TG amine-donor substrates in reducing conditions, revealing for the first time a role for TG2, which we show to be externalised via extracellular vesicles, in MUC1 stabilisation via calcium-dependent transamidation. A specific antibody towards TGM2_v2 revealed its restricted nuclear location compared to the canonical long form of TG2 (TGM2_v1), which is predominantly cytosolic, suggesting that this form contributes to the previously suggested TG2-mediated NF-κB activation and AR transcriptional repression. As TGM2_v2 transcription was increased in biopsies of early-stage prostate adenocarcinoma (PRAD) patients compared to subjects presenting inflammatory prostatitis, and total TG2 protein expression significantly increased in PRAD versus normal tissue, the role of TG2 and its truncated form as a prostate malignancy marker is suggested. In conclusion, this investigation has provided the first unbiased discovery of a novel pathway mediated by TG2 via MUC1, which is shown to contribute to androgen insensitivity and malignancy of PCa cells and be upregulated in PCa biopsies, with potential relevance to cancer immune evasion.
BRD4-targeting PROTAC as a unique tool to study biomolecular condensates
Authors: Shi Yi , Liao Yuan , Liu Qianlong , Ni Zhihao , Zhang Zhenzhen , Shi Minglei , Li Pilong , Li Haitao , Rao Yu
Published: May 2023

Biomolecular condensates play key roles in various biological processes. However, specific condensation modulators are currently lacking. PROTAC is a new technology that can use small molecules to degrade target proteins specifically. PROTAC molecules are expected to regulate biomolecular condensates dynamically by degrading/recovering key molecules in biomolecular condensates. In this study, we employed a BRD4-targeting PROTAC molecule to regulate the super-enhancer (SE) condensate and monitored the changes of SE condensate under PROTAC treatment using live-cell imaging and high-throughput sequencing technologies. As a result, we found that BRD4-targeting PROTACs can significantly reduce the BRD4 condensates, and we established a quantitative method for tracking BRD4 condensates by PROTAC and cellular imaging. Surprisingly and encouragingly, BRD4 condensates were observed to preferentially form and play specialized roles in biological process regulation for the first time. Additionally, BRD4 PROTAC makes it possible to observe the dynamics of other condensate components under the continued disruption of BRD4 condensates. Together, these results shed new light on research methods for liquid-liquid phase separation (LLPS), and specifically demonstrate that PROTAC presents a powerful and distinctive tool for the study of biomolecular condensates.
Abdominal obesity is a more important causal risk factor for pancreatic cancer than overall obesity
Authors: Maina Jared G. , Pascat Vincent , Zudina Liudmila , Ulrich Anna , Pupko Igor , Bonnefond Amélie , Balkhiyarova Zhanna , Kaakinen Marika , Froguel Philippe , Prokopenko Inga
Published: May 2023

Obesity and type 2 diabetes (T2D) are associated with increased risk of pancreatic cancer. Here we assessed the relationship between pancreatic cancer and two distinct measures of obesity, namely total adiposity, using BMI, versus abdominal adiposity, using BMI adjusted waist-to-hip ratio (WHRadjBMI) by utilising polygenic scores (PGS) and Mendelian randomisation (MR) analyses. We constructed z-score weighted PGS for BMI and WHRadjBMI using publicly available data and tested for their association with pancreatic cancer defined in UK biobank (UKBB). Using publicly available summary statistics, we then performed bi-directional MR analyses between the two obesity traits and pancreatic cancer. PGSBMI was significantly (multiple testing-corrected) associated with pancreatic cancer (OR[95%CI] = 1.0804[1.025–1.14], P = 0.0037). The significance of association declined after T2D adjustment (OR[95%CI] = 1.073[1.018–1.13], P = 0.00904). PGSWHRadjBMI association with pancreatic cancer was at the margin of statistical significance (OR[95%CI] = 1.047[0.99–1.104], P = 0.086). T2D adjustment effectively lost any suggestive association of PGSWHRadjBMI with pancreatic cancer (OR[95%CI] = 1.039[0.99–1.097], P = 0.14). MR analyses showed a nominally significant causal effect of WHRadjBMI on pancreatic cancer (OR[95%CI] = 1.00095[1.00011–1.0018], P = 0.027) but not for BMI on pancreatic cancer. Overall, we show that abdominal adiposity measured using WHRadjBMI, may be a more important causal risk factor for pancreatic cancer compared to total adiposity, with T2D being a potential driver of this relationship.
Repeat or single-dose lentiviral vector administration to mouse lungs? It’s all about the timing
Authors: Donnelley Martin , Cmielewski Patricia , Knight Emma , Carpentieri Chantelle , McCarron Alexandra , Rout-Pitt Nathan , Parsons David , Farrow Nigel
Published: May 2023

Lentiviral vectors are attractive delivery vehicles for cystic fibrosis gene therapy owing to their low immunogenicity and ability to integrate into the host cell genome, thereby producing long-term, stable gene expression. Nonetheless, repeat dosing may be required to increase initial expression levels, and/or boost levels when they wane. The primary aim of this study was to determine if repeat dosing of a VSV-G pseudotyped LV vector delivered into mouse lungs is more effective than a single dose. C57Bl/6 mouse lungs were conditioned with lysophosphatidylcholine, followed one-hour later by a LV vector carrying the luciferase reporter gene, using six different short-term (≤1 wk) and long-term (>1 wk) dosing schedules. Luciferase expression was quantified using bioluminescence imaging over 12 months. Most dosing schedules produced detectable bioluminescence over the 12-month period, but the shorter intervals (≤1 wk) produced higher levels of flux than the longest interval (five doses at least 1-month apart). Ex vivo lung analysis at 12 months showed that the estimated mean flux for the group that received two doses 1-week apart was significantly greater than the single dose group and the two groups that received doses over a period greater than 1-week. These results suggest that early consecutive multiple doses are more effective at improving gene expression in mouse lungs at 12 months, than longer repeat dosing intervals.
Structural basis for activation of CB1 by an endocannabinoid analog
Authors: Krishna Kumar Kaavya , Robertson Michael J. , Thadhani Elina , Wang Haoqing , Suomivuori Carl-Mikael , Powers Alexander S. , Ji Lipin , Nikas Spyros P. , Dror Ron O. , Inoue Asuka , Makriyannis Alexandros , Skiniotis Georgios , Kobilka Brian
Published: May 2023

Endocannabinoids (eCBs) are endogenous ligands of the cannabinoid receptor 1 (CB1), a G protein-coupled receptor that regulates a number of therapeutically relevant physiological responses. Hence, understanding the structural and functional consequences of eCB-CB1 interactions has important implications for designing effective drugs targeting this receptor. To characterize the molecular details of eCB interaction with CB1, we utilized AMG315, an analog of the eCB anandamide to determine the structure of the AMG315-bound CB1 signaling complex. Compared to previous structures, the ligand binding pocket shows some differences. Using docking, molecular dynamics simulations, and signaling assays we investigated the functional consequences of ligand interactions with the “toggle switch” residues F2003.36and W3566.48. Further, we show that ligand-TM2 interactions drive changes to residues on the intracellular side of TM2 and are a determinant of efficacy in activating G protein. These intracellular TM2 rearrangements are unique to CB1 and are exploited by a CB1-specific allosteric modulator.
Cationic crosslinked carbon dots-adjuvanted intranasal vaccine induces protective immunity against Omicron-included SARS-CoV-2 variants
Authors: Lei Hong , Alu Aqu , Yang Jingyun , He Xi , He Cai , Ren Wenyan , Chen Zimin , Hong Weiqi , Chen Li , He Xuemei , Yang Li , Li Jiong , Wang Zhenling , Wang Wei , Wei Yuquan , Lu Shuaiyao , Lu Guangwen , Song Xiangrong , Wei Xiawei
Published: May 2023

Mucosal immunity plays a significant role in the first-line defense against viruses transmitted and infected through the respiratory system, such as SARS-CoV-2. However, the lack of effective and safe adjuvants currently limits the development of COVID-19 mucosal vaccines. In the current study, we prepare an intranasal vaccine containing cationic crosslinked carbon dots (CCD) and a SARS-CoV-2 antigen, RBD-HR with spontaneous antigen particlization. Intranasal immunization with CCD/RBD-HR induces high levels of antibodies with broad-spectrum neutralization against authentic viruses/pseudoviruses of Omicron-included variants and protects immunized female BALB/c mice from Omicron infection. Despite strong systemic cellular immune response stimulation, the intranasal CCD/RBD-HR vaccine also induces potent mucosal immunity as determined by the generation of tissue-resident T cells in the lungs and airway. Moreover, CCD/RBD-HR not only activates professional antigen-presenting cells (APCs), dendritic cells, but also effectively targets nasal epithelial cells, promotes antigen binding via sialic acid, and surprisingly provokes the antigen-presenting of nasal epithelial cells. We demonstrate that CCD is a promising intranasal vaccine adjuvant for provoking strong mucosal immunity and might be a candidate adjuvant for intranasal vaccine development for many types of infectious diseases, including COVID-19.
Shape distortion in sintering results from nonhomogeneous temperature activating a long-range mass transport
Authors: Ritchie Sandra M. , Kovacevic Sasa , Deshmukh Prithviraj , Christodoulides Alexander D. , Malen Jonathan A. , Mesarovic Sinisa Dj. , Panat Rahul P.
Published: May 2023

Sintering theory predicts no long-range mass transport or distortion for uniformly heated particles during particle coalescence. However, in sintering-based manufacturing processes, permanent part distortion is often observed. The driving forces and mechanisms leading to this phenomenon are not understood, and efforts to reduce distortion are largely limited to a trial-and-error approach. In this paper, we demonstrate that distortion during sintering results from mass-transport driven by nonhomogeneous temperature distribution. We then show that hitherto unknown mass transport mechanisms, working in the direction opposite to temperature gradient are the likely cause of distortion. The experimental setup, designed for this purpose, enables the quantification of distortion during sintering. Two possible mass transport mechanisms are defined, and the continuum model applicable to both is formulated. The model accurately predicts the transient and permanent distortion observed during experiments, including their size dependence. Methods to control distortion that can give rise to 4D printing are discussed.
Non-enzymatic oligonucleotide ligation in coacervate protocells sustains compartment-content coupling
Authors: Fraccia Tommaso P. , Martin Nicolas
Published: May 2023

Modern cells are complex chemical compartments tightly regulated by an underlying DNA-encoded program. Achieving a form of coupling between molecular content, chemical reactions, and chassis in synthetic compartments represents a key step to the assembly of evolvable protocells but remains challenging. Here, we design coacervate droplets that promote non-enzymatic oligonucleotide polymerization and that restructure as a result of the reaction dynamics. More specifically, we rationally exploit complexation between end-reactive oligonucleotides able to stack into long physical polymers and a cationic azobenzene photoswitch to produce three different phases—soft solids, liquid crystalline or isotropic coacervates droplets—each of them having a different impact on the reaction efficiency. Dynamical modulation of coacervate assembly and dissolution via trans-cis azobenzene photo-isomerization is used to demonstrate cycles of light-actuated oligonucleotide ligation. Remarkably, changes in the population of polynucleotides during polymerization induce phase transitions due to length-based DNA self-sorting to produce multiphase coacervates. Overall, by combining a tight reaction-structure coupling and environmental responsiveness, our reactive coacervates provide a general route to the non-enzymatic synthesis of polynucleotides and pave the way to the emergence of a primitive compartment-content coupling in membrane-free protocells.
Orbital character of the spin-reorientation transition in TbMn6Sn6
Authors: Riberolles S. X. M. , Slade Tyler J. , Dally R. L. , Sarte P. M. , Li Bing , Han Tianxiong , Lane H. , Stock C. , Bhandari H. , Ghimire N. J. , Abernathy D. L. , Canfield P. C. , Lynn J. W. , Ueland B. G. , McQueeney R. J.
Published: May 2023

Ferromagnetic (FM) order in a two-dimensional kagome layer is predicted to generate a topological Chern insulator without an applied magnetic field. The Chern gap is largest when spin moments point perpendicular to the kagome layer, enabling the capability to switch topological transport properties, such as the quantum anomalous Hall effect, by controlling the spin orientation. In TbMn6Sn6, the uniaxial magnetic anisotropy of the Tb3+ ion is effective at generating the Chern state within the FM Mn kagome layers while a spin-reorientation (SR) transition to easy-plane order above TSR = 310 K provides a mechanism for switching. Here, we use inelastic neutron scattering to provide key insights into the fundamental nature of the SR transition. The observation of two Tb excitations, which are split by the magnetic anisotropy energy, indicates an effective two-state orbital character for the Tb ion, with a uniaxial ground state and an isotropic excited state. The simultaneous observation of both modes below TSR confirms that orbital fluctuations are slow on magnetic and electronic time scales < ps and act as a spatially-random orbital alloy. A thermally-driven critical concentration of isotropic Tb ions triggers the SR transition.
Enhancement of superconducting properties in the La–Ce–H system at moderate pressures
Authors: Chen Wuhao , Huang Xiaoli , Semenok Dmitrii V. , Chen Su , Zhou Di , Zhang Kexin , Oganov Artem R. , Cui Tian
Published: May 2023

Ternary hydrides are regarded as an important platform for exploring high-temperature superconductivity at relatively low pressures. Here, we successfully synthesized the hcp-(La,Ce)H9-10 at 113 GPa with the initial La/Ce ratio close to 3:1. The high-temperature superconductivity was strikingly observed at 176 K and 100 GPa with the extrapolated upper critical field Hc2(0) reaching 235 T. We also studied the binary La-H system for comparison, which exhibited a Tc of 103 K at 78 GPa. The Tc and Hc2(0) of the La-Ce-H are respectively enhanced by over 80 K and 100 T with respect to the binary La-H and Ce-H components. The experimental results and theoretical calculations indicate that the formation of the solid solution contributes not only to enhanced stability but also to superior superconducting properties. These results show how better superconductors can be engineered in the new hydrides by large addition of alloy-forming elements.
Resveratrol intervention attenuates chylomicron secretion via repressing intestinal FXR-induced expression of scavenger receptor SR-B1
Authors: Pang Juan , Raka Fitore , Heirali Alya Abbas , Shao Weijuan , Liu Dinghui , Gu Jianqiu , Feng Jia Nuo , Mineo Chieko , Shaul Philip W. , Qian Xiaoxian , Coburn Bryan , Adeli Khosrow , Ling Wenhua , Jin Tianru
Published: May 2023

Two common features of dietary polyphenols have hampered our mechanistic understanding of their beneficial effects for decades: targeting multiple organs and extremely low bioavailability. We show here that resveratrol intervention (REV-I) in high-fat diet (HFD)-challenged male mice inhibits chylomicron secretion, associated with reduced expression of jejunal but not hepatic scavenger receptor class B type 1 (SR-B1). Intestinal mucosa-specific SR-B1-/- mice on HFD-challenge exhibit improved lipid homeostasis but show virtually no further response to REV-I. SR-B1 expression in Caco-2 cells cannot be repressed by pure resveratrol compound while fecal-microbiota transplantation from mice on REV-I suppresses jejunal SR-B1 in recipient mice. REV-I reduces fecal levels of bile acids and activity of fecal bile-salt hydrolase. In Caco-2 cells, chenodeoxycholic acid treatment stimulates both FXR and SR-B1. We conclude that gut microbiome is the primary target of REV-I, and REV-I improves lipid homeostasis at least partially via attenuating FXR-stimulated gut SR-B1 elevation.
The impact of introduction of the 10-valent pneumococcal conjugate vaccine on pneumococcal carriage in Nigeria
Authors: Adamu Aishatu L. , Ojal J. , Abubakar Isa A. , Odeyemi Kofo A. , Bello Musa M. , Okoromah Christy A. N. , Karia Boniface , Karani Angela , Akech Donald. , Inem Victor , Scott J. Anthony G. , Adetifa Ifedayo M. O.
Published: May 2023

Pneumococcal conjugate vaccines (PCVs) protect against invasive pneumococcal disease (IPD) among vaccinees. However, at population level, this protection is driven by indirect effects. PCVs prevent nasopharyngeal acquisition of vaccine-serotype (VT) pneumococci, reducing onward transmission. Each disease episode is preceded by infection from a carrier, so vaccine impacts on carriage provide a minimum estimate of disease reduction in settings lacking expensive IPD surveillance. We documented carriage prevalence and vaccine coverage in two settings in Nigeria annually (2016–2020) following PCV10 introduction in 2016. Among 4,684 rural participants, VT carriage prevalence fell from 21 to 12% as childhood (<5 years) vaccine coverage rose from 7 to 84%. Among 2,135 urban participants, VT carriage prevalence fell from 16 to 9% as uptake rose from 15 to 94%. Within these ranges, carriage prevalence declined with uptake. Increasing PCV10 coverage reduced pneumococcal infection at all ages, implying at least a comparable reduction in IPD.
Cellular automata imbedded memristor-based recirculated logic in-memory computing
Authors: Liu Yanming , Tian He , Wu Fan , Liu Anhan , Li Yihao , Sun Hao , Lanza Mario , Ren Tian-Ling
Published: May 2023

Memristor-based circuits offer low hardware costs and in-memory computing, but full-memristive circuit integration for different algorithm remains limited. Cellular automata (CA) has been noticed for its well-known parallel, bio-inspired, computational characteristics. Running CA on conventional chips suffers from low parallelism and high hardware costs. Establishing dedicated hardware for CA remains elusive. We propose a recirculated logic operation scheme (RLOS) using memristive hardware and 2D transistors for CA evolution, significantly reducing hardware complexity. RLOS’s versatility supports multiple CA algorithms on a single circuit, including elementary CA rules and more complex majority classification and edge detection algorithms. Results demonstrate up to a 79-fold reduction in hardware costs compared to FPGA-based approaches. RLOS-based reservoir computing is proposed for edge computing development, boasting the lowest hardware cost (6 components/per cell) among existing implementations. This work advances efficient, low-cost CA hardware and encourages edge computing hardware exploration.
Phase II trial of neoadjuvant sitravatinib plus nivolumab in patients undergoing nephrectomy for locally advanced clear cell renal cell carcinoma
Authors: Karam Jose A. , Msaouel Pavlos , Haymaker Cara L. , Matin Surena F. , Campbell Matthew T. , Zurita Amado J. , Shah Amishi Y. , Wistuba Ignacio I. , Marmonti Enrica , Duose Dzifa Y. , Parra Edwin R. , Soto Luisa Maren Solis , Laberiano-Fernandez Caddie , Lozano Marisa , Abraham Alice , Hallin Max , Chin Curtis D. , Olson Peter , Der-Torossian Hirak , Yan Xiaohong , Tannir Nizar M. , Wood Christopher G.
Published: May 2023

Sitravatinib is an immunomodulatory tyrosine kinase inhibitor that can augment responses when combined with programmed death-1 inhibitors such as nivolumab. We report a single-arm, interventional, phase 2 study of neoadjuvant sitravatinib in combination with nivolumab in patients with locally advanced clear cell renal cell carcinoma (ccRCC) prior to curative nephrectomy (NCT03680521). The primary endpoint was objective response rate (ORR) prior to surgery with a null hypothesis ORR = 5% and the alternative hypothesis set at ORR = 30%. Secondary endpoints were safety; pharmacokinetics (PK) of sitravatinib; immune effects, including changes in programmed cell death–ligand 1 expression; time-to-surgery; and disease-free survival (DFS). Twenty patients were evaluable for safety and 17 for efficacy. The ORR was 11.8%, and 24-month DFS probability was 88·0% (95% CI 61.0 to 97.0). There were no grade 4/5 treatment-related adverse events. Sitravatinib PK did not change following the addition of nivolumab. Correlative blood and tissue analyses showed changes in the tumour microenvironment resulting in an immunologically active tumour by the time of surgery (median time-to-surgery: 50 days). The primary endpoint of this study was not met as short-term neoadjuvant sitravatinib and nivolumab did not substantially increase ORR.
Nuclear spin diffusion in the central spin system of a GaAs/AlGaAs quantum dot
Authors: Millington-Hotze Peter , Manna Santanu , Covre da Silva Saimon F. , Rastelli Armando , Chekhovich Evgeny A.
Published: May 2023

The spin diffusion concept provides a classical description of a purely quantum-mechanical evolution in inhomogeneously polarized many-body systems such as nuclear spin lattices. The central spin of a localized electron alters nuclear spin diffusion in a way that is still poorly understood. Here, spin diffusion in a single GaAs/AlGaAs quantum dot is witnessed in the most direct manner from oscillatory spin relaxation dynamics. Electron spin is found to accelerate nuclear spin relaxation, from which we conclude that the long-discussed concept of a Knight-field-gradient diffusion barrier does not apply to GaAs epitaxial quantum dots. Our experiments distinguish between non-diffusion relaxation and spin diffusion, allowing us to conclude that diffusion is accelerated by the central electron spin. Such acceleration is observed up to unexpectedly high magnetic fields – we propose electron spin-flip fluctuations as an explanation. Diffusion-limited nuclear spin lifetimes range between 1 and 10 s, which is sufficiently long for quantum information storage and processing.
Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein
Authors: Neuberger Arthur , Trofimov Yury A. , Yelshanskaya Maria V. , Nadezhdin Kirill D. , Krylov Nikolay A. , Efremov Roman G. , Sobolevsky Alexander I.
Published: May 2023

Calcium-selective oncochannel TRPV6 is the major driver of cell proliferation in human cancers. While significant effort has been invested in the development of synthetic TRPV6 inhibitors, natural channel blockers have been largely neglected. Here we report the structure of human TRPV6 in complex with the plant-derived phytoestrogen genistein, extracted from Styphnolobium japonicum, that was shown to inhibit cell invasion and metastasis in cancer clinical trials. Despite the pharmacological value, the molecular mechanism of TRPV6 inhibition by genistein has remained enigmatic. We use cryo-EM combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to show that genistein binds in the intracellular half of the TRPV6 pore and acts as an ion channel blocker and gating modifier. Genistein binding to the open channel causes pore closure and a two-fold symmetrical conformational rearrangement in the S4–S5 and S6-TRP helix regions. The unprecedented mechanism of TRPV6 inhibition by genistein uncovers new possibilities in structure-based drug design.
Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer
Authors: Sun Chenglong , Wang Anqiang , Zhou Yanhe , Chen Panpan , Wang Xiangyi , Huang Jianpeng , Gao Jiamin , Wang Xiao , Shu Liebo , Lu Jiawei , Dai Wentao , Bu Zhaode , Ji Jiafu , He Jiuming
Published: May 2023

Mapping tumor metabolic remodeling and their spatial crosstalk with surrounding non-tumor cells can fundamentally improve our understanding of tumor biology, facilitates the designing of advanced therapeutic strategies. Here, we present an integration of mass spectrometry imaging-based spatial metabolomics and lipidomics with microarray-based spatial transcriptomics to hierarchically visualize the intratumor metabolic heterogeneity and cell metabolic interactions in same gastric cancer sample. Tumor-associated metabolic reprogramming is imaged at metabolic-transcriptional levels, and maker metabolites, lipids, genes are connected in metabolic pathways and colocalized in the heterogeneous cancer tissues. Integrated data from spatial multi-omics approaches coherently identify cell types and distributions within the complex tumor microenvironment, and an immune cell-dominated “tumor-normal interface” region where tumor cells contact adjacent tissues are characterized with distinct transcriptional signatures and significant immunometabolic alterations. Our approach for mapping tissue molecular architecture provides highly integrated picture of intratumor heterogeneity, and transform the understanding of cancer metabolism at systemic level.
Patterns of ontogenetic evolution across extant marsupials reflect different allometric pathways to ecomorphological diversity
Authors: Wilson Laura A. B. , López-Aguirre Camilo , Archer Michael , Hand Suzanne J. , Flores David , Abdala Fernando , Giannini Norberto P.
Published: May 2023

The relatively high level of morphological diversity in Australasian marsupials compared to that observed among American marsupials remains poorly understood. We undertake a comprehensive macroevolutionary analysis of ontogenetic allometry of American and Australasian marsupials to examine whether the contrasting levels of morphological diversity in these groups are reflected in their patterns of allometric evolution. We collate ontogenetic series for 62 species and 18 families of marsupials (n = 2091 specimens), spanning across extant marsupial diversity. Our results demonstrate significant lability of ontogenetic allometric trajectories among American and Australasian marsupials, yet a phylogenetically structured pattern of allometric evolution is preserved. Here we show that species diverging more than 65 million years ago converge in their patterns of ontogenetic allometry under animalivorous and herbivorous diets, and that Australasian marsupials do not show significantly greater variation in patterns of ontogenetic allometry than their American counterparts, despite displaying greater magnitudes of extant ecomorphological diversity.