bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prenatal programming of environmental sensitivity
Authors: Hartman Sarah , Belsky Jay , Pluess Michael 
Published: May 2023

AbstractAccording 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

AbstractLate-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

Abstract
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

AbstractMultiple 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

AbstractAndrogen 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

AbstractBiomolecular 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

AbstractObesity 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

AbstractLentiviral 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

AbstractEndocannabinoids (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

AbstractMucosal 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

AbstractSintering 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

AbstractModern 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

AbstractFerromagnetic (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.