bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vulnerability to global warming of the critically endangered Añelo Sand Dunes Lizard (Liolaemus cuyumhue) from the Monte Desert, Patagonia Argentina
Authors: Brizio M. Victoria , Cabezas-Cartes Facundo , Fernández Jimena B. , Gómez Alés Rodrigo , Avila Luciano J. 
Published: June 2021

The body temperature of lizards is strongly influenced by the thermal quality of microhabitats, exploiting the favourable environmental temperatures, and avoiding exposure to extreme thermal conditions. For these reasons, reptile populations are considered to be especially vulnerable to changes in environmental temperatures produced by climate change. Here, we study the thermal physiology of the critically endangered Añelo Sand Dunes Lizard (Liolaemus cuyumhue Avila, Morando, Perez and Sites, 2009). We hypothesise that (i) there is a thermal coadaptation between optimal temperature for locomotor performance of L. cuyumhue and its thermal preference; (ii) L. cuyumhue lives in an environment with low thermal quality; and (iii) a rise in environmental temperatures due to global warming will impose a decrement in locomotor speed represented by lower warming tolerance and narrower thermal safety margins, increasing their already high vulnerability. We recorded field body temperatures (T b), preferred body temperatures (T pref), the operative temperature (T e), and the thermal sensitivity of locomotion at different body temperatures. Our results indicate that this lizard is not currently under environmental stress or exceeding its thermal limits, but that it is thermoregulating below T pref to avoid overheating, and that an increase in environmental temperature higher than 3.5 °C will strongly affect the use of microhabitats with direct sun exposure.
A minimal supersymmetric SU(5) missing-partner model
Authors: Ellis John , Evans Jason L. , Nagata Natsumi , Olive Keith A. 
Published: June 2021

AbstractWe explore a missing-partner model based on the minimal SU(5) gauge group with $$\mathbf{75} $$
75
, $$\mathbf{50} $$
50
and $$\overline{\mathbf{50 }}$$

50
¯

Higgs representations, assuming a super-GUT CMSSM scenario in which soft supersymmetry-breaking parameters are universal at some high scale $$M_{\mathrm{in}}$$

M
in

above the GUT scale $$M_{\mathrm{GUT}}$$

M
GUT

. We identify regions of parameter space that are consistent with the cosmological dark matter density, the measured Higgs mass and the experimental lower limit on $$\tau (p \rightarrow K^+ \nu )$$

τ
(
p
→

K
+

ν
)

. These constraints can be satisfied simultaneously along stop coannihilation strips in the super-GUT CMSSM with $$\tan \beta \sim $$

tan
β
∼

3.5–5 where the input gaugino mass $$m_{1/2} \sim $$

m

1
/
2

∼

15–25 TeV, corresponding after strong renormalization by the large GUT Higgs representations between $$M_{\mathrm{in}}$$

M
in

and $$M_{\mathrm{GUT}}$$

M
GUT

to $$m_{\mathrm{LSP}}, m_{{\tilde{t}}_1} \sim $$

m
LSP

,

m

t
~

1

∼

2.5–5 TeV and $$m_{{\tilde{g}}} \sim $$

m

g
~

∼

13–20 TeV, with the light-flavor squarks significantly heavier. We find that $$\tau (p \rightarrow K^+ \nu ) \lesssim 3 \times 10^{34}$$

τ

(
p
→

K
+

ν
)

≲
3
×

10
34

years throughout the allowed range of parameter space, within the range of the next generation of searches with the JUNO, DUNE and Hyper-Kamiokande experiments.
Two conductive mechanisms in LaMnO3 thin film: Adiabatic and nonadiabatic small polaronic hopping
Authors: Wang Weiyuan , Fan Jiyu , Zheng Huan , Wang Jing , Liu Hao , Wang Caixia , Ma Chunlan , Ling Langsheng , Xu Jingtao , Yang Hao 
Published: June 2021

We have presented the structural, surface morphology, magnetic and resistivity data for perovskite LaMnO3 epitaxial thin films which are fabricated on well-oriented (001) LaAlO3 substrates by pulsed laser deposition technique. X-ray diffraction [Formula: see text]–[Formula: see text] linear scans and reciprocal space mapping measurement confirm that the out-of-plane and in-plane epitaxial relationship are LMO(001)/LAO(001) and LMO(110)/LAO(110), respectively. Surface roughness determined by atomic force microscopy was no more than 0.3 nm. In the whole studied temperature range, all films only show a paramagnetic behavior instead of any magnetic phase transitions. Correspondingly, the electron transport behaviors always exhibit an insulting state as the temperature changes from high to low. However, we find that none of theoretical models can individually be used to understand their conductive mechanisms. Further studies indicated that charge carries of high and low temperature region obey adiabatic and nonadiabatic small polaronic hopping mechanisms, respectively. This finding offers new ways of exploiting the abnormal ferromagnetism in LaMnO3 multilayer thin films.
Bidirectional Cross-talk between MAOA and AR Promotes Hormone-Dependent and Castration-Resistant Prostate Cancer
Authors: Wei Jing , Yin Lijuan , Li Jingjing , Wang Jing , Pu Tianjie , Duan Peng , Lin Tzu-Ping , Gao Allen C. , Wu Boyang Jason 
Published: June 2021

Abstract

Androgen receptor (AR) is the primary oncogenic driver of prostate cancer, including aggressive castration-resistant prostate cancer (CRPC). The molecular mechanisms controlling AR activation in general and AR reactivation in CRPC remain elusive. Here we report that monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, reciprocally interacts with AR in prostate cancer. MAOA was induced by androgens through direct AR binding to a novel intronic androgen response element of the MAOA gene, which in turn promoted AR transcriptional activity via upregulation of Shh/Gli-YAP1 signaling to enhance nuclear YAP1–AR interactions. Silencing MAOA suppressed AR-mediated prostate cancer development and growth, including CRPC, in mice. MAOA expression was elevated and positively associated with AR and YAP1 in human CRPC. Finally, genetic or pharmacologic targeting of MAOA enhanced the growth-inhibition efficacy of enzalutamide, darolutamide, and apalutamide in both androgen-dependent and CRPC cells. Collectively, these findings identify and characterize an MAOA–AR reciprocal regulatory circuit with coamplified effects in prostate cancer. Moreover, they suggest that cotargeting this complex may be a viable therapeutic strategy to treat prostate cancer and CRPC.

Significance:
MAOA and AR comprise a positive feedback loop in androgen-dependent and CRPC, providing a mechanistic rationale for combining MAOA inhibition with AR-targeted therapies for prostate cancer treatment.
A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes
Authors: Calagua Carla , Ficial Miriam , Jansen Caroline S. , Hirz Taghreed , del Balzo Luke , Wilkinson Scott , Lake Ross , Ku Anson T. , Voznesensky Olga , Sykes David B. , Saylor Philip J. , Ye Huihui , Signoretti Sabina , Kissick Haydn , Sowalsky Adam G. , Balk Steven P. , Einstein David J. 
Published: June 2021

Abstract

Purpose:
A subset of primary prostate cancer expresses programmed death-ligand 1 (PD-L1), but whether they have a unique tumor immune microenvironment or genomic features is unclear.

Experimental Design:
We selected PD-L1–positive high-grade and/or high-risk primary prostate cancer, characterized tumor-infiltrating lymphocytes with multiplex immunofluorescence, and identified genomic alterations in immunogenic and nonimmunogenic tumor foci.

Results:
One quarter of aggressive localized prostate cancer cases (29/115) had tumor PD-L1 expression more than 5%. This correlated with increased density of CD8+ T cells, a large fraction coexpressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8+PD-1+ cells did not express terminal exhaustion markers (TIM3 or LAG3), while a subset expressed TCF1. Consistent with these CD8+PD-1+TCF1+ cells being progenitors, they were found in antigen-presenting cell niches in close proximity to MHC-II+ cells. CD8 T-cell density in immunogenic prostate cancer and renal cell carcinoma (RCC) was nearly identical. Shallow RB1 and BRCA2 losses, and deep deletions of CHD1, were prevalent, the latter being strongly associated with a dendritic cell gene set in The Cancer Genome Atlas. Tumor mutation burden was variable; neither high microsatellite instability nor CDK12 alterations were present.

Conclusions:
A subset of localized prostate cancer is immunogenic, manifested by PD-L1 expression and CD8+ T-cell content comparable with RCC. The CD8+ T cells include effector cells and exhausted progenitor cells, which may be expanded by immune checkpoint inhibitors (ICI). Genomic losses of RB1, BRCA2, and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of patients with localized prostate cancer.
RASAL2 Confers Collateral MEK/EGFR Dependency in Chemoresistant Triple-Negative Breast Cancer
Authors: Koh Siang-Boon , Ross Kenneth , Isakoff Steven J. , Melkonjan Nsan , He Lei , Matissek Karina J. , Schultz Andrew , Mayer Erica L. , Traina Tiffany A. , Carey Lisa A. , Rugo Hope S. , Liu Minetta C. , Stearns Vered , Langenbucher Adam , Saladi Srinivas Vinod , Ramaswamy Sridhar , Lawrence Michael S. , Ellisen Leif W. 
Published: June 2021

Abstract

Purpose:
While chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC), identifying and managing chemoresistant tumors has proven elusive. We sought to discover hallmarks and therapeutically actionable features of refractory TNBC through molecular analysis of primary chemoresistant TNBC specimens.

Experimental Design:
We performed transcriptional profiling of tumors from a phase II clinical trial of platinum chemotherapy for advanced TNBC (TBCRC-009), revealing a gene expression signature that identified de novo chemorefractory tumors. We then employed pharmacogenomic data mining, proteomic and other molecular studies to define the therapeutic vulnerabilities of these tumors.

Results:
We reveal the RAS-GTPase-activating protein (RAS-GAP) RASAL2 as an upregulated factor that mediates chemotherapy resistance but also an exquisite collateral sensitivity to combination MAP kinase kinase (MEK1/2) and EGFR inhibitors in TNBC. Mechanistically, RASAL2 GAP activity is required to confer kinase inhibitor sensitivity, as RASAL2-high TNBCs sustain basal RAS activity through suppression of negative feedback regulators SPRY1/2, together with EGFR upregulation. Consequently, RASAL2 expression results in failed feedback compensation upon co-inhibition of MEK1/2 and EGFR that induces synergistic apoptosis in vitro and in vivo. In patients with TNBC, high RASAL2 levels predict clinical chemotherapy response and long-term outcomes, and are associated via direct transcriptional regulation with activated oncogenic Yes-Associated Protein (YAP). Accordingly, chemorefractory patient-derived TNBC models exhibit YAP activation, high RASAL2 expression, and tumor regression in response to MEK/EGFR inhibitor combinations despite well-tolerated intermittent dosing.

Conclusions:
These findings identify RASAL2 as a mediator of TNBC chemoresistance that rewires MAPK feedback and cross-talk to confer profound collateral sensitivity to combination MEK1/2 and EGFR inhibitors.
Identification and Validation of T-cell Receptors TargetingRASHotspot Mutations in Human Cancers for Use in Cell-based Immunotherapy
Authors: Levin Noam , Paria Biman C. , Vale Nolan R. , Yossef Rami , Lowery Frank J. , Parkhurst Maria R. , Yu Zhiya , Florentin Maria , Cafri Gal , Gartner Jared J. , Shindorf Mackenzie L. , Ngo Lien T. , Ray Satyajit , Kim Sanghyun P. , Copeland Amy R. , Robbins Paul F. , Rosenberg Steven A. 
Published: June 2021

AbstractPurpose:Immunotherapies mediate the regression of human tumors through recognition of tumor antigens by immune cells that trigger an immune response. Mutations in the RAS oncogenes occur in about 30% of all patients with cancer. These mutations play an important role in both tumor establishment and survival and are commonly found in hotspots. Discovering T-cell receptors (TCR) that recognize shared mutated RAS antigens presented on MHC class I and class II molecules are thus promising reagents for “off-the-shelf” adoptive cell therapies (ACT) following insertion of the TCRs into lymphocytes.Experimental Design:In this ongoing work, we screened for RAS antigen recognition in tumor-infiltrating lymphocytes (TIL) or by in vitro stimulation of peripheral blood lymphocytes (PBL). TCRs recognizing mutated RAS were identified from the reactive T cells. The TCRs were then reconstructed and virally transduced into PBLs and tested.Results:Here, we detect and report multiple novel TCR sequences that recognize nonsynonymous mutant RAS hotspot mutations with high avidity and specificity and identify the specific class-I and -II MHC restriction elements involved in the recognition of mutant RAS.Conclusions:The TCR library directed against RAS hotspot mutations described here recognize RAS mutations found in about 45% of the Caucasian population and about 60% of the Asian population and represent promising reagents for “off-the-shelf” ACTs.
Endothelial Recovery in Bare Metal Stents and Drug-Eluting Stents on a Single-Cell Level
Authors: Cornelissen Anne , Guo Liang , Fernandez Raquel , Kelly Michael C. , Janifer Christine , Kuntz Salome , Sakamoto Atsushi , Jinnouchi Hiroyuki , Sato Yu , Paek Ka Hyun , Kolodgie Frank D. , Romero Maria E. , Surve Dipti , Virmani Renu , Finn Aloke V. 
Published: June 2021

Objective:
Healing processes, particularly reendothelialization, are essential for vascular homeostasis after plain old balloon angioplasty and stent implantation. Drug-eluting stents (DES) are commonly used for percutaneous coronary intervention because restenosis rates are reduced as compared with bare metal stents (BMS). However, in addition to understanding the nature of regenerated endothelial cells, concerns over incomplete stent healing persist, and the molecular effects of antiproliferative drug coatings on endothelium remain poorly understood.

Approach and Results:
We used the rabbit iliac artery model to analyze differences in stent endothelialization in BMS and DES. Histology and immunohistochemistry confirmed that stent coverage was significantly greater in BMS than in DES at 30 days after stent implantation. Single-cell RNA sequencing revealed a more immature transcriptomic signature of neointimal endothelial cell harvested from stented arteries in comparison with native and plain old balloon angioplasty–treated arteries. Whereas the genetic signature of BMS was overall proangiogenic with enrichment of genes involved in endothelial proliferation, sprouting, and migration, as well as extracellular matrix assembly, DES-derived endothelial cell showed upregulation of genes associated with angiogenesis inhibition and endothelial activation.

Conclusions:
Single-cell RNA sequencing analysis identified unique transcriptional changes within regenerated endothelium after plain old balloon angioplasty and stent implantation. These data suggest unique endothelial transcriptional differences, which characterize the different response of the endothelium to vascular injury and may help explain why long-term responses in DES remain suboptimal.
Smooth Muscle Overexpression of PGC1α Attenuates Atherosclerosis in Rabbits
Authors: Wei Zhe , Chong Hoshun , Jiang Qixia , Tang Yuhang , Xu Jinhong , Wang Haoquan , Shi Yanteng , Cui Le , Li Jing , Zhang Yujing , Xue Yunxing , Li Jutang , Liu George , Chen Xi , Wang Dongjin , Zhang Chen-Yu , Jiang Xiaohong 
Published: June 2021

Rationale:
Targeting vascular smooth muscle cell (VSMC) phenotypic switching is a promising therapeutic approach for atherosclerosis. Dysregulation of PGC1α (peroxisome proliferator-activated receptor gamma, coactivator 1α), a key regulator of cellular energy metabolism, has been implicated in the pathogenesis of atherosclerosis, yet its role in atherosclerosis remains controversial.

Objective:
The current study aimed to determine whether and how PGC1α in VSMCs regulates atherosclerosis progression.

Methods and Results:
We generated transgenic rabbits with SMC-specific PGC1α overexpression and showed that these rabbits developed significantly less aortic atherosclerosis than their nontransgenic littermates after high-cholesterol diet feeding, while total plasma cholesterol levels were similar. As indicated by the restored expression of VSMC differentiation marker genes, the high-cholesterol diet-induced phenotypic switching in the aortic media was largely reversed in transgenic rabbits, accompanied by decreased levels of synthetic phenotype genes, proinflammatory cytokines, adhesion molecules, macrophage infiltration, MMPs (matrix metalloproteinases), reactive oxygen species production and senescence. Ex vivo studies further showed that VSMC-specific PGC1α overexpression markedly suppressed the promotive effect of high-cholesterol diet feeding on the association of SRF (serum response factor) with ELK1 (ETS transcription factor ELK1), a TCF (ternary complex factor) that acts as a myogenic repressor in VSMCs, thereby preserving the VSMC contractile phenotype. Furthermore, knockdown of PGC1α remarkably increased ERK (extracellular signal-regulated kinase)1/2-ELK-1 signaling, which promoted phenotypic switching and proliferation of cultured rabbit VSMCs. In addition, we showed that PGC1α can regulate EGFR (epidermal growth factor receptor)-ERK1/2 MAPK (mitogen-activated protein kinase) signaling via modulating PPARγ (peroxisome proliferator-activated receptor γ) activity in RVSMCs (rabbit vascular smooth muscle cells). Finally, we showed that these beneficial results of SMC-specific PGC1α overexpression can be extrapolated from rabbits to human VSMCs and clinical settings.

Conclusions:
We demonstrated a critical role of PGC1α in maintaining the contractile phenotype of VSMCs and highlighted the therapeutic potential of PGC1α for atherosclerosis.
Unveiling Complexity and Multipotentiality of Early Heart Fields
Authors: Zhang Qingquan , Carlin Daniel , Zhu Fugui , Cattaneo Paola , Ideker Trey , Evans Sylvia M. , Bloomekatz Joshua , Chi Neil C. 
Published: June 2021

Rationale:
Extraembryonic tissues, including the yolk sac and placenta, and the heart within the embryo, work to provide crucial nutrients to the embryo. The association of congenital heart defects with extraembryonic tissue defects further supports the potential developmental relationship between the heart and extraembryonic tissues. Although the development of early cardiac lineages has been well-studied, the developmental relationship between cardiac lineages, including epicardium, and extraembryonic mesoderm remains to be defined.

Objective:
To explore the developmental relationships between cardiac and extraembryonic lineages.

Methods and Results:
Through high-resolution single-cell and genetic lineage/clonal analyses, we show an unsuspected clonal relationship between extraembryonic mesoderm and cardiac lineages. Single-cell transcriptomics and trajectory analyses uncovered 2 mesodermal progenitor sources contributing to left ventricular cardiomyocytes, 1 embryonic and the other with an extraembryonic gene expression signature. Additional lineage-tracing studies revealed that the extraembryonic-related progenitors reside at the embryonic/extraembryonic interface in gastrulating embryos and produce distinct cell types forming the pericardium, septum transversum, epicardium, dorsolateral regions of the left ventricle and atrioventricular canal myocardium, and extraembryonic mesoderm. Clonal analyses demonstrated that these progenitors are multipotent, giving rise to not only cardiomyocytes and serosal mesothelial cell types but also, remarkably, extraembryonic mesoderm.

Conclusions:
Overall, our results reveal the location of previously unknown multipotent cardiovascular progenitors at the embryonic/extraembryonic interface and define the earliest embryonic origins of serosal mesothelial lineages, including the epicardium, which contributes fibroblasts and vascular support cells to the heart. The shared lineage relationship between embryonic cardiovascular lineages and extraembryonic mesoderm revealed by our studies underscores an underappreciated blurring of boundaries between embryonic and extraembryonic mesoderm. Our findings suggest unexpected underpinnings of the association between congenital heart disease and placental insufficiency anomalies and the potential utility of extraembryonic cells for generating cardiovascular cell types for heart repair.
Time to Evacuation and Functional Outcome After Minimally Invasive Endoscopic Intracerebral Hemorrhage Evacuation
Authors: Kellner Christopher P. , Song Rui , Ali Muhammad , Nistal Dominic A. , Samarage Milan , Dangayach Neha S. , Liang John , McNeill Ian , Zhang Xiangnan , Bederson Joshua B. , Mocco J 
Published: June 2021

Background and Purpose:
We present a retrospective analysis of patients who underwent minimally invasive endoscopic intracerebral hemorrhage (ICH) evacuation to identify variables that were associated with long-term outcome.

Methods:

Minimally invasive endoscopic ICH evacuation was performed on patients with supratentorial ICH who fit prespecified clinical inclusion and exclusion criteria. Demographic, clinical, and radiographic factors previously demonstrated to impact functional outcome in ICH were included in a univariate analysis to identify factors associated with favorable outcome (modified Rankin Scale score, 0–3) at 6 months. Factors associated with a favorable outcome in the univariate analysis (
P
≤0.20) were included in a multivariate logistic regression analysis with the same dependent variable.

Results:

Ninety patients underwent MIS endoscopic ICH evacuation within 72 hours of ictus. In a multivariate analysis, factors associated with good long-term functional outcome included time to evacuation (per hour; OR, 0.95 [95% CI, 0.92–0.98],
P
=0.004), age (per decade, odds ratio [OR], 0.49 [95% CI, 0.28–0.77],
P
=0.005), presence of intraventricular hemorrhage (OR, 0.15 [95% CI, 0.04–0.47],
P
=0.002), and lobar location (OR, 18.5 [95% CI, 4.5–103],
P
=0.0005). Early evacuation was not associated with an increased risk of rebleeding.

Conclusions:
Young age, lack of intraventricular hemorrhage, lobar location, and time to evacuation were independently associated with good long-term functional outcome in patients undergoing minimally invasive endoscopic ICH evacuation. The OR for time to evacuation suggests that for each additional hour, there was a 5% reduction in the odds of achieving a favorable outcome.