bluuebunny/crossref_metadata_2025 huggingface dataset:
Lentinan protects against pancreatic β‐cell failure in chronic ethanol consumption‐induced diabetic mice via enhancing β‐cell antioxidant capacity
Authors: Wu Tijun , Wang Jiahui , Zhang Yaru , Shao Yixue , Li Xirui , Guo Yuqing , Dong Wenyu , Wang Lin , Chen Fang , Han Xiao
Published: April 2021

Chronic ethanol consumption is a well‐established independent risk factor for type 2 diabetes mellitus (T2DM). Recently, increasing studies have confirmed that excessive heavy ethanol exerts direct harmful effect on pancreatic β‐cell mass and function, which may be a mechanism of pancreatic β‐cell failure in T2DM. In this study, we evaluated the effect of Lentinan (LNT), an active ingredient purified from the bodies of Lentinus edodes, on pancreatic β‐cell apoptosis and dysfunction caused by ethanol and the possible mechanisms implicated. Functional studies reveal that LNT attenuates chronic ethanol consumption‐induced impaired glucose metabolism in vivo. In addition, LNT ameliorates chronic ethanol consumption‐induced β‐cell dysfunction, which is characterized by reduced insulin synthesis, defected insulin secretion and increased cell apoptosis. Furthermore, mechanistic assays suggest that LNT enhances β‐cell antioxidant capacity and ameliorates ethanol‐induced oxidative stress by activating Nrf‐2 antioxidant pathway. Our results demonstrated that LNT prevents ethanol‐induced pancreatic β‐cell dysfunction and apoptosis, and therefore may be a potential pharmacological agent for preventing pancreatic β‐cell failure associated with T2DM and stress‐induced diabetes.
CDR1as regulated by hnRNPM maintains stemness of periodontal ligament stem cells via miR‐7/KLF4
Authors: Gu Xiuge , Li Xiaoyu , Jin Ye , Zhang Zijie , Li Mengying , Liu Dongxu , Wei Fulan
Published: April 2021

CDR1as is a well‐identified circular RNA with regulatory roles in a variety of physiological processes. However, the effects of CDR1as on stemness of periodontal ligament stem cells (PDLSCs) and the underlying mechanisms remain unclear. In this study, we detect CDR1as in human PDLSCs, and subsequently demonstrate that CDR1as maintains PDLSC stemness. Knockdown of CDR1as decreases the expression levels of stemness‐related genes and impairs the cell's multi‐differentiation and cell migration abilities, while overexpression of CDR1as increases the expression levels of stemness‐related genes and enhances these abilities. Furthermore, our results indicate that the RNA‐binding protein hnRNPM directly interacts with CDR1as and regulates its expression in PDLSCs. In addition, we show that CDR1as promotes the expression of stemness‐related genes in PDLSCs by inhibiting miR‐7‐mediated suppression of KLF4 expression. Collectively, our results demonstrate that CDR1as participates in the molecular circuitry that regulates PDLSC stemness.
Bicarbonate ion transport by the electrogenic Na+/HCO3− cotransporter, NBCe1, is required for normal electrical slow‐wave activity in mouse small intestine
Authors: Zhao Wenchang , Zhang Liwen , Ermilov Leonid G. , Colmenares Aguilar Maria Gabriela , Linden David R. , Eisenman Seth T. , Romero Michael F. , Farrugia Gianrico , Sha Lei , Gibbons Simon J.
Published: April 2021

Background

Normal gastrointestinal motility depends on electrical slow‐wave activity generated by interstitial cells of Cajal (ICC) in the tunica muscularis of the gastrointestinal tract. A requirement for HCO3− in extracellular solutions used to record slow waves indicates a role for HCO3− transport in ICC pacemaking. The Slc4a4 gene transcript encoding the electrogenic Na+/HCO3− cotransporter, NBCe1, is enriched in mouse small intestinal myenteric region ICC (ICC‐MY) that generate slow waves. This study aimed to determine how extracellular HCO3− concentrations affect electrical activity in mouse small intestine and to determine the contribution of NBCe1 activity to these effects.

Methods

Immunohistochemistry and sharp electrode electrical recordings were used.

Key Results

The NBCe1 immunoreactivity was localized to ICC‐MY of the tunica muscularis. In sharp electrode electrical recordings, removal of HCO3‐ from extracellular solutions caused significant, reversible, depolarization of the smooth muscle and a reduction in slow‐wave amplitude and frequency. In 100 mM HCO3−, the muscle hyperpolarized and slow wave amplitude and frequency increased. The effects of replacing extracellular Na+ with Li+, an ion that does not support NBCe1 activity, were similar to, but larger than, the effects of removing HCO3‐. There were no additional changes to electrical activity when HCO3‐ was removed from Li+ containing solutions. The Na+/HCO3− cotransport inhibitor, S‐0859 (30µM) significantly reduced the effect of removing HCO3− on electrical activity.

Conclusions & Inferences

These studies demonstrate a major role for Na+/HCO3− cotransport by NBCe1 in electrical activity of mouse small intestine and indicated that regulation of intracellular acid:base homeostasis contributes to generation of normal pacemaker activity in the gastrointestinal tract.
Raffinose accumulation and preferential allocation of carbon (14C) to developing leaves impart salinity tolerance in sugar beet
Authors: Naguib Wassem B. , Divte Pandurang R. , Chandra Amaresh , Sathee Lekshmy , Singh Bhupinder , Mandal Pranab Kumar , Anand Anjali
Published: April 2021

Sugar beet is a salt‐tolerant crop that can be explored for crop production in degraded saline soils. Seeds of multigerm genotypes LKC‐2006 (susceptible) and LKC‐HB (tolerant) were grown in 150 mM NaCl, from germination to 60 days after sowing, to decipher the mechanism of salinity tolerance at the vegetative stage. The biomass of the root and leaf were maintained in the tolerant genotype, LKC‐HB, under saline conditions. Na+/K+ ratios were similar in roots and leaves of LKC‐HB, with lower values under salinity compared to LKC 2006. Infrared temperatures were 0.96°C lower in LKC‐HB than in LKC‐2006, which helped regulate the leaf water status under stressed conditions. Pulse‐chase experiment showed that 14C photosynthate was preferentially allocated towards the development of new leaves in the tolerant genotype. The sugar profile of leaves and roots showed accumulation of raffinose in leaves of LKC‐HB, indicating a plausible role in imparting salinity tolerance by serving as an osmolyte or scavenger. The molecular analysis of the genes responsible for raffinose synthesis revealed an 18‐fold increase in the expression of BvRS2 in the tolerant genotype, suggesting its involvement in raffinose synthesis. Our study accentuated that raffinose accumulation in leaves is vital for inducing salinity tolerance and maintenance of shoot dry weight in sugar beet.
Enhancers as potential targets for engineering salinity stress tolerance in crop plants
Authors: Jain Mukesh , Garg Rohini
Published: April 2021

Enhancers represent noncoding regulatory regions of the genome located distantly from their target genes. They regulate gene expression programs in a context‐specific manner via interacting with promoters of one or more target genes and are generally associated with transcription factor binding sites and epi(genomic)/chromatin features, such as regions of chromatin accessibility and histone modifications. The enhancers are difficult to identify due to the modularity of their associated features. Although enhancers have been studied extensively in human and animals, only a handful of them has been identified in few plant species till date due to nonavailability of plant‐specific experimental and computational approaches for their discovery. Being an important regulatory component of the genome, enhancers represent potential targets for engineering agronomic traits, including salinity stress tolerance in plants. Here, we provide a review of the available experimental and computational approaches along with the associated sequence and chromatin/epigenetic features for the discovery of enhancers in plants. In addition, we provide insights into the challenges and future prospects of enhancer research in plant biology with emphasis on potential applications in engineering salinity stress tolerance in crop plants.
Functional and molecular adaptations of quadriceps and hamstring muscles to blood flow restricted training in patients with ACL rupture
Authors: Kacin Alan , Drobnič Matej , Marš Tomaž , Miš Katarina , Petrič Maja , Weber Daša , Tomc Žargi Tina , Martinčič David , Pirkmajer Sergej
Published: April 2021

Effects of low‐load blood flow restricted (LL‐BFR) training remain unexplored in patients with ACL rupture. Our hypothesis was that LL‐BFR training triggers augmented gains in knee muscle strength and size, which are paralleled with transcriptional responses of hypoxia‐regulated genes and myokines. Eighteen volunteers (age 37.5 ± 9 years) planned for ACL reconstruction, participated in the study. Twelve were divided between BFR group, performing 9 sessions of LL‐BFR exercise, and SHAM‐BFR group performing equal training with sham vascular occlusion. Six subjects served as a control for muscle biopsy analysis. Cross‐sectional area (CSA) and isokinetic strength of knee muscles were assessed before and after the training. Change in CSAquad was significantly (p < 0.01) larger in BFR (4.9%) compared with SHAM‐BFR (1.3%). Similarly, change in peak torque of knee extensors was significantly (p < 0.05) larger in BFR (14%) compared with SHAM‐BFR (−1%). The decrease in fatigue index of knee extensors (6%) was larger (p < 0.01) in BFR than in SHAM‐BFR (2%). mRNA expression of HIF‐1α in the vastus lateralis was reduced (p < 0.05) in SHAM‐BFR, while VEGF‐A mRNA tended to be higher in BFR. The mRNA expression of myostatin and its receptor were reduced (p < 0.05) in the semitendinosus after both types of training. Expression of IL‐6, its receptors IL‐6Rα and gp130, as well as musclin were similar in control and training groups. In conclusion, our results show augmented strength and endurance of knee extensors but less of the flexors. LL‐BFR training is especially effective for conditioning of knee extensors in this population.
Social norms, social identities and the COVID‐19 pandemic: Theory and recommendations
Authors: Neville Fergus G. , Templeton Anne , Smith Joanne R. , Louis Winnifred R.
Published: April 2021

Sustained mass behaviour change is needed to tackle the COVID‐19 pandemic, but many of the required changes run contrary to existing social norms (e.g., physical closeness with in‐group members). This paper explains how social norms and social identities are critical to explaining and changing public behaviour. Recommendations are presented for how to harness these social processes to maximise adherence to COVID‐19 public health guidance. Specifically, we recommend that public health messages clearly define who the target group is, are framed as identity‐affirming rather than identity‐contradictory, include complementary injunctive and descriptive social norm information, are delivered by in‐group members and that support is provided to enable the public to perform the requested behaviours.
Negative modulation of SA signaling components by the capsid protein of tobacco mosaic virus is required for viral long‐distance movement
Authors: Venturuzzi Andrea Laura , Rodriguez Maria Cecilia , Conti Gabriela , Leone Melisa , Caro Maria Del Pilar , Montecchia Juan Francisco , Zavallo Diego , Asurmendi Sebastian
Published: April 2021

An important aspect of plant–virus interaction is the way viruses dynamically move over long distances and how plant immunity modulates viral systemic movement. Salicylic acid (SA), a well‐characterized hormone responsible for immune responses against virus, is activated through different transcription factors including TGA and WRKY. In tobamoviruses, evidence suggests that capsid protein (CP) is required for long‐distance movement, although its precise role has not been fully characterized yet. Previously, we showed that the CP of Tobacco Mosaic Virus (TMV)‐Cg negatively modulates the SA‐mediated defense. In this study, we analyzed the impact of SA‐defense mechanism on the long‐distance transport of a truncated version of TMV (TMV ∆CP virus) that cannot move to systemic tissues. The study showed that the negative modulation of NPR1 and TGA10 factors allows the long‐distance transport of TMV ∆CP virus. Moreover, we observed that the stabilization of DELLA proteins promotes TMV ∆CP systemic movement. We also characterized a group of genes, part of a network modulated by CP, involved in TMV ∆CP long‐distance transport. Altogether, our results indicate that CP‐mediated downregulation of SA signaling pathway is required for the virus systemic movement, and this role of CP may be linked to its ability to stabilize DELLA proteins.
Spatial patterning of scent in petunia corolla is discriminated by bees and involves the ABCG1 transporter
Authors: Skaliter Oded , Kitsberg Yaarit , Sharon Elad , Shklarman Elena , Shor Ekaterina , Masci Tania , Yue Yuling , Arien Yael , Tabach Yuval , Shafir Sharoni , Vainstein Alexander
Published: April 2021

Floral guides are patterned cues that direct the pollinator to the plant reproductive organs. The spatial distribution of showy visual and olfactory traits allows efficient plant–pollinator interactions. Data on the mechanisms underlying floral volatile patterns or their interactions with pollinators are lacking. Here we characterize the spatial emission patterns of volatiles from the corolla of the model plant Petunia × hybrida and reveal the ability of honeybees to distinguish these patterns. Along the adaxial epidermis, in correlation with cell density, the petal base adjacent to reproductive organs emitted significantly higher levels of volatiles than the distal petal rim. Volatile emission could also be differentiated between the two epidermal surfaces: emission from the adaxial side was significantly higher than that from the abaxial side. Similar emission patterns were also observed in other petunias, Dianthus caryophyllus (carnation) and Argyranthemum frutescens (Marguerite daisy). Analyses of transcripts involved in volatile production/emission revealed lower levels of the plasma‐membrane transporter ABCG1 in the abaxial versus adaxial epidermis. Transient overexpression of ABCG1 enhanced emission from the abaxial epidermis to the level of the adaxial epidermis, suggesting its involvement in spatial emission patterns in the epidermal layers. Proboscis extension response experiments showed that differences in emission levels along the adaxial epidermis, that is, petal base versus rim, detected by GC‐MS are also discernible by honeybees.
Plant genomics in Africa: present and prospects
Authors: Ghazal Hassan , Adam Yagoub , Idrissi Azami Abdellah , Sehli Sofia , Nyarko Hannah N. , Chaouni Bouchra , Olasehinde Grace , Isewon Itunuoluwa , Adebiyi Marion , Ajani Olayinka , Matovu Enock , Obembe Olawole , Ajamma Yvonne , Kuzamunu Gaston , Pandam Salifu Samson , Kayondo Jonathan , Benkahla Alia , Adebiyi Ezekiel
Published: April 2021

Plants are the world’s most consumed goods. They are of high economic value and bring many health benefits. In most countries in Africa, the supply and quality of food will rise to meet the growing population’s increasing demand. Genomics and other biotechnology tools offer the opportunity to improve subsistence crops and medicinal herbs in the continent. Significant advances have been made in plant genomics, which have enhanced our knowledge of the molecular processes underlying both plant quality and yield. The sequencing of complex genomes of African plant species, facilitated by the continuously evolving next‐generation sequencing technologies and advanced bioinformatics approaches, has provided new opportunities for crop improvement. This review summarizes the achievements of genome sequencing projects of endemic African plants in the last two decades. We also present perspectives and challenges for future plant genomic studies that will accelerate important plant breeding programs for African communities. These challenges include a lack of basic facilities, a lack of sequencing and bioinformatics facilities, and a lack of skills to design genomics studies. However, it is imperative to state that African countries have become key players in the plant genome revolution and genome derived‐biotechnology. Therefore, African governments should invest in public plant genomics research and applications, establish bioinformatics platforms and training programs, and stimulate university and industry partnerships to fully deploy plant genomics, particularly in the fields of agriculture and medicine.
Contributions to $$ZZV^*$$ ($$V=\gamma ,Z,Z'$$) couplings from CP violating flavor changing couplings
Authors: Hernández-Juárez A. I. , Moyotl A. , Tavares-Velasco G.
Published: April 2021

The one-loop contributions to the trilinear neutral gauge boson couplings $$ZZV^*$$

Z
Z

V
∗

($$V=\gamma ,Z,Z'$$

V
=
γ
,
Z
,

Z
′

), parametrized in terms of one CP-conserving $$f_5^{V}$$

f
5
V

and one CP-violating $$f_4^{V}$$

f
4
V

form factors, are calculated in models with CP-violating flavor changing neutral current couplings mediated by the Z gauge boson and an extra neutral gauge boson $$Z'$$

Z
′

. Analytical results are presented in terms of Passarino-Veltman scalar functions. Constraints on the vector and axial couplings of the Z gauge boson $$\left| g_{{VZ}}^{tu}\right| < 0.0096$$

g

VZ

tu

<
0.0096

and $$\left| g_{{VZ}}^{tc}\right| <0.011$$

g

VZ

tc

<
0.011

are obtained from the current experimental data on the $$t\rightarrow Z q$$

t
→
Z
q

decays. It is found that in the case of the $$ZZ\gamma ^*$$

Z
Z

γ
∗

vertex the only non-vanishing form factor is $$f_5^{\gamma }$$

f
5
γ

, which can be of the order of $$10^{-3}$$

10

-
3

, whereas for the $$ZZZ^*$$

Z
Z

Z
∗

vertex both form factors $$f_5^{Z}$$

f
5
Z

and $$f_4^{Z}$$

f
4
Z

are non-vanishing and can be of the order of $$10^{-6}$$

10

-
6

and $$10^{-5}$$

10

-
5

, respectively. Our estimates for $$f_5^{\gamma }$$

f
5
γ

and $$f_5^{Z}$$

f
5
Z

are smaller than those predicted by the standard model, where $$f_4^{Z}$$

f
4
Z

is absent up to the one loop level. We also estimate the $$ZZ{Z'}^{*}$$

Z
Z

Z
′

∗

form factors arising from both diagonal and non-diagonal $$Z'$$

Z
′

couplings within a few extension models. It is found that in the diagonal case $$f_{5}^{Z'}$$

f

5

Z
′

is the only non-vanishing form factor and its real and imaginary parts can be of the order of $$10^{-1}$$

10

-
1

–$$10^{-2}$$

10

-
2

and $$ 10^{-2}$$

10

-
2

–$$10^{-3}$$

10

-
3

, respectively, with the dominant contributions arising from the light quarks and leptons. In the non-diagonal case $$f_{5}^{Z^\prime }$$

f

5

Z
′

can be of the order of $$10^{-4}$$

10

-
4

, whereas $$f_4^{Z'}$$

f
4

Z
′

can reach values as large as $$10^{-7}$$

10

-
7

–$$10^{-8}$$

10

-
8

, with the largest contributions arising from the $$Z'tq$$

Z
′

t
q

couplings.
Genetically generated ASCII trees
Authors: Pugh Alec
Published: April 2021

This project, inspired by the article: "On genetic algorithms and Lindenmayer systems" by Gabriela Ochoa, implements an ASCII tree-generation program using L-systems.
Results on Complex Partial b-Metric Space with an Application
Authors: Mani Gunaseelan , Gnanaprakasam Arul Joseph , Kalaichelvan Ramakrishnan , Gaba Yaé Ulrich
Published: April 2021

In this paper, we prove a fixed point theorem in complex partial

b

-metric space under new contraction mapping. The proved results generalize and extend some of the well-known results in the literature. We also give some applications of our main results.
High Serum Alkaline Phosphatase Flare after First-Line Androgen Deprivation Therapy Predicts Poor Prognosis in Metastatic Prostate Cancer Patients Treated with Second-Generation Androgen Receptor Targeted Therapy
Authors: Kojima Satoko , Masuda Hiroshi , Suyama Takahito , Hou Kyokushin , Mikami Kousuke , Araki Kazuhiro , Naya Yukio
Published: April 2021

Objectives. To determine whether an alkaline phosphatase (ALP) flare after androgen deprivation therapy (ADT) is associated with the treatment response in castration-resistant prostate cancer (CRPC) and predicts the prognosis of metastatic prostate cancer (PCa) patients. Methods. One hundred and nineteen patients diagnosed with metastatic PCa between 2008 and 2017 were retrospectively studied. The ALP flare ratio was calculated as the ratio of ALP levels 1 month after beginning ADT to ALP levels at diagnosis. The association of the ALP flare ratio with the prostate-specific antigen (PSA) response to CRPC treatment (second-generation androgen receptor targeted therapy (ART) or docetaxel), time to CRPC, and overall survival (OS) were investigated. Results. The time to CRPC and OS was significantly longer in patients with an ALP flare ratio less than 1.33 compared to a ratio more than 1.33. No difference in PSA response was seen regarding the ALP flare ratio in both ART and docetaxel treatment. Second-generation ART-treated patients with a low ALP flare ratio showed longer OS than those with a higher ALP flare ratio (

p
=
0.0367

). However, no difference was seen between a high and low ALP flare ratio (

p
=
0.8054

) in docetaxel-treated patients. The ALP flare ratio was the most significant prognostic factor for OS (

p
<
0.0001

). Conclusions. A higher ALP flare ratio after first-line ADT was a significant prognostic factor in metastatic PCa, especially in patients treated with second-generation ART for CRPC. Chemotherapy for patients with a higher ALP flare ratio 1 month after induction of ADT may be a clinically relevant decision.
Automorphism Group and Other Properties of Zero Component Graph over a Vector Space
Authors: Ou Shikun , Fan Yanqi , Li Qunfang
Published: April 2021

In this paper, we introduce an undirected simple graph, called the zero component graph on finite-dimensional vector spaces. It is shown that two finite-dimensional vector spaces are isomorphic if and only if their zero component graphs are isomorphic, and any automorphism of a zero component graph can be uniquely decomposed into the product of a permutation automorphism and a regular automorphism. Moreover, we find the dominating number, as well as the independent number, and characterize the minimum independent dominating sets, maximum independent sets, and planarity of the graph. In the case that base fields are finite, we calculate the fixing number and metric dimension of the zero component graphs and determine vector spaces whose zero component graphs are Hamiltonian.
Higher Frequency of Undetected Acute Coronary Syndrome in Elderly Patients with Chest Pain Who Visited the Emergency Department: A Large‐Cohort Retrospective Study
Authors: Hong Ki Hun , Bae Sung Jin , Lee Dong Hoon , Lee Choung Ah. , Park Sang Hyun , Kim Duk Ho , Kim Eui Chung , Lim Jee Yong , Han Sangsoo , Choi Yoon Hee
Published: April 2021

Background. Acute coronary syndrome (ACS) is a critical disease encountered in the emergency department (ED). Despite the development of diagnostic tools, it may be difficult to diagnose ACS because of atypical symptoms and equivocal test results. We investigated the difference in the rates of revisit and undetected ACS between adult and elderly patients who visited the ED with chest pain. Method. Data from 11,323 patients who visited the ED with chest pain at university hospitals in Korea were retrospectively analyzed. The cohort was categorized into two age groups: the adult (30–64 years) and elderly (>65 years). Baseline characteristic data (age, sex, vital signs, triage category, etc.) were obtained. We selected patients who revisited the ED within 30 d and investigated whether ACS was diagnosed. Result. The revisit rate was higher in the elderly (12%) than in the adult group (8.3%). The rate of undetected ACS among the revisited patients was 2.91% (18/7,186) in adults and 6.08% (16/1,998) in elderly patients. Conclusion. Elderly patients with chest pain had an increased rate of ED revisits and undetected ACS than adult patients. We recommend that old patients should be hospitalized to observe the progression of cardiac complaints or receive short‐term follow‐up.
Treatment of Miller I Mandibular Gingival Recessions Using PRF vs. Connective Graft
Authors: Garzon Hernan S. , Alfonso Camilo , Vega Francisco J. , García Andrea , Muñoz Ana , Jaimes Gustavo , Isaza Katherine , Rivera Katherine
Published: April 2021

Gingival recession (GR) can cause aesthetic and functional problems. Using connective tissue graft (CTG) and coronally advanced flap (CAF) is considered the technique of choice for treating GR. Considering the morbidity resulting from taking CTG, different alternative biomaterials have been described, including plasma-rich fibrin (PRF) membrane. Studies in lower teeth are few because of the complexity of the factors that can influence obtaining less predictable outcomes. Objective. To compare between CAF + PRF and CAF + CTG in the treatment of lower teeth Miller I gingival recession. Methodology. Split-mouth included 26 isolated GR (13 in each side of the mouth). The left side was treated with CAF + PRF and the right side with CAF + CTG. Clinical variables, probing depth (PD), GR, keratinized tissue (KT), vestibular soft tissue thickness (VSTT), and teeth sensitivity (TS), were assessed at the baseline. GR, KT, VSTT, extraoral inflammation (EI), and patient discomfort (PaD) were assessed at 45 days. Results. Statistically greater VSTT at 45 days was obtained using CAF + CTG (

p

 < 0.05). Less EI and PaD were obtained using CAF + PRF (

p

 < 0.05). No change was observed in GR, KT, and TS values in the intergroup or intragroup comparisons. Conclusion. Even with the limitations of this study, using PRF and CTG in lower teeth demonstrated an improvement in terms of root coverage, although it was without a total percentage of coverage. Regarding the VSTT, better results were obtained using the CTG + CAF, suggesting eventually long-term stable clinical results. We suggest a combined technique for future investigations.
[Retracted] MicroRNA‐4325 Suppresses Cell Progression in Hepatocellular Carcinoma via GATA‐Binding Protein 6
Authors: Huo Xiaoxia , Zhou Houmin , Li Tiantian
Published: April 2021

MicroRNAs (miRs) are regulators of the formation and development of hepatocellular carcinoma (HCC). The biological role of miR‐4325 in HCC has yet to be determined. This study is aimed at dissecting the role of miR‐4325 in HCC and the underlying mechanism. Reverse transcription‐quantitative PCR (RT‐qPCR) was used to detect miR‐4325 expression in HCC tissue specimens and cells. Cell proliferation, migration, and invasion were assessed by using the MTT assay and Transwell assay, respectively. The miR‐4325 target was predicted based on bioinformatics analysis and validated using the dual‐luciferase reporter assay. Rescue experiments in the cells were utilized to functionally characterize the downstream molecular targets of miR‐4325. We observed that miR‐4325 expression levels were significantly reduced in both HCC tissue specimens and cell lines. Meanwhile, a lower miR‐4325 level was associated with a poorer prognosis. Gain and loss of function assays revealed that miR‐4325 markedly downregulated HCC cell growth, migration, and invasion. Moreover, we identified GATA‐binding protein 6 (GATA6) as a miR‐4325 target and found that GATA6 was abnormally expressed in HCC. Rescue assays demonstrated that the regulatory function of miR‐4325 in HCC was mediated by GATA6. Taken together, miR‐4325 suppresses HCC cell growth, migration, and invasion by targeting GATA6, suggesting that miR‐4325 may potentially serve as a novel therapeutic target for HCC.
Relaxant Effects of the Aqueous Extract of Excoecaria grahamii (Euphorbiaceae) Leaves on Uterine Horn Contractility in Wistar Rats
Authors: Dabiré Prosper A. , Ouédraogo Youssoufou , Somé Abel A. , Sawadogo Stanislas , Ouédraogo Issaka , Ilboudo Edith M. , Belemtougri Raymond G.
Published: April 2021

In uterine smooth muscle, the effects of Excoecaria grahamii are not yet documented. To fill this gap, we investigated the pharmacological effect of Excoecaria grahamii on the contraction of the rat isolated uterine horns. The isolated segments were exposed to different concentrations of the aqueous extract of Excoecaria grahamii leaves and pharmacological drugs. The results showed that Excoecaria grahamii aqueous extract decreased the amplitude and frequency by concentration‐related manner. IC50 values were 2.4 and 2.6, respectively, for amplitude and frequency. Our study revealed that the extract did not act through histamine H2‐receptors or the nitric oxide pathway. It also inhibited uterine contractions induced by oxytocin and potassium chloride (KCl). These data suggest that Excoecaria grahamii active compound can be used for calming uterine contractions. The action of Excoecaria grahamii showed that it can be useful to fight against diseases which caused uterotonic effects. It can be useful to prevent preterm birth and pains caused by menstruations but further investigation is needed to clarify the mechanism action.
[Retracted] Analysis of Development Mechanism of Giant Cell Arteritis in Nude Mouse Model through Color Duplex Sonography and Computerized Tomography Nanocontrast Agent
Authors: Chen Fugang , Li Yang , Zhou Hongyan , Sun Chuang , Li Sun , Wang Lu , Li Xin , Liu Xiaoqiang
Published: April 2021

To explore the application value of color duplex sonography and enhanced computerized tomography (CT) inspection based on a nanocontrast agent in diagnosis and pathogenesis in giant cell arteritis (GCA), the GCA nude mouse model was constructed. In this study, 40 healthy male BalB/c nude mice aged 6‐8 weeks were randomly divided into a control group (no model) and an experimental group (model), with 20 mice in each group, and the temporal artery tissue of GCA patients diagnosed as positive by temporal artery biopsy was implanted into nude mice to construct a GCA nude mouse model. Abdominal aortic biopsy and immunohistochemistry were used to verify the success of the GCA nude mouse model. All nude mice were subjected to color duplex sonography and enhanced CT examination based on a nanocontrast agent. At the same time, the basic indicators such as body weight, temperature, white blood cell (WBC), lymphocytes (LYM), hemoglobin (HGB), and platelet (PLT) were measured, and the protein expression levels of interleukin‐6 (IL‐6) and signal transducer and activator of transcription 3 (STAT3) were detected by immunohistochemistry. The results showed that the temporal artery wall of the nude mice in the experimental group thickened and the lumen was significantly narrowed, indicating that the cell arteritis model of nude mice was successfully constructed; ultrasound examination showed that the right superficial temporal artery vascular cavity narrowed, the blood flow signal changed like a filling defect around the periphery, and there was a low echo halo. CT examination showed that the left superficial temporal artery narrowed, and the inner diameter of the narrow segment of blood vessels changed like a bead. The body weight of nude mice in the experimental group decreased significantly after the modeling was completed (P < 0.05); after modeling, the body temperature of the nude mice in the experimental group increased significantly (P < 0.05); LYM and HGB values of nude mice in the experimental group were significantly lower than those in the control group (P < 0.05); the content of IL‐6, STAT3, IL‐6, and STAT3 proteins in the arterial tissue of nude mice in the experimental group was lower than that of the control group (P < 0.05), indicating that color duplex sonography and CT contrast agent technology can be used in the diagnosis and development mechanism research of GC.
An Inventory Model for Perishable Items with Price-, Stock-, and Time-Dependent Demand Rate considering Shelf-Life and Nonlinear Holding Costs
Authors: Macías-López Adrián , Cárdenas-Barrón Leopoldo Eduardo , Peimbert-García Rodrigo E. , Mandal Buddhadev
Published: April 2021

Nowadays, consumers are more health conscious than before, and their demand of fresh items has intensely increased. In this context, an effective and efficient inventory management of the perishable items is needed in order to avoid the relevant losses due to their deterioration. Furthermore, the demand of products is influenced by several factors such as price, stock, and freshness state, among others. Hence, this research work develops an inventory model for perishable items, constrained by both physical and freshness condition degradations. The demand for perishable items is a multivariate function of price, current stock quantity, and freshness condition. Specific to price, six different price-dependent demand functions are used: linear, isoelastic, exponential, logit, logarithmic, and polynomial. By working with perishable items that eventually deteriorate, this inventory model also takes into consideration the expiration date, a salvage value, and the cost of deterioration. In addition, the holding cost is modelled as a quadratic function of time. The proposed inventory model jointly determines the optimal price, the replenishment cycle time, and the order quantity, which together result in maximum total profit per unit of time. The inventory model has a wide application since it can be implemented in several fields such as food goods (milk, vegetables, and meat), organisms, and ornamental flowers, among others. Some numerical examples are presented to illustrate the use of the inventory model. The results show that increasing the value of the shelf-life results in an increment in price, inventory cycle time, quantity ordered, and profits that are generated for all price demand functions. Finally, a sensitivity analysis is performed, and several managerial insights are provided.
Digital‐Twin‐Based Evaluation of Nearly Zero‐Energy Building for Existing Buildings Based on Scan‐to‐BIM
Authors: Zhao Liang , Zhang Hong , Wang Qian , Wang Haining
Published: April 2021

In recent years, the global energy environment has become increasingly severe, and the problems such as global warming, soaring carbon emissions, and excessive use of petrochemical energy have attracted increasing attention from all walks of life. The construction industry, which accounts for about 30% of the total energy consumption, needs to effectively manage and use renewable energy. The application of building information model (BIM) in the evaluation of retrofitting schemes of existing buildings is one of the main research issues in the field of building digital twins at present. The method of this research is to use 3D laser scanning technology to efficiently create the building energy model (BEM) of existing buildings and to identify and evaluate the feasibility of existing building retrofitting schemes. The purpose of this research is to evaluate the retrofitting scheme of existing buildings based on the concept of nearly zero‐energy buildings (nZEBs), aiming to improve the energy efficiency of existing buildings and use clean energy to satisfy building energy demand. According to the case study in this paper, an nZEBs solution suitable for the building can reduce building energy costs by 14.1%, increase solar photovoltaic power generation by 24.13%, and reduce carbon dioxide emissions by 4306.0 kg CO2eq/a.
Risk Factors and a Scoring System to Predict ARDS in Patients with COVID-19 Pneumonia in Korea: A Multicenter Cohort Study
Authors: Seo Jun-Won , Kim Seong Eun , Choi Eun Young , Hong Kyung Soo , Oh Tae Hoon , Kim Uh. Jin , Kang Seung-Ji , Park Kyung-Hwa , Jung Sook-In , Kim Da Young , Yun Na Ra , Kim Dong-Min , Kim Hwa Pyung , Hur Jian , Jang Hee-Chang
Published: April 2021

Predictive studies of acute respiratory distress syndrome (ARDS) in patients with coronavirus disease 2019 (COVID-19) are limited. In this study, the predictors of ARDS were investigated and a score that can predict progression to ARDS in patients with COVID-19 pneumonia was developed. All patients who were diagnosed with COVID-19 pneumonia between February 1, 2020, and May 15, 2020, at five university hospitals in Korea were enrolled. Their demographic, clinical, and epidemiological characteristics and the outcomes were collected using the World Health Organization COVID-19 Case Report Form. A logistic regression analysis was performed to determine the predictors for ARDS. The receiver operating characteristic (ROC) curves were constructed for the scoring model. Of the 166 patients with COVID-19 pneumonia, 37 (22.3%) patients developed ARDS. The areas under the curves for the infiltration on a chest X-ray, C-reactive protein, neutrophil/lymphocyte ratio, and age, for prediction of ARDS were 0.91, 0.90, 0.87, and 0.80, respectively (all

P
<
0.001

). The COVID-19 ARDS Prediction Score (CAPS) was constructed using age (≥60 years old), C-reactive protein (≥5 mg/dL), and the infiltration on a chest X-ray (≥22%), with each predictor allocated 1 point. The area under the curve of COVID-19 ARDS prediction score (CAPS) for prediction of ARDS was 0.90 (95% CI 0.86–0.95;

P
<
0.001

). It provided 100% sensitivity and 75% specificity when the CAPS score cutoff value was 2 points. CAPS, which consists of age, C-reactive protein, and the area of infiltration on a chest X-ray, was predictive of the development of ARDS in patients with COVID-19 pneumonia.
VEGF Contributes to Mesenchymal Stem Cell-Mediated Reversion of Nor1-Dependent Hypertrophy in iPS Cell-Derived Cardiomyocytes
Authors: Philipp Denise , Holthaus Michelle , Basoah Vida , Pfannkuche Kurt , Suhr Laura , Wahlers Thorsten , Paunel-Görgülü Adnana
Published: April 2021

Myocardial hypertrophy is present in many heart diseases, representing a strong predictor of adverse cardiovascular outcomes. Regarding therapeutic intervention, mesenchymal stem cells (MSCs) have been suggested to significantly reduce cardiac hypertrophy and progression to heart failure. Preconditioning of MSCs was previously demonstrated to highly improve their paracrine activity resulting in modulation of immune responses and the progression of diseases. Here, we studied the effects of bone marrow-derived preconditioned MSCs on hypertrophied induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) and also sought to identify MSC-derived antihypertrophic molecules. Phenylephrine (PE) was used to induce hypertrophy in murine iPS-CM, and markers of hypertrophy were identified by microarray analysis. Murine MSCs were treated with IFN-γ and IL-1β to enhance their paracrine activity, and transcriptional profiling was performed by microarray analysis. Hypertrophied iPS-CM were subsequently cocultured with preconditioned MSCs or MSC-conditioned medium (CM), respectively. Effects on hypertrophied iPS-CM were studied by cell area quantification, real-time PCR, and western blot. In some experiments, cells were incubated with fractions of MSC-CM obtained by ultrafiltration or by MSC-CM supplemented with inhibitory antibodies. Intracellular and extracellular levels of vascular endothelial growth factor (VEGF) were evaluated by western blot and ELISA. PE-induced hypertrophy in iPS-CM was associated with an upregulation of neuron-derived orphan receptor (Nor1) expression, activation of Akt, and inhibition of both strongly prevented hypertrophy induction in iPS-CM. VEGF secreted by preconditioned MSCs provoked hypertrophy regression in iPS-CM, and a negative correlation between Nor1 expression and hypertrophic growth could be evidenced. Our results demonstrate that Nor1 expression strongly supports hypertrophy in iPS-CM. Moreover, the secretome of preconditioned MSCs triggered regression of hypertrophy in iPS-CM in a VEGF-dependent manner. We suggest that the delivery of the MSC-derived secretome may represent a therapeutic strategy to limit cardiac hypertrophy. However, additional in vivo studies are needed to prove this hypothesis.
Oncogenic KRAS Recruits an Expansive Transcriptional Network through Mutant p53 to Drive Pancreatic Cancer Metastasis
Authors: Kim Michael P. , Li Xinqun , Deng Jenying , Zhang Yun , Dai Bingbing , Allton Kendra L. , Hughes Tara G. , Siangco Christian , Augustine Jithesh J. , Kang Ya'an , McDaniel Joy M. , Xiong Shunbin , Koay Eugene J. , McAllister Florencia , Bristow Christopher A. , Heffernan Timothy P. , Maitra Anirban , Liu Bin , Barton Michelle C. , Wasylishen Amanda R. , Fleming Jason B. , Lozano Guillermina
Published: April 2021

Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic KRAS mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the TP53 tumor suppressor in nearly 70% of patients. Most TP53 alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis, yet the extent of direct cooperation between KRAS effectors and mutant p53 remains largely undefined. We show that oncogenic KRAS effectors activate CREB1 to allow physical interactions with mutant p53 that hyperactivate multiple prometastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the prometastatic, pioneer transcription factor FOXA1, activating its transcriptional network while promoting WNT/β-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced FOXA1 and β-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic KRAS and mutant p53 to mitigate metastasis.

Significance:

Oncogenic KRAS and mutant p53 are the most commonly mutated oncogene and tumor suppressor gene in human cancers, yet direct interactions between these genetic drivers remain undefined. We identified a cooperative node between oncogenic KRAS effectors and mutant p53 that can be therapeutically targeted to undermine cooperation and mitigate metastasis.

This article is highlighted in the In This Issue feature, p. 1861
Lysine Demethylase 5A Is Required for MYC-Driven Transcription in Multiple Myeloma
Authors: Ohguchi Hiroto , Park Paul M.C. , Wang Tingjian , Gryder Berkley E. , Ogiya Daisuke , Kurata Keiji , Zhang Xiaofeng , Li Deyao , Pei Chengkui , Masuda Takeshi , Johansson Catrine , Wimalasena Virangika K. , Kim Yong , Hino Shinjiro , Usuki Shingo , Kawano Yawara , Samur Mehmet K. , Tai Yu-Tzu , Munshi Nikhil C. , Matsuoka Masao , Ohtsuki Sumio , Nakao Mitsuyoshi , Minami Takashi , Lauberth Shannon , Khan Javed , Oppermann Udo , Durbin Adam D. , Anderson Kenneth C. , Hideshima Teru , Qi Jun
Published: April 2021

Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3 lysine 4 trimethy­lation (H3K4me3), a histone mark associated with activate gene transcription. We identify that KDM5A interacts with the P-TEFb complex and cooperates with MYC to control MYC-targeted genes in multiple myeloma cells. We develop a cell-permeable and selective KDM5 inhibitor, JQKD82, that increases H3K4me3 but paradoxically inhibits downstream MYC-driven transcriptional output in vitro and in vivo. Using genetic ablation together with our inhibitor, we establish that KDM5A supports MYC target gene transcription independent of MYC itself by supporting TFIIH (CDK7)- and P-TEFb (CDK9)–mediated phosphorylation of RNAPII. These data identify KDM5A as a unique vulnerability in multiple myeloma functioning through regulation of MYC target gene transcription and establish JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for multiple myeloma.

Significance:

We delineate the function of KDM5A in activating the MYC-driven transcriptional landscape. We develop a cell-permeable KDM5 inhibitor to define the activating role of KDM5A on MYC target gene expression and implicate the therapeutic potential of this compound in mouse models and multiple myeloma patient samples.

See related video from the AACR Annual Meeting 2021: https://vimeo.com/554896826
ROBO1 Promotes Homing, Dissemination, and Survival of Multiple Myeloma within the Bone Marrow Microenvironment
Authors: Bianchi Giada , Czarnecki Peter G. , Ho Matthew , Roccaro Aldo M. , Sacco Antonio , Kawano Yawara , Gullà Annamaria , Samur Anil Aktas , Chen Tianzeng , Wen Kenneth , Tai Yu-Tzu , Moscvin Maria , Wu Xinchen , Camci-Unal Gulden , Da Vià Matteo C. , Bolli Niccolo' , Sewastianik Tomasz , Carrasco Ruben D. , Ghobrial Irene M. , Anderson Kenneth C.
Published: April 2021

The bone marrow (BM) microenvironment actively promotes multiple myeloma pathogenesis, and therapies targeting both cancer cells and the niche are highly effective. We were interested in identifying novel signaling pathways supporting multiple myeloma–BM cross-talk. Mutations in the transmembrane receptor Roundabout 1 (ROBO1) were recently identified in patients with multiple myeloma; however, their functional consequences are uncertain. Through protein structure–function studies, we discovered that ROBO1 is necessary for multiple myeloma adhesion to BM stromal and endothelial cells and that ROBO1 knockout (KO) compromises BM homing and engraftment in a disseminated mouse model. ROBO1 KO significantly decreases multiple myeloma proliferation in vitro and intra- and extramedullary tumor growth in vivo. Mechanistically, the ROBO1 C-terminus is cleaved in a ligand-independent fashion and is sufficient to promote multiple myeloma proliferation. Vice versa, mutants lacking the cytoplasmic domain, including the human-derived G674* truncation, act dominantly negative. Interactomic and RNA-sequencing studies suggest that ROBO1 may be involved in RNA processing, supporting further studies.

Significance:

ROBO1 is highly expressed in t(4;14) multiple myeloma and supports homing and dissemination to the BM niche. ROBO1 knockout causes reduced tumor growth in intramedullary and extramedullary myeloma animal models, while the ROBO1 C-terminus is cleaved in multiple fragments and it is necessary and sufficient to sustain myeloma proliferation.
Clinical Significance of Novel Subtypes of Acute Lymphoblastic Leukemia in the Context of Minimal Residual Disease–Directed Therapy
Authors: Jeha Sima , Choi John , Roberts Kathryn G. , Pei Deqing , Coustan-Smith Elaine , Inaba Hiroto , Rubnitz Jeffrey E. , Ribeiro Raul C. , Gruber Tanja A. , Raimondi Susana C. , Karol Seth E. , Qu Chunxu , Brady Samuel W. , Gu Zhaohui , Yang Jun J. , Cheng Cheng , Downing James R. , Evans Williams E. , Relling Mary V. , Campana Dario , Mullighan Charles G. , Pui Ching-Hon
Published: April 2021

We evaluated clinical significance of recently identified subtypes of acute lymphoblastic leukemia (ALL) in 598 children treated with minimal residual disease (MRD)–directed therapy. Among the 16 B-cell ALL (B-ALL) and 8 T-cell ALL subtypes identified by next-generation sequencing, ETV6–RUNX1, high-hyperdiploid, and DUX4-rearranged B-ALL had the best 5-year event-free survival rates (95.0%–98.4%); TCF3–PBX1, PAX5-altered (PAX5alt), T-cell, early T-cell precursor (ETP), intrachromosomal amplification of chromosome 21 (iAMP21), and hypodiploid ALL intermediate rates (80.0%–88.2%); and BCR–ABL1, BCR–ABL1-like, ETV6–RUNX1-like, and KMT2A-rearranged ALL the worst rates (64.1%–76.2%). All but 3 of the 142 patients with day 8 blood MRD <0.01% remained in remission. Among new subtypes, intensified therapy based on day 15 MRD ≥1% improved outcome of DUX4-rearranged, BCR–ABL1-like, and ZNF384-rearranged ALL, and achievement of day 42 MRD <0.01% did not preclude relapse of PAX5alt, MEF2D-rearranged, and ETV6–RUNX1-like ALL. Thus, new subtypes including DUX4-rearranged, PAX5alt, BCR–ABL1-like, ETV6–RUNX1-like, MEF2D-rearranged, and ZNF384-rearranged ALL have important prognostic and therapeutic implications.

Significance:

Genomic analyses and MRD should be used together for risk-directed treatment of childhood ALL. Six recently described subtypes—DUX4-rearranged, PAX5alt, BCR–ABL1-like, ETV6–RUNX1-like, MEF2D-rearranged, and ZNF384-rearranged ALL—had prognostic and therapeutic significance with contemporary risk-directed treatment.

See related commentary by Segers and Cools, p. 294.

See related video from the AACR Annual Meeting 2021: https://vimeo.com/558556916