bluuebunny/crossref_metadata_2025 huggingface dataset:
Eutrophication and Deoxygenation Forcing of Marginal Marine Organic Carbon Burial During the PETM
Authors: Papadomanolaki Nina M. , Sluijs Appy , Slomp Caroline P.
Published: February 2022

The Paleocene‐Eocene Thermal Maximum (PETM) is recognized globally by a negative excursion in stable carbon isotope ratios (δ13C) in sedimentary records, termed the carbon isotope excursion (CIE). Based on the CIE, the cause, duration, and mechanisms of recovery of the event have been assessed. Here, we focus on the role of increased organic carbon burial on continental margins as a key driver of CO2drawdown and global exogenic δ13C during the recovery phase. Using new and previously published sediment proxy data, we show evidence for widespread enhanced primary production, low oxygen waters, and high organic carbon (Corg) burial in marginal and restricted environments throughout the δ13C excursion. With a new biogeochemical box model for deep and marginal environments, we show that increased phosphorus availability and water column stratification on continental margins can explain the increased Corgburial during the PETM. Deoxygenation and recycling of phosphorus relative to Corgwere relatively mild, compared to modern day anoxic marine systems. Our model reproduces the conditions reconstructed by field data, resulting in a burial of 6,000 Pg across the PETM, in excess of late Paleocene burial, and ∼3,300 Pg C for the critical first 40 kyr of the recovery, primarily located on continental margins. This value is consistent with prior data and model estimates (∼2,000–3,000 Pg C). To reproduce global exogenic δ13C patterns, this Corgburial implies an injection of 5,000–10,000 Pg C during the first ∼100–150 kyr of the PETM, depending on the source's δ13C (−11‰ to −55‰).
Attention‐Based Machine Vision Models and Techniques for Solar Wind Speed Forecasting Using Solar EUV Images
Authors: Brown Edward J. E. , Svoboda Filip , Meredith Nigel P. , Lane Nicholas , Horne Richard B.
Published: February 2022

Extreme ultraviolet images taken by the Atmospheric Imaging Assembly on board the Solar Dynamics Observatory make it possible to use deep vision techniques to forecast solar wind speed—a difficult, high‐impact, and unsolved problem. At a 4 day time horizon, this study uses attention‐based models and a set of methodological improvements to deliver an 11.1% lower RMSE and a 17.4% higher prediction correlation compared to the previous work testing on the period from 2010 to 2018. Our analysis shows that attention‐based models combined with our pipeline consistently outperform convolutional alternatives. Our study shows a large performance improvement by using a 30 min as opposed to a daily sampling frequency. Our model has learned relationships between coronal holes' characteristics and the speed of their associated high‐speed streams, agreeing with empirical results. Our study finds a strong dependence of our best model on the phase of the solar cycle, with the best performance occurring in the declining phase.
Mountains Sway to the Seismic Song of Earth
Authors: Sima Richard
Published: February 2022

The Matterhorn in the Swiss Alps is in constant motion, gently swaying back and forth about once every 2 seconds.
Integrated microfluidic single-cell immunoblotting chip enables high-throughput isolation, enrichment and direct protein analysis of circulating tumor cells
Authors: Abdulla Aynur , Zhang Ting , Li Shanhe , Guo Wenke , Warden Antony R. , Xin Yufang , Maboyi Nokuzola , Lou Jiatao , Xie Haiyang , Ding Xianting
Published: February 2022

Effective capture and analysis of a single circulating tumor cell (CTC) is instrumental for early diagnosis and personalized therapy of tumors. However, due to their extremely low abundance and susceptibility to interference from other cells, high-throughput isolation, enrichment, and single-cell-level functional protein analysis of CTCs within one integrated system remains a major challenge. Herein, we present an integrated multifunctional microfluidic system for highly efficient and label-free CTC isolation, CTC enrichment, and single-cell immunoblotting (ieSCI). The ieSCI-chip is a multilayer microfluidic system that combines an inertia force-based cell sorter with a membrane filter for label-free CTC separation and enrichment and a thin layer of a photoactive polyacrylamide gel with microwell arrays at the bottom of the chamber for single-cell immunoblotting. The ieSCI-chip successfully identified a subgroup of apoptosis-negative (Bax-negative) cells, which traditional bulk analysis did not detect, from cisplatin-treated cells. Furthermore, we demonstrated the clinical application of the ieSCI-chip with blood samples from breast cancer patients for personalized CTC epithelial-to-mesenchymal transition (EMT) analysis. The expression level of a tumor cell marker (EpCAM) can be directly determined in isolated CTCs at the single-cell level, and the therapeutic response to anticancer drugs can be simultaneously monitored. Therefore, the ieSCI-chip provides a promising clinical translational tool for clinical drug response monitoring and personalized regimen development.
Deubiquitylase OTUD6B stabilizes the mutated pVHL and suppresses cell migration in clear cell renal cell carcinoma
Authors: Guo Kai , Wei Yinghua , Wang Ze , Zhang Xiaoli , Zhang Xin , Liu Xinxin , Wu Wenyong , Wu Zhengsheng , Zhang Lingqiang , Cui Chun-Ping
Published: February 2022

Von Hippel-Lindau (VHL) is an important tumor suppressor, and its inactivation is a hallmark of inherited VHL disease and most sporadic clear cell renal cell carcinoma (ccRCC). VHL protein (pVHL) with missense point mutations are unstable and degraded by the proteasome because of the disruption of elongin binding. Deubiquitylase ovarian tumor domain-containing 6B (OTUD6B) had been documented to couple pVHL and elongin B to form stable VHL - elonginB - elonginC complex, which protects pVHL from degradation. However, whether OTUD6B governs the stability of pVHL wild type and the missense mutants in ccRCC remains largely elusive. Here, we reported that low OTUD6B level predicted poorer survival in ccRCC patients with VHL missense mutation, but not frameshift deletion and nonsense mutation. OTUD6B is able to interact with wild type pVHL and tumor-derived pVHL missense mutants, except for pVHL I151T, and decrease their ubiquitylation and proteasomal degradation in ccRCC cells. Functionally, we revealed that OTUD6B depletion enhanced cell migration and HIF-2α level in ccRCC cells in a pVHL dependent manner. In addition, OTUD6B depletion reduced the inhibitory effects of ectopic pVHL missense mutants on cell migration and HIF-2α level, except for pVHL I151T. Thus, we speculated that I151 residue might be one of key sites of pVHL binding to OTUD6B. These results suggested that OTUD6B is an important regulator for the stability of pVHL missense mutants, which provides a potential therapeutic strategy for ccRCC with VHL mutations.
Long non-coding RNA PAARH promotes hepatocellular carcinoma progression and angiogenesis via upregulating HOTTIP and activating HIF-1α/VEGF signaling
Authors: Wei Huamei , Xu Zuoming , Chen Liucui , Wei Qing , Huang Zihua , Liu Guoman , Li Wenchuan , Wang Jianchu , Tang Qianli , Pu Jian
Published: February 2022

Hepatocellular carcinoma (HCC) is one of the leading lethal malignancies and a hypervascular tumor. Although some long non-coding RNAs (lncRNAs) have been revealed to be involved in HCC. The contributions of lncRNAs to HCC progression and angiogenesis are still largely unknown. In this study, we identified a HCC-related lncRNA, CMB9-22P13.1, which was highly expressed and correlated with advanced stage, vascular invasion, and poor survival in HCC. We named this lncRNA Progression and Angiogenesis Associated RNA in HCC (PAARH). Gain- and loss-of function assays revealed that PAARH facilitated HCC cellular growth, migration, and invasion, repressed HCC cellular apoptosis, and promoted HCC tumor growth and angiogenesis in vivo. PAARH functioned as a competing endogenous RNA to upregulate HOTTIP via sponging miR-6760-5p, miR-6512-3p, miR-1298-5p, miR-6720-5p, miR-4516, and miR-6782-5p. The expression of PAARH was significantly positively associated with HOTTIP in HCC tissues. Functional rescue assays verified that HOTTIP was a critical mediator of the roles of PAARH in modulating HCC cellular growth, apoptosis, migration, and invasion. Furthermore, PAARH was found to physically bind hypoxia inducible factor-1 subunit alpha (HIF-1α), facilitate the recruitment of HIF-1α to VEGF promoter, and activate VEGF expression under hypoxia, which was responsible for the roles of PAARH in promoting angiogenesis. The expression of PAARH was positively associated with VEGF expression and microvessel density in HCC tissues. In conclusion, these findings demonstrated that PAARH promoted HCC progression and angiogenesis via upregulating HOTTIP and activating HIF-1α/VEGF signaling. PAARH represents a potential prognostic biomarker and therapeutic target for HCC.
Modulation of Hippo signaling by Mnat9 N-acetyltransferase for normal growth and tumorigenesis in Drosophila
Authors: Mok Jung-Wan , Choi Kwang-Wook
Published: February 2022

Hippo signaling is a conserved mechanism for controlling organ growth. Increasing evidence suggests that Hippo signaling is modulated by various cellular factors for normal development and tumorigenesis. Hence, identification of these factors is pivotal for understanding the mechanism for the regulation of Hippo signaling. Drosophila Mnat9 is a putative N-acetyltransferase that is required for cell survival by affecting JNK signaling. Here we show that Mnat9 is involved in the negative regulation of Hippo signaling. RNAi knockdown of Mnat9 in the eye disc suppresses the rough eye phenotype of overexpressing Crumbs (Crb), an upstream factor of the Hippo pathway. Conversely, Mnat9 RNAi enhances the eye phenotype caused by overexpressing Expanded (Ex) or Warts (Wts) that acts downstream to Crb. Similar genetic interactions between Mnat9 and Hippo pathway genes are found in the wing. The reduced wing phenotype of Mnat9 RNAi is suppressed by overexpression of Yorkie (Yki), while it is suppressed by knockdown of Hippo upstream factors like Ex, Merlin, or Kibra. Mnat9 co-immunoprecipitates with Mer, implying their function in a protein complex. Furthermore, Mnat9 overexpression together with Hpo knockdown causes tumorous overgrowth in the abdomen. Our data suggest that Mnat9 is required for organ growth and can induce tumorous growth by negatively regulating the Hippo signaling pathway.
BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells
Authors: Azzoni Violette , Wicinski Julien , Macario Manon , Castagné Martin , Finetti Pascal , Ambrosova Katerina , Rouault Célia D. , Sergé Arnaud , Farina Anne , Agavnian Emilie , Coslet Sergiu , Josselin Emmanuelle , Guille Arnaud , Adelaide José , Zacharioudakis Emmanouil , Castellano Rémy , Bertucci Francois , Birnbaum Daniel , Rodriguez Raphael , Charafe-Jauffret Emmanuelle , Ginestier Christophe
Published: February 2022

Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells’ (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.
The feedback loop of ANKHD1/lncRNA MALAT1/YAP1 strengthens the radioresistance of CRC by activating YAP1/AKT signaling
Authors: Yao Ping-an , Wu Yong , Zhao Kui , Li Yecheng , Cao Jianping , Xing Chungen
Published: February 2022

Innate radioresistance substantially limits the effectiveness of radiotherapy for colorectal cancer (CRC); thus, a strategy to enhance the radiosensitivity of CRC is urgently needed. Herein, we reported that ankyrin repeat and KH domain containing 1 (ANKHD1) serves as a key regulator of radioresistance in CRC. ANKHD1 was highly expressed in CRC tissues and was highly correlated with Yes-associated protein 1 (YAP1) in CRC. Our results first revealed that ANKHD1 knockdown could increase the radiosensitivity of CRC by regulating DNA-damage repair, both in vitro and in vivo. Furthermore, the interactive regulation between ANKHD1 or YAP1 and lncRNA MALAT1 was revealed by RIP and RNA pull-down assays. Moreover, our results also demonstrated that MALAT1 silencing can radiosensitize CRC cells to IR through YAP1/AKT axis, similar to ANKHD1 silencing. Taken together, we report a feedback loop of ANKHD1/MALAT1/YAP1 that synergistically promotes the transcriptional coactivation of YAP1 and in turn enhances the radioresistance of CRC by regulating DNA-damage repair, probably via the YAP1/AKT axis. Our results suggested that targeting the YAP1/AKT axis downstream of ANKHD1/MALAT1/YAP1 may enhance the radiosensitivity of CRC.
Mesencephalic astrocyte-derived neurotrophic factor reprograms macrophages to ameliorate acetaminophen-induced acute liver injury via p38 MAPK pathway
Authors: Hou Xin , Liu Qi , Gao Yimin , Yong Liang , Xie Huiyuan , Li Wenting , Zhou Yuping , Liu Jun , Feng Lijie , Xu Long , Shen Yuxian , Wang Hua
Published: February 2022

Acetaminophen (APAP)-induced liver injury (AILI) is the most frequent cause of acute liver failure; but the underlying mechanisms still remain obscure. Macrophages and endoplasmic reticulum (ER) stress play an important role in the pathogenesis of AILI. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly identified 18-kDa soluble protein, whose expression and secretion are stimulated by ER stress. To investigate the role of myeloid cell MANF in the pathogenesis of AILI, we assayed serum and liver samples from AILI model mice and patients with drug-induced liver injury (DILI). We demonstrated that the levels of MANF were elevated in patients with DILI and in mice with AILI. Moreover, myeloid-specific MANF knockout mice were generated and used. It was observed that a delayed liver recovery from myeloid-specific MANF gene knockout mice following APAP overdose compared to that from wild-type mice. MANF deficiency in myeloid cells resulted in increased infiltrating monocyte-derived macrophages (MoMFs) but reduced restorative Ly6Clow macrophages after APAP treatment. MANF supplementation increased restorative Ly6Clow macrophages and subsequently alleviated liver injury. Moreover, MANF could enhance IL-10 expression and phagocytosis in macrophages via p38 MAPK pathway. Altogether, MANF seems to be a critical immune modulator in promoting liver repair via reducing and reprogramming MoMFs. MANF perhaps promoted the phenotype conversion of pro-inflammatory MoMFs to pro-restorative Ly6Clow MoMFs via p38 MAPK pathway, particularly through enhancing IL-10 and phagocytosis.
NR4A1 promotes LEF1 expression in the pathogenesis of papillary thyroid cancer
Authors: Jiang Cen , He Jianli , Xu Sunwang , Wang Qi , Cheng Jinke
Published: February 2022

The morbidity of papillary thyroid cancer (PTC) is on the rise, but its pathogenesis is still poorly understood. NR4A1 is a transcription factor primarily involving a wide range of pathophysiological responses, but its relationship with PTC malignancy remains unclear. This study demonstrates that high NR4A1 expression is strongly associated with poor survival outcomes in PTC patients. The depletion of NR4A1 significantly inhibited the proliferation of PTC cells by negating the LEF1-mediated oncogenic alteration. Mechanistically, NR4A1 directly binds to the promoter region of LEF1 and leads to crosstalk with histone acetylation and DNA demethylation to transcriptionally upregulate LEF1 expression, subsequently promoting downstream growth-related genes expressions in PTC. In the light of our findings, NR4A1 may be an emerging driving factor in PTC pathogenesis and progression.
Constitutive activation of canonical Wnt signaling disrupts choroid plexus epithelial fate
Authors: Parichha Arpan , Suresh Varun , Chatterjee Mallika , Kshirsagar Aditya , Ben-Reuven Lihi , Olender Tsviya , Taketo M. Mark , Radosevic Velena , Bobic-Rasonja Mihaela , Trnski Sara , Holtzman Michael J. , Jovanov-Milosevic Nataša , Reiner Orly , Tole Shubha
Published: February 2022

The choroid plexus secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the choroid plexus epithelium arises from the Wnt- expressing cortical hem. Canonical Wnt signaling pathway molecules such as nuclear β-CATENIN are expressed in the mouse and human embryonic choroid plexus epithelium indicating that this pathway is active. Point mutations in human β-CATENIN are known to result in the constitutive activation of canonical Wnt signaling. In a mouse model that recapitulates this perturbation, we report a loss of choroid plexus epithelial identity and an apparent transformation of this tissue to a neuronal identity. Aspects of this phenomenon are recapitulated in human embryonic stem cell derived organoids. The choroid plexus is also disrupted when β-Catenin is conditionally inactivated. Together, our results indicate that canonical Wnt signaling is required in a precise and regulated manner for normal choroid plexus development in the mammalian brain.
Buxus and Tetracentron genomes help resolve eudicot genome history
Authors: Chanderbali Andre S. , Jin Lingling , Xu Qiaoji , Zhang Yue , Zhang Jingbo , Jian Shuguang , Carroll Emily , Sankoff David , Albert Victor A. , Howarth Dianella G. , Soltis Douglas E. , Soltis Pamela S.
Published: February 2022

Ancient whole-genome duplications (WGDs) characterize many large angiosperm lineages, including angiosperms themselves. Prominently, the core eudicot lineage accommodates 70% of all angiosperms and shares ancestral hexaploidy, termed gamma. Gamma arose via two WGDs that occurred early in eudicot history; however, the relative timing of these is unclear, largely due to the lack of high-quality genomes among early-diverging eudicots. Here, we provide complete genomes for Buxus sinica (Buxales) and Tetracentron sinense (Trochodendrales), representing the lineages most closely related to core eudicots. We show that Buxus and Tetracentron are both characterized by independent WGDs, resolve relationships among early-diverging eudicots and their respective genomes, and use the RACCROCHE pipeline to reconstruct ancestral genome structure at three key phylogenetic nodes of eudicot diversification. Our reconstructions indicate genome structure remained relatively stable during early eudicot diversification, and reject hypotheses of gamma arising via inter-lineage hybridization between ancestral eudicot lineages, involving, instead, only stem lineage core eudicot ancestors.
Immunomodulatory matrix-bound nanovesicles mitigate acute and chronic pristane-induced rheumatoid arthritis
Authors: Crum Raphael J. , Hall Kelsey , Molina Catalina Pineda , Hussey George S. , Graham Emma , Li Hongshuai , Badylak Stephen F.
Published: February 2022

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints affecting ~7.5 million people worldwide. Disease pathology is driven by an imbalance in the ratio of pro-inflammatory vs. anti-inflammatory immune cells, especially macrophages. Modulation of macrophage phenotype, specifically an M1 to M2, pro- to anti-inflammatory transition, can be induced by biologic scaffold materials composed of extracellular matrix (ECM). The ECM-based immunomodulatory effect is thought to be mediated in part through recently identified matrix-bound nanovesicles (MBV) embedded within ECM. Isolated MBV was delivered via intravenous (i.v.) or peri-articular (p.a.) injection to rats with pristane-induced arthritis (PIA). The results of MBV administration were compared to intraperitoneal (i.p.) administration of methotrexate (MTX), the clinical standard of care. Relative to the diseased animals, i.p. MTX, i.v. MBV, and p.a. MBV reduced arthritis scores in both acute and chronic pristane-induced arthritis, decreased synovial inflammation, decreased adverse joint remodeling, and reduced the ratio of synovial and splenic M1 to M2 macrophages (p < 0.05). Both p.a. and i.v. MBV reduced the serum concentration of RA and PIA biomarkers CXCL10 and MCP-3 in the acute and chronic phases of disease (p < 0.05). Flow-cytometry revealed the presence of a systemic CD43hi/His48lo/CD206+, immunoregulatory monocyte population unique to p.a. and i.v. MBV treatment associated with disease resolution. The results show that the therapeutic efficacy of MBV is equal to that of MTX for the management of acute and chronic pristane-induced arthritis and, further, this effect is associated with modulation of local synovial macrophages and systemic myeloid populations.
Reconstruction of 100-year dynamics in Daphnia spawning activity revealed by sedimentary DNA
Authors: Tsugeki Narumi , Nakane Kai , Doi Hideyuki , Ochi Natsuki , Kuwae Michinobu
Published: February 2022

Environmental DNA (eDNA) is currently developing as a powerful tool for assessing aquatic species dynamics. However, its utility as an assessment tool for quantification remain under debate as the sources of eDNA for different species is not always known. Therefore, accumulating information about eDNA sources from different species is urgently required. The objective of our study was to evaluate whether sedimentary DNA targeting two Daphnia species, D. galeata and D. pulicaria, could track Daphnia population dynamics and resting egg production. Applying a quantitative PCR targeting the mitochondrial 12S rRNA gene on sediment cores collected in Lake Biwa, Japan, we compared sedimentary DNA concentration of Daphnia with the abundance of remains and ephippia, reflecting their abundance and resting egg production, respectively. We found that the sedimentary DNA concentrations of Daphnia for the past century were inconsistent with their population abundance. However, the concentration was highly correlated with the resting egg production. Our results provide evidence that ephippia with resting eggs, released during spawning activities, was a significant source of Daphnia DNA archived in sediments. Our work provides critical insights for using sedimentary DNA as a monitoring tool for egg production dating back 100 years.
Systematic comparative analysis of strand-specific RNA-seq library preparation methods for low input samples
Authors: Naphade Swati , Bhatnagar Rajat , Hanson-Smith Victor , Choi Irene , Zhang Alice
Published: February 2022

Despite the recent precipitous decline in the cost of genome sequencing, library preparation for RNA-seq is still laborious and expensive for applications such as high throughput screening. Limited availability of RNA generated by some experimental workflows poses an additional challenge and increases the cost of RNA library preparation. In a search for low cost, automation-compatible RNA library preparation kits that maintain strand specificity and are amenable to low input RNA quantities, we systematically tested two recent commercial technologies—Swift RNA and Swift Rapid RNA, presently offered by Integrated DNA Technologies (IDT) —alongside the Illumina TruSeq stranded mRNA, the de facto standard workflow for bulk transcriptomics. We used the Universal Human Reference RNA (UHRR) (composed of equal quantities of total RNA from 10 human cancer cell lines) to benchmark gene expression in these kits, at input quantities ranging between 10 to 500 ng. We found normalized read counts between all treatment groups to be in high agreement. Compared to the Illumina TruSeq stranded mRNA kit, both Swift RNA library kits offer shorter workflow times enabled by their patented Adaptase technology. We also found the Swift RNA kit to produce the fewest number of differentially expressed genes and pathways directly attributable to input mRNA amount.
Unprecedently large 37Cl/35Cl equilibrium isotopic fractionation on nano-confinement of chloride anion
Authors: Pokora Mateusz , Paneth Agata , Paneth Piotr
Published: February 2022

Confinement can result in unusual properties leading to new, exciting discoveries in the nano-realm. One such consequence of confinement at the nanoscale is extremally large isotopic fractionation, especially at sub-van der Waals distances. Herein, on the example of chlorine isotope effects, we show that at conditions of nanoencapsulation these effects may reach values by far larger than observed for the bulk environment, which in the case of nanotubes can lead to practical applications (e.g., in isotopic enrichment) and needs to be considered in analytical procedures that employ nanomaterials.
Generation mechanism and prediction of an observed extreme rogue wave
Authors: Gemmrich Johannes , Cicon Leah
Published: February 2022

Rogue waves are individual ocean surface waves with crest height $$\eta$$
η
or trough-to-crest height H that are large compared to the significant wave height $$H_s$$

H
s

of the underlying sea state: $$H/H_s>2.2$$

H
/

H
s

>
2.2

or $$\eta /H_s>1.25$$

η
/

H
s

>
1.25

. The physics of rogue wave generation and the potential of predicting the rogue wave risk are open questions. Only a few rogue waves in high sea states have been observed directly, but they can pose a danger to marine operations, onshore and offshore structures, and beachgoers. Here we report on a 17.6m high rogue wave in coastal waters with $$\eta /H_s=1.98$$

η
/

H
s

=
1.98

and $$H/H_s=2.9$$

H
/

H
s

=
2.9

which are likely the largest normalized heights ever recorded. Simulations of random superposition of Stokes waves in intermediate water depth show good agreement with the observation. Non-linear wave modulational instability, a well known cause for rogue waves in laboratory settings, did not contribute significantly to the rogue wave generation. A parameter obtained from a routine spectral wave forecast provides a practical risk prediction for rogue waves. These results confirm that probabilistic prediction of oceanic rogue waves based on random superposition of steep waves are possible and should replace predictions based on modulational instability.
Identification of novel leads as potent inhibitors of HDAC3 using ligand-based pharmacophore modeling and MD simulation
Authors: Kumbhar Navanath , Nimal Snehal , Barale Sagar , Kamble Subodh , Bavi Rohit , Sonawane Kailas , Gacche Rajesh
Published: February 2022

In the landscape of epigenetic regulation, histone deacetylase 3 (HDAC3) has emerged as a prominent therapeutic target for the design and development of candidate drugs against various types of cancers and other human disorders. Herein, we have performed ligand-based pharmacophore modeling, virtual screening, molecular docking, and MD simulations to design potent and selective inhibitors against HDAC3. The predicted best pharmacophore model ‘Hypo 1’ showed excellent correlation (R2 = 0.994), lowest RMSD (0.373), lowest total cost value (102.519), and highest cost difference (124.08). Hypo 1 consists of four salient pharmacophore features viz. one hydrogen bond acceptor (HBA), one ring aromatic (RA), and two hydrophobic (HYP). Hypo 1 was validated by Fischer's randomization with a 95% of confidence level and the external test set of 60 compounds with a good correlation coefficient (R2 = 0.970). The virtual screening of chemical databases, drug-like properties calculations followed by molecular docking resulted in identifying 22 representative hit compounds. Performed 50 ns of MD simulations on top three hits were retained the salient π-stacking, Zn2+ coordination, hydrogen bonding, and hydrophobic interactions with catalytic residues from the active site pocket of HDAC3. Total binding energy calculated by MM-PBSA showed that the Hit 1 and Hit 2 formed stable complexes with HDAC3 as compared to reference TSA. Further, the PLIP analysis showed a close resemblance between the salient pharmacophore features of Hypo 1 and the presence of molecular interactions in co-crystallized FDA-approved drugs. We conclude that the screened hit compounds may act as potent inhibitors of HDAC3 and further preclinical and clinical studies may pave the way for developing them as effective therapeutic agents for the treatment of different cancers and neurodegenerative disorders.
Completely predatory development is described in a braconid wasp
Authors: Ranjith A. P. , Quicke Donald L. J. , Manjusha K. , Butcher Buntika A. , Nasser M.
Published: February 2022

Hymenopteran parasitoids are well known for their ubiquitous diversity, important ecological roles and biocontrol potential. We report the first detailed documentation of mite predation by a parasitoid wasp,Bracon predatoriusRanjith & Quicke sp. nov., (Insecta: Hymenoptera), first case of obligate predatory behaviour in the family Braconidae and first case of mite feeding within the superfamily Ichneumonoidea. Larvae of a new wasp species are shown to develop entirely as predators of eriophyid mites that induce leaf galls in a commercially important plant. They display highly modified head capsule morphology that we interpret as being associated with this atypical life style. We propose that the new feeding strategy evolved separately from recently described entomophytophagy in another species of the same genus. The divergent larval morphological adaptations of both species indicate a high degree of evolutionary developmental plasticity in the developmental stage.
Purification and characterization of human adipose-resident microvascular endothelial progenitor cells
Authors: Saito Natsumi , Shirado Takako , Funabashi-Eto Hitomi , Wu Yunyan , Mori Masanori , Asahi Rintaro , Yoshimura Kotaro
Published: February 2022

Human adipose tissue is a rich source of adipose-derived stem cells (ASCs) and vascular endothelial progenitor cells (EPCs). However, no standardized method has been established for the isolation and purification of adipose-derived EPCs (AEPCs). The aim of this study was to establish a method for the isolation and purification of AEPCs. The stromal vascular fraction (SVF) was extracted from human lipoaspirates, and the CD45−CD31+ fraction of the SVF was collected by magnetic-activated cell sorting (MACS). The CD45−CD31+ fraction was cultured for 4.5 days, followed by a second MACS separation to collect the CD31+ fraction. Purified AEPCs were expanded without being overwhelmed by proliferating ASCs, indicating that a high level (> 95%) of AEPC purification is a key factor for their successful isolation and expansion. AEPCs exhibited typical endothelial markers, including CD31, von Willebrand factor, and the isolectin-B4 binding capacity. AEPCs formed colonies, comparable to cultured human umbilical vein endothelial cells (HUVECs). Both AEPCs and HUVECs formed capillary-like networks in the tube formation assay, with no significant difference in network lengths. We are the first to establish a purification and expansion method to isolate these cells. Because adipose tissue is a clinically accessible and abundant tissue, AEPCs may have potential advantages as a therapeutic tool for regenerative medicine.
β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicity
Authors: Denha Sarah A. , Atang Alexandra E. , Hays Thomas S. , Avery Adam W.
Published: February 2022

Recent structural studies of β-III-spectrin and related cytoskeletal proteins revealed N-terminal sequences that directly bind actin. These sequences are variable in structure, and immediately precede a conserved actin-binding domain composed of tandem calponin homology domains (CH1 and CH2). Here we investigated in Drosophila the significance of the β-spectrin N-terminus, and explored its functional interaction with a CH2-localized L253P mutation that underlies the neurodegenerative disease spinocerebellar ataxia type 5 (SCA5). We report that pan-neuronal expression of an N-terminally truncated β-spectrin fails to rescue lethality resulting from a β-spectrin loss-of-function allele, indicating that the N-terminus is essential to β-spectrin function in vivo. Significantly, N-terminal truncation rescues neurotoxicity and defects in dendritic arborization caused by L253P. In vitro studies show that N-terminal truncation eliminates L253P-induced high-affinity actin binding, providing a mechanistic basis for rescue. These data suggest that N-terminal sequences may be useful therapeutic targets for small molecule modulation of the aberrant actin binding associated with SCA5 β-spectrin and spectrin-related disease proteins.
In vitro regeneration and Agrobacterium-mediated genetic transformation of Dragon’s Head plant (Lallemantia iberica)
Authors: Ebrahimzadegan Rahman , Maroufi Asad
Published: February 2022

Dragon’s head plant (Lallemantia iberica), is a flowering species belongs to the mint family (Lamiaceae). The species contains valuable essential oils, mucilage and oil which are used in pharmaceutical and food industries. Tissue culture is a feasible strategy to attain large‐scale production of plantlets with a huge potential to produce plants with superior quality. The objective of this study was to develop a simple and efficient method for regeneration and transformation of L. iberica. To reach this goal, the regeneration ability of various explants including leaf, cotyledonary node, hypocotyl and cotyledon segments was investigated in MS medium supplemented with diverse concentrations of NAA (Naphthalene acetic acid) and BAP (6-Benzyl Amino Purine). According to the results, cotyledonary nodes showed the best regeneration response. The maximum rate of regeneration (and number of induced shoots was achieved in 1 mg l−1 BAP in combination with 0.05 mg l−1 NAA from the cotyledonary nodes. Additionally, through the optimized regeneration technique Agrobacterium-mediated transformation of L. iberica was successfully accomplished. Gene transfer was assessed on leaf samples from regenerated plantlets under a fluorescent microscope to detect the GFP signals. Moreover, transgene integration and its expression were confirmed by PCR and RT-PCR analysis, respectively. The establishment of these efficient regeneration and genetic transformation methods paved the way for further application such as plant improvement, functional analysis and gene editing.
m6A-related lncRNAs predict prognosis and indicate immune microenvironment in acute myeloid leukemia
Authors: Zhong Fangmin , Yao Fangyi , Cheng Ying , Liu Jing , Zhang Nan , Li Shuqi , Li Meiyong , Huang Bo , Wang Xiaozhong
Published: February 2022

Acute myeloid leukemia (AML) is a complex hematologic malignancy. Survival rate of AML patients is low. N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) play important roles in AML tumorigenesis and progression. However, the relationship between lncRNAs and biological characteristics of AML, as well as how lncRNAs influence the prognosis of AML patients, remain unclear. In this study. In this study, Pearson correlation analysis was used to identify lncRNAs related to m6A regulatory genes, namely m6A-related lncRNAs. And we analyzed their roles and prognostic values in AML. m6A-related lncRNAs associated with patient prognosis were screened using univariate Cox regression analysis, followed by systematic analysis of the relationship between these genes and AML clinicopathologic and biologic characteristics. Furthermore, we examined the characteristics of tumor immune microenvironment (TIME) using different IncRNA clustering models. Using LASSO regression, we identified the risk signals related to prognosis of AML patients. We then constructed and verified a risk model based on m6A-related lncRNAs for independent prediction of overall survival in AML patients. Our results indicate that risk scores, calculated based on risk-related signaling, were related to the clinicopathologic characteristics of AML and level of immune infiltration. Finally, we examined the expression level of TRAF3IP2-AS1 in patient samples through real-time polymerase chain reaction analysis and in GEO datasets, and we identified a interaction relationship between SRSF10 and TRAF3IP2-AS1 through in vitro assays. Our study shows that m6A-related lncRNAs, evaluated using the risk prediction model, can potentially be used to predict prognosis and design immunotherapy in AML patients.
Analysis of antiretroviral therapy switch rate and switching pattern for people living with HIV from a national database in Japan
Authors: Naito Toshio , Mori Hirotake , Fujibayashi Kazutoshi , Fukushima Shinichi , Yuda Mayumi , Fukui Nobuyuki , Tsukamoto Shotaro , Suzuki Mai , Goto-Hirano Keiko , Kuwatsuru Ryohei
Published: February 2022

To report the status of switch rates and time-to-switch of antiretroviral therapy (ART) regimens by evaluating anchor drug classes and common switching patterns in Japanese people living with human immunodeficiency virus (HIV, PLWH). This cross-sectional cohort study extracted data of 28,089 PLWH from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), which contains data representing the entire population of Japan. PLWH with first prescription records of ART administered between January 2011 and March 2019 were identified (n = 16,069). The median time-to-switch and switch rates of anchor drug classes were estimated by Kaplan–Meier analysis. Brookmeyer–Crowley and Greenwood methods were used to estimate 95% confidence intervals for switch rates and median days, respectively. Switch rates were compared between anchor drug classes by year using log-rank tests. A total of 3108 (19.3%) PLWH switched anchor drug classes from first to second regimens. Switch rates increased continuously over 8 years for non-nucleoside reverse transcriptase inhibitors (NNRTIs) (14.9–65.5%) and protease inhibitors (PIs) (13.2–67.7%), with median time-to-switch of 1826 and 1583 days, respectively. Integrase strand transfer inhibitors (INSTIs) maintained a low switch rate (3.0–7.6%), precluding median-days calculation. Overall, the majority of patients treated initially with NNRTIs and PIs switched to INSTIs regardless of switching times (< 1 year: 67.3% and 85.9%, respectively; ≥ 1 year: 95.5% and 93.6%, respectively). The foremost switching strategies for first-to-second ART regimens are from NNRTIs or PIs to INSTIs regimens that maintain low switch rates long term. There was no observable difference in trend between sex, age and status of AIDS disease at first ART regimen. INSTIs HIV agents may be the most durable anchor drug class for PLWH receiving ART.
Application of flexible pin for planetary gear set of wind turbine gearbox
Authors: Yoo Ho-Gil , Chung Woo-Jin , Kim Beom-Soo , Park Young-Jun , Kim Su-Chul , Lee Geun-Ho
Published: February 2022

Wind turbines are eco-friendly energy sources that generate electricity from wind power. Among their various components, gearboxes constitute the most critical loss owing to their longest downtime. To guarantee their durability, a flexible pin was designed based on the original straddle-mounted pin for enhanced tooth load sharing and distribution in the planetary gear set (PGS) of a wind turbine gearbox (WTGB). The improved durability was evaluated by calculating the mesh load factor and face load factor for contact stress and comparing these values with those of the original straddle-mounted pin. The mesh load factor decreased from 1.37 to 1.08, whereas the maximum face load factor decreased slightly, moderating the overall safety factor variation. Furthermore, the structure of the proposed flexible pin model was analyzed and verified that no static failure or interference occurred. Additionally, microgeometry optimization was applied to improve the load distribution. Therefore, it was verified that a flexible pin applied to a single helical-geared PGS, thus far considered impossible, enhances the durability of WTGBs by improving the load sharing and distribution of a PGS. Consequently, the possibility of designing single helical-geared planetary gearboxes with flexible pins to take advantages of both helical gears and flexible pins was shown analytically.
The effect of territorial awareness in a three-species cyclic predator–prey model
Authors: Wang Xiaoyue , Lu Yikang , Shi Lei , Park Junpyo
Published: February 2022

Recognizing territories is essential to decide behavior of population either human or animals, and interaction between groups or individuals according to the territorial awareness is universal. Understanding various mechanisms which affect on such species behaviors can be possible by evolutionary games, and in particular, the rock–paper–scissors (RPS) game has been played a key role as a paradigmatic model to explore biodiversity from microbiota to societies. Among paramount mechanisms in systems of RPS, the role of intraspecific interaction has been recently noted in terms of promoting biodiversity. Since intraspecific interaction is defined by an invasive reaction between individuals in the same group, the interaction may be also sensitive to the territorial awareness. To explore how territorial awareness-based intraspecific interaction can affect species biodiversity, we endow species with the mechanism in the classic RPS game. By means of the Monte-Carlo method, we find the phenomenon that the presence of species’ territorial awareness has an impact on intraspecific interaction which ultimately affects species biodiversity. At the same time, we also find that territorial awareness can play a significant role to the average waiting time for extinction which is numerically elucidated by exploiting the quantity: interface width statistic. Unlike prior research that concentrated solely on the relationship between interaction frequency and species diversity, our results shed lights on the important role of territorial awareness in models of RPS, and they reveal fascinating evolutionary outcomes in structured populations that are a unique consequence of such awareness behavior.
Astrocytes deficient in circadian clock gene Bmal1 show enhanced activation responses to amyloid-beta pathology without changing plaque burden
Authors: McKee Celia A. , Lee Jiyeon , Cai Yuqi , Saito Takashi , Saido Takaomi , Musiek Erik S.
Published: February 2022

An emerging link between circadian clock function and neurodegeneration has indicated a critical role for the molecular clock in brain health. We previously reported that deletion of the core circadian clock gene Bmal1abrogates clock function and induces cell-autonomous astrocyte activation. Regulation of astrocyte activation has important implications for protein aggregation, inflammation, and neuronal survival in neurodegenerative conditions such as Alzheimer's disease (AD). Here, we investigated how astrocyte activation induced byBmal1deletion regulates astrocyte gene expression, amyloid-beta (Aβ) plaque-associated activation, and plaque deposition. To address these questions, we crossed astrocyte-specificBmal1knockout mice (Aldh1l1-CreERT2;Bmal1fl/fl, termed BMAL1 aKO), to the APP/PS1-21 and the APPNL-G-Fmodels of Aβ accumulation. Transcriptomic profiling showed that BMAL1 aKO induced a unique transcriptional profile affecting genes involved in both the generation and elimination of Aβ. BMAL1 aKO mice showed exacerbated astrocyte activation around Aβ plaques and altered gene expression. However, this astrogliosis did not affect plaque accumulation or neuronal dystrophy in either model. Our results demonstrate that the striking astrocyte activation induced byBmal1knockout does not influence Aβ deposition, which indicates that the effect of astrocyte activation on plaque pathology in general is highly dependent on the molecular mechanism of activation.
Nanometer-thick copper films with low resistivity grown on 2D material surfaces
Authors: Liu Yu-Wei , Zhang Dun-Jie , Tsai Po-Cheng , Chiang Chen-Tu , Tu Wei-Chen , Lin Shih-Yen
Published: February 2022

Thin Copper (Cu) films (15 nm) are deposited on different 2D material surfaces through e-beam deposition. With the assist of van der Waals epitaxy growth mode on 2D material surfaces, preferential planar growth is observed for Cu films on both MoS2and WSe2surfaces at room temperature, which will induce a polycrystalline and continuous Cu film formation. Relative low resistivity values 6.07 (MoS2) and 6.66 (WSe2) μΩ-cm are observed for the thin Cu films. At higher growth temperature 200 °C, Cu diffusion into the MoS2layers is observed while the non-sulfur 2D material WSe2can prevent Cu diffusion at the same growth temperature. By further increasing the deposition rates, a record-low resistivity value 4.62 μΩ-cm for thin Cu films is observed for the sample grown on the WSe2surface. The low resistivity values and the continuous Cu films suggest a good wettability of Cu films on 2D material surfaces. The thin body nature, the capability to prevent Cu diffusion and the unique van der Waals epitaxy growth mode of 2D materials will make non-sulfur 2D materials such as WSe2a promising candidate to replace the liner/barrier stack in interconnects with reducing linewidths.
Allele-specific transcription factor binding in a cellular model of orofacial clefting
Authors: Ruff Katharina L. M. , Hollstein Ronja , Fazaal Julia , Thieme Frederic , Gehlen Jan , Mangold Elisabeth , Knapp Michael , Welzenbach Julia , Ludwig Kerstin U.
Published: February 2022

Non-syndromic cleft lip with/without cleft palate (nsCL/P) is a frequent congenital malformation with multifactorial etiology. While recent genome-wide association studies (GWAS) have identified several nsCL/P risk loci, the functional effects of the associated non-coding variants are largely unknown. Furthermore, additional risk loci remain undetected due to lack of power. As genetic variants might alter binding of transcription factors (TF), we here hypothesized that the integration of data from TF binding sites, expression analyses and nsCL/P GWAS might help to (i) identify functionally relevant variants at GWAS loci, and (ii) highlight novel risk variants that have been previously undetected. Analysing the craniofacial TF TFAP2A in human embryonic palatal mesenchyme (HEPM) cells, we identified 2845 TFAP2A ChIP-seq peaks, several of which were located near nsCL/P candidate genes (e.g. MSX1 and SPRY2). Comparison with independent data suggest that 802 of them might be specific to craniofacial development, and genes near these peaks are enriched in processes relevant to nsCL/P. Integration with nsCL/P GWAS data, however, did not show robust evidence for co-localization of common nsCL/P risk variants with TFAP2A ChIP-seq peaks. This data set represents a new resource for the analyses of craniofacial processes, and similar approaches with additional cell lines and TFs could be applied to generate further insights into nsCL/P etiology.