bluuebunny/crossref_metadata_2025 huggingface dataset:
Let-7f miRNA regulates SDF-1α- and hypoxia-promoted migration of mesenchymal stem cells and attenuates mammary tumor growth upon exosomal release
Authors: Egea Virginia , Kessenbrock Kai , Lawson Devon , Bartelt Alexander , Weber Christian , Ries Christian
Published: May 2021

Bone marrow-derived human mesenchymal stem cells (hMSCs) are recruited to damaged or inflamed tissues where they contribute to tissue repair. This multi-step process involves chemokine-directed invasion of hMSCs and on-site release of factors that influence target cells or tumor tissues. However, the underlying molecular mechanisms are largely unclear. Previously, we described that microRNA let-7f controls hMSC differentiation. Here, we investigated the role of let-7f in chemotactic invasion and paracrine anti-tumor effects. Incubation with stromal cell-derived factor-1α (SDF-1α) or inflammatory cytokines upregulated let-7f expression in hMSCs. Transfection of hMSCs with let-7f mimics enhanced CXCR4-dependent invasion by augmentation of pericellular proteolysis and release of matrix metalloproteinase-9. Hypoxia-induced stabilization of the hypoxia-inducible factor 1 alpha in hMSCs promoted cell invasion via let-7f and activation of autophagy. Dependent on its endogenous level, let-7f facilitated hMSC motility and invasion through regulation of the autophagic flux in these cells. In addition, secreted let-7f encapsulated in exosomes was increased upon upregulation of endogenous let-7f by treatment of the cells with SDF-1α, hypoxia, or induction of autophagy. In recipient 4T1 tumor cells, hMSC-derived exosomal let-7f attenuated proliferation and invasion. Moreover, implantation of 3D spheroids composed of hMSCs and 4T1 cells into a breast cancer mouse model demonstrated that hMSCs overexpressing let-7f inhibited tumor growth in vivo. Our findings provide evidence that let-7f is pivotal in the regulation of hMSC invasion in response to inflammation and hypoxia, suggesting that exosomal let-7f exhibits paracrine anti-tumor effects.
Regulation of sarcomagenesis by the empty spiracles homeobox genes EMX1 and EMX2
Authors: Jimenez-García Manuel Pedro , Lucena-Cacace Antonio , Otero-Albiol Daniel , Carnero Amancio
Published: May 2021

The EMX (Empty Spiracles Homeobox) genesEMX1andEMX2are two homeodomain gene members of the EMX family of transcription factors involved in the regulation of various biological processes, such as cell proliferation, migration, and differentiation, during brain development and neural crest migration. They play a role in the specification of positional identity, the proliferation of neural stem cells, and the differentiation of certain neuronal cell phenotypes. In general, they act as transcription factors in early embryogenesis and neuroembryogenesis from metazoans to higher vertebrates. TheEMX1andEMX2’s potential as tumor suppressor genes has been suggested in some cancers. Our work showed thatEMX1/EMX2act as tumor suppressors in sarcomas by repressing the activity of stem cell regulatory genes (OCT4,SOX2,KLF4,MYC,NANOG,NES, andPROM1). EMX protein downregulation, therefore, induced the malignance and stemness of cells both in vitro and in vivo. In murine knockout (KO) models lackingEmxgenes, 3MC-induced sarcomas were more aggressive and infiltrative, had a greater capacity for tumor self-renewal, and had higher stem cell gene expression andnestinexpression than those in wild-type models. These results showing that EMX genes acted as stemness regulators were reproduced in different subtypes of sarcoma. Therefore, it is possible that the EMX genes could have a generalized behavior regulating proliferation of neural crest-derived progenitors. Together, these results indicate that theEMX1andEMX2genes negatively regulate these tumor-altering populations or cancer stem cells, acting as tumor suppressors in sarcoma.
Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue
Authors: Georgiadi Anastasia , Lopez-Salazar Valeria , Merahbi Rabih El- , Karikari Rhoda Anane , Ma Xiaochuan , Mourão André , Klepac Katarina , Bühler Lea , Alfaro Ana Jimena , Kaczmarek Isabell , Linford Adam , Bosma Madeleen , Shilkova Olga , Ritvos Olli , Nakamura Nobuhiro , Hirose Shigehisa , Lassi Maximilian , Teperino Raffaele , Machado Juliano , Scheideler Marcel , Dietrich Arne , Geerlof Arie , Feuchtinger Annette , Blutke Andreas , Fischer Katrin , Müller Timo Dirk , Kessler Katharina , Schöneberg Torsten , Thor Doreen , Hornemann Silke , Kruse Michael , Nawroth Peter , Pivovarova-Ramich Olga , Pfeiffer Andreas Friedrich Hermann , Sattler Michael , Blüher Matthias , Herzig Stephan
Published: May 2021

The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.
Event generation and statistical sampling for physics with deep generative models and a density information buffer
Authors: Otten Sydney , Caron Sascha , de Swart Wieske , van Beekveld Melissa , Hendriks Luc , van Leeuwen Caspar , Podareanu Damian , Ruiz de Austri Roberto , Verheyen Rob
Published: May 2021

Simulating nature and in particular processes in particle physics require expensive computations and sometimes would take much longer than scientists can afford. Here, we explore ways to a solution for this problem by investigating recent advances in generative modeling and present a study for the generation of events from a physical process with deep generative models. The simulation of physical processes requires not only the production of physical events, but to also ensure that these events occur with the correct frequencies. We investigate the feasibility of learning the event generation and the frequency of occurrence with several generative machine learning models to produce events like Monte Carlo generators. We study three processes: a simple two-body decay, the processes e+e− → Z → l+l− and $$pp\to t\bar{t}$$
p
p
→
t

t

¯

including the decay of the top quarks and a simulation of the detector response. By buffering density information of encoded Monte Carlo events given the encoder of a Variational Autoencoder we are able to construct a prior for the sampling of new events from the decoder that yields distributions that are in very good agreement with real Monte Carlo events and are generated several orders of magnitude faster. Applications of this work include generic density estimation and sampling, targeted event generation via a principal component analysis of encoded ground truth data, anomaly detection and more efficient importance sampling, e.g., for the phase space integration of matrix elements in quantum field theories.
Self-association of MreC as a regulatory signal in bacterial cell wall elongation
Authors: Martins Alexandre , Contreras-Martel Carlos , Janet-Maitre Manon , Miyachiro Mayara M. , Estrozi Leandro F. , Trindade Daniel Maragno , Malospirito Caíque C. , Rodrigues-Costa Fernanda , Imbert Lionel , Job Viviana , Schoehn Guy , Attrée Ina , Dessen Andréa
Published: May 2021

The elongasome, or Rod system, is a protein complex that controls cell wall formation in rod-shaped bacteria. MreC is a membrane-associated elongasome component that co-localizes with the cytoskeletal element MreB and regulates the activity of cell wall biosynthesis enzymes, in a process that may be dependent on MreC self-association. Here, we use electron cryo-microscopy and X-ray crystallography to determine the structure of a self-associated form of MreC from Pseudomonas aeruginosa in atomic detail. MreC monomers interact in head-to-tail fashion. Longitudinal and lateral interfaces are essential for oligomerization in vitro, and a phylogenetic analysis of proteobacterial MreC sequences indicates the prevalence of the identified interfaces. Our results are consistent with a model where MreC’s ability to alternate between self-association and interaction with the cell wall biosynthesis machinery plays a key role in the regulation of elongasome activity.
Observed interannual changes beneath Filchner-Ronne Ice Shelf linked to large-scale atmospheric circulation
Authors: Hattermann Tore , Nicholls Keith W. , Hellmer Hartmut H. , Davis Peter E. D. , Janout Markus A. , Østerhus Svein , Schlosser Elisabeth , Rohardt Gerd , Kanzow Torsten
Published: May 2021

Floating ice shelves are the Achilles’ heel of the Antarctic Ice Sheet. They limit Antarctica’s contribution to global sea level rise, yet they can be rapidly melted from beneath by a warming ocean. At Filchner-Ronne Ice Shelf, a decline in sea ice formation may increase basal melt rates and accelerate marine ice sheet mass loss within this century. However, the understanding of this tipping-point behavior largely relies on numerical models. Our new multi-annual observations from five hot-water drilled boreholes through Filchner-Ronne Ice Shelf show that since 2015 there has been an intensification of the density-driven ice shelf cavity-wide circulation in response to reinforced wind-driven sea ice formation in the Ronne polynya. Enhanced southerly winds over Ronne Ice Shelf coincide with westward displacements of the Amundsen Sea Low position, connecting the cavity circulation with changes in large-scale atmospheric circulation patterns as a new aspect of the atmosphere-ocean-ice shelf system.
Inorganic-organic competitive coating strategy derived uniform hollow gradient-structured ferroferric oxide-carbon nanospheres for ultra-fast and long-term lithium-ion battery
Authors: Xia Yuan , Zhao Tiancong , Zhu Xiaohang , Zhao Yujuan , He Haili , Hung Chin-te , Zhang Xingmiao , Chen Yan , Tang Xinlei , Wang Jinxiu , Li Wei , Zhao Dongyuan
Published: May 2021

The gradient-structure is ideal nanostructure for conversion-type anodes with drastic volume change. Here, we demonstrate an inorganic-organic competitive coating strategy for constructing gradient-structured ferroferric oxide-carbon nanospheres, in which the deposition of ferroferric oxide nanoparticles and polymerization of carbonaceous species are competitive and well controlled by the reaction thermodynamics. The synthesized gradient-structure with a uniform size of ~420 nm consists of the ferroferric oxide nanoparticles (4–8 nm) in carbon matrix, which are aggregated into the inner layer (~15 nm) with high-to-low component distribution from inside to out, and an amorphous carbon layer (~20 nm). As an anode material, the volume change of the gradient-structured ferroferric oxide-carbon nanospheres can be limited to ~22% with ~7% radial expansion, thus resulting in stable reversible specific capacities of ~750 mAh g−1 after ultra-long cycling of 10,000 cycles under ultra-fast rate of 10 A g−1. This unique inorganic-organic competitive coating strategy bring inspiration for nanostructure design of functional materials in energy storage.
Covalency does not suppress O2 formation in 4d and 5d Li-rich O-redox cathodes
Authors: House Robert A. , Marie John-Joseph , Park Joohyuk , Rees Gregory J. , Agrestini Stefano , Nag Abhishek , Garcia-Fernandez Mirian , Zhou Ke-Jin , Bruce Peter G.
Published: May 2021

Layered Li-rich transition metal oxides undergo O-redox, involving the oxidation of the O2− ions charge compensated by extraction of Li+ ions. Recent results have shown that for 3d transition metal oxides the oxidized O2− forms molecular O2 trapped in the bulk particles. Other forms of oxidised O2− such as O22− or (O–O)n− with long bonds have been proposed, based especially on work on 4 and 5d transition metal oxides, where TM–O bonding is more covalent. Here, we show, using high resolution RIXS that molecular O2 is formed in the bulk particles on O2‒ oxidation in the archetypal Li-rich ruthenates and iridate compounds, Li2RuO3, Li2Ru0.5Sn0.5O3 and Li2Ir0.5Sn0.5O3. The results indicate that O-redox occurs across 3, 4, and 5d transition metal oxides, forming O2, i.e. the greater covalency of the 4d and 5d compounds still favours O2. RIXS and XAS data for Li2IrO3 are consistent with a charge compensation mechanism associated primarily with Ir redox up to and beyond the 5+ oxidation state, with no evidence of O–O dimerization.
Self-rectifying resistive memory in passive crossbar arrays
Authors: Jeon Kanghyeok , Kim Jeeson , Ryu Jin Joo , Yoo Seung-Jong , Song Choongseok , Yang Min Kyu , Jeong Doo Seok , Kim Gun Hwan
Published: May 2021

Conventional computing architectures are poor suited to the unique workload demands of deep learning, which has led to a surge in interest in memory-centric computing. Herein, a trilayer (Hf0.8Si0.2O2/Al2O3/Hf0.5Si0.5O2)-based self-rectifying resistive memory cell (SRMC) that exhibits (i) large selectivity (ca. 104), (ii) two-bit operation, (iii) low read power (4 and 0.8 nW for low and high resistance states, respectively), (iv) read latency (<10 μs), (v) excellent non-volatility (data retention >104 s at 85 °C), and (vi) complementary metal-oxide-semiconductor compatibility (maximum supply voltage ≤5 V) is introduced, which outperforms previously reported SRMCs. These characteristics render the SRMC highly suitable for the main memory for memory-centric computing which can improve deep learning acceleration. Furthermore, the low programming power (ca. 18 nW), latency (100 μs), and endurance (>106) highlight the energy-efficiency and highly reliable random-access memory of our SRMC. The feasible operation of individual SRMCs in passive crossbar arrays of different sizes (30 × 30, 160 × 160, and 320 × 320) is attributed to the large asymmetry and nonlinearity in the current-voltage behavior of the proposed SRMC, verifying its potential for application in large-scale and high-density non-volatile memory for memory-centric computing.
TNF controls a speed-accuracy tradeoff in the cell death decision to restrict viral spread
Authors: Oyler-Yaniv Jennifer , Oyler-Yaniv Alon , Maltz Evan , Wollman Roy
Published: May 2021

Rapid death of infected cells is an important antiviral strategy. However, fast decisions that are based on limited evidence can be erroneous and cause unnecessary cell death and subsequent tissue damage. How cells optimize their death decision making strategy to maximize both speed and accuracy is unclear. Here, we show that exposure to TNF, which is secreted by macrophages during viral infection, causes cells to change their decision strategy from “slow and accurate” to “fast and error-prone”. Mathematical modeling combined with experiments in cell culture and whole organ culture show that the regulation of the cell death decision strategy is critical to prevent HSV-1 spread. These findings demonstrate that immune regulation of cellular cognitive processes dynamically changes a tissues’ tolerance for self-damage, which is required to protect against viral spread.
Genetic architecture and lifetime dynamics of inbreeding depression in a wild mammal
Authors: Stoffel M. A. , Johnston S. E. , Pilkington J. G. , Pemberton J. M.
Published: May 2021

Inbreeding depression is ubiquitous, but we still know little about its genetic architecture and precise effects in wild populations. Here, we combine long-term life-history data with 417 K imputed SNP genotypes for 5952 wild Soay sheep to explore inbreeding depression on a key fitness component, annual survival. Inbreeding manifests in long runs of homozygosity (ROH), which make up nearly half of the genome in the most inbred individuals. The ROH landscape varies widely across the genome, with islands where up to 87% and deserts where only 4% of individuals have ROH. The fitness consequences of inbreeding are severe; a 10% increase in individual inbreeding FROH is associated with a 60% reduction in the odds of survival in lambs, though inbreeding depression decreases with age. Finally, a genome-wide association scan on ROH shows that many loci with small effects and five loci with larger effects contribute to inbreeding depression in survival.
RETRACTED ARTICLE: Production of viable chicken by allogeneic transplantation of primordial germ cells induced from somatic cells
Authors: Zhao Ruifeng , Zuo Qisheng , Yuan Xia , Jin Kai , Jin Jing , Ding Ying , Zhang Chen , Li Tingting , Jiang Jingyi , Li Jiancheng , Zhang Ming , Shi Xiang , Sun Hongyan , Zhang Yani , Xu Qi , Chang Guobin , Zhao Zhenhua , Li Bing , Wu Xinsheng , Zhang Yang , Song Jiuzhou , Chen Guohong , Li Bichun
Published: May 2021

The allogeneic transplantation of primordial germ cells (PGCs) derived from somatic cells overcomes the limitation of avian cloning. Here, we transdifferentiate chicken embryo fibroblasts (CEFs) from black feathered Langshan chickens to PGCs and transplant them into White Plymouth Rock chicken embryos to produce viable offspring with characteristics inherited from the donor. We express Oct4/Sox2/Nanog/Lin28A (OSNL) to reprogram CEFs to induced pluripotent stem cells (iPSCs), which are further induced to differentiate into PGCs by BMP4/BMP8b/EGF. DNA demethylation, histone acetylation and glycolytic activation elevate the iPSC induction efficiency, while histone acetylation and glycolytic inhibition facilitate PGCs formation. The induced PGCs (iPGCs) are transplanted into the recipients, which are self-crossed to produce 189/509 somatic cells derived chicken with the donor’s characteristics. Microsatellite analysis and genome sequencing confirm the inheritance of genetic information from the donor. Thus, we demonstrate the feasibility of avian cloning from somatic cells.
Wide field light-sheet microscopy with lens-axicon controlled two-photon Bessel beam illumination
Authors: Takanezawa Sota , Saitou Takashi , Imamura Takeshi
Published: May 2021

Two-photon excitation can lower phototoxicity and improve penetration depth, but its narrow excitation range restricts its applications in light-sheet microscopy. Here, we propose simple illumination optics, a lens-axicon triplet composed of an axicon and two convex lenses, to generate longer extent Bessel beams. This unit can stretch the beam full width at half maximum of 600–1000 μm with less than a 4-μm waist when using a 10× illumination lens. A two-photon excitation digital scanned light-sheet microscope possessing this range of field of view and ~2–3-μm axial resolution is constructed and used to analyze the cellular dynamics over the whole body of medaka fish. We demonstrate long-term time-lapse observations over several days and high-speed recording with ~3 mm3 volume per 4 s of the embryos. Our system is minimal and suppresses laser power loss, which can broaden applications of two-photon excitation in light-sheet microscopy.
The limits of near field immersion microwave microscopy evaluated by imaging bilayer graphene moiré patterns
Authors: Ohlberg Douglas A. A. , Tami Diego , Gadelha Andreij C. , Neto Eliel G. S. , Santana Fabiano C. , Miranda Daniel , Avelino Wellington , Watanabe Kenji , Taniguchi Takashi , Campos Leonardo C. , Ramirez Jhonattan C. , do Rego Cássio Gonçalves , Jorio Ado , Medeiros-Ribeiro Gilberto
Published: May 2021

Near field scanning Microwave Impedance Microscopy can resolve structures as small as 1 nm using radiation with wavelengths of 0.1 m. Combining liquid immersion microscopy concepts with exquisite force control exerted on nanoscale water menisci, concentration of electromagnetic fields in nanometer-size regions was achieved. As a test material we use twisted bilayer graphene, because it provides a sample where the modulation of the moiré superstructure pattern can be systematically tuned from Ångstroms up to tens of nanometers. Here we demonstrate that a probe-to-pattern resolution of 108 can be obtained by analyzing and adjusting the tip-sample distance influence on the dynamics of water meniscus formation and stability.
Distinct place cell dynamics in CA1 and CA3 encode experience in new environments
Authors: Dong Can , Madar Antoine D. , Sheffield Mark E. J.
Published: May 2021

When exploring new environments animals form spatial memories that are updated with experience and retrieved upon re-exposure to the same environment. The hippocampus is thought to support these memory processes, but how this is achieved by different subnetworks such as CA1 and CA3 remains unclear. To understand how hippocampal spatial representations emerge and evolve during familiarization, we performed 2-photon calcium imaging in mice running in new virtual environments and compared the trial-to-trial dynamics of place cells in CA1 and CA3 over days. We find that place fields in CA1 emerge rapidly but tend to shift backwards from trial-to-trial and remap upon re-exposure to the environment a day later. In contrast, place fields in CA3 emerge gradually but show more stable trial-to-trial and day-to-day dynamics. These results reflect different roles in CA1 and CA3 in spatial memory processing during familiarization to new environments and constrain the potential mechanisms that support them.
The impact of chromosomal fusions on 3D genome folding and recombination in the germ line
Authors: Vara Covadonga , Paytuví-Gallart Andreu , Cuartero Yasmina , Álvarez-González Lucía , Marín-Gual Laia , Garcia Francisca , Florit-Sabater Beatriu , Capilla Laia , Sanchéz-Guillén Rosa Ana , Sarrate Zaida , Aiese Cigliano Riccardo , Sanseverino Walter , Searle Jeremy B. , Ventura Jacint , Marti-Renom Marc A. , Le Dily François , Ruiz-Herrera Aurora
Published: May 2021

The spatial folding of chromosomes inside the nucleus has regulatory effects on gene expression, yet the impact of genome reshuffling on this organization remains unclear. Here, we take advantage of chromosome conformation capture in combination with single-nucleotide polymorphism (SNP) genotyping and analysis of crossover events to study how the higher-order chromatin organization and recombination landscapes are affected by chromosomal fusions in the mammalian germ line. We demonstrate that chromosomal fusions alter the nuclear architecture during meiosis, including an increased rate of heterologous interactions in primary spermatocytes, and alterations in both chromosome synapsis and axis length. These disturbances in topology were associated with changes in genomic landscapes of recombination, resulting in detectable genomic footprints. Overall, we show that chromosomal fusions impact the dynamic genome topology of germ cells in two ways: (i) altering chromosomal nuclear occupancy and synapsis, and (ii) reshaping landscapes of recombination.
Controlling COVID-19 via test-trace-quarantine
Authors: Kerr Cliff C. , Mistry Dina , Stuart Robyn M. , Rosenfeld Katherine , Hart Gregory R. , Núñez Rafael C. , Cohen Jamie A. , Selvaraj Prashanth , Abeysuriya Romesh G. , Jastrzębski Michał , George Lauren , Hagedorn Brittany , Panovska-Griffiths Jasmina , Fagalde Meaghan , Duchin Jeffrey , Famulare Michael , Klein Daniel J.
Published: May 2021

Initial COVID-19 containment in the United States focused on limiting mobility, including school and workplace closures. However, these interventions have had enormous societal and economic costs. Here, we demonstrate the feasibility of an alternative control strategy, test-trace-quarantine: routine testing of primarily symptomatic individuals, tracing and testing their known contacts, and placing their contacts in quarantine. We perform this analysis using Covasim, an open-source agent-based model, which has been calibrated to detailed demographic, mobility, and epidemiological data for the Seattle region from January through June 2020. With current levels of mask use and schools remaining closed, we find that high but achievable levels of testing and tracing are sufficient to maintain epidemic control even under a return to full workplace and community mobility and with low vaccine coverage. The easing of mobility restrictions in June 2020 and subsequent scale-up of testing and tracing programs through September provided real-world validation of our predictions. Although we show that test-trace-quarantine can control the epidemic in both theory and practice, its success is contingent on high testing and tracing rates, high quarantine compliance, relatively short testing and tracing delays, and moderate to high mask use. Thus, in order for test-trace-quarantine to control transmission with a return to high mobility, strong performance in all aspects of the program is required.
A pan-African spatial assessment of human conflicts with lions and elephants
Authors: Di Minin Enrico , Slotow Rob , Fink Christoph , Bauer Hans , Packer Craig
Published: May 2021

African lions (Panthera leo) and African savanna (Loxodonta africana) and forest (L. cyclotis) elephants pose threats to people, crops, and livestock, and are themselves threatened with extinction. Here, we map these human-wildlife conflicts across Africa. Eighty-two percent of sites containing lions and elephants are adjacent to areas with considerable human pressure. Areas at severe risk of conflict (defined as high densities of humans, crops, and cattle) comprise 9% of the perimeter of these species’ ranges and are found in 18 countries hosting, respectively, ~ 74% and 41% of African lion and elephant populations. Although a variety of alternative conflict-mitigation strategies could be deployed, we focus on assessing the potential of high-quality mitigation fences. Our spatial and economic assessments suggest that investments in the construction and maintenance of strategically located mitigation fences would be a cost-effective strategy to support local communities, protect people from dangerous wildlife, and prevent further declines in lion and elephant populations.
Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer (“METRIC”): a randomized multicenter study
Authors: Vahdat Linda T. , Schmid Peter , Forero-Torres Andres , Blackwell Kimberly , Telli Melinda L. , Melisko Michelle , Möbus Volker , Cortes Javier , Montero Alberto J. , Ma Cynthia , Nanda Rita , Wright Gail S. , He Yi , Hawthorne Thomas , Bagley Rebecca G. , Halim Abdel-Baset , Turner Christopher D. , Yardley Denise A.
Published: May 2021

The METRIC study (NCT#0199733) explored a novel antibody–drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1–14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine.
NRG Oncology/NSABP B-47 menstrual history study: impact of adjuvant chemotherapy with and without trastuzumab
Authors: Ganz Patricia A. , Cecchini Reena S. , Fehrenbacher Louis , Geyer Charles E. , Rastogi Priya , Crown John P. , Thirlwell Michael P. , Ellison David M. , Boileau Jean-Francois , Flynn Patrick J. , Jeong Jong-Hyeon , Mamounas Eleftherios P. , Wolmark Norman
Published: May 2021

The NRG Oncology/NSABP B-47 menstrual history (MH) study examined trastuzumab effects on menstrual status and associated circulating reproductive hormones. MH was evaluated by questions related to hysterectomy, oophorectomy, and reported menstrual changes. Pre/perimenopausal women were assessed at entry, 3, 6, 12, 18, 24, 30, and 36 months. Consenting women had estradiol and FSH measurement at entry, 3, 6, 12, 18, and 24 months. Logistic regression determined predictors of amenorrhea and hormone levels at 12, 24, and 36 months. Between 2/8/2011 and 2/10/2015, 3270 women with node-positive/high-risk node-negative HER2-low breast cancer were enrolled. There were 1,458 women enrolled in the MH study; 1231 consented to baseline blood samples. Trastuzumab did not contribute to a higher amenorrhea rate. Amenorrhea predictors were consistent with earlier studies; however, to our knowledge, this is the largest prospective study to include serial reproductive hormone measurements to 24 months and clinical amenorrhea reports to 36 months. These data can help to counsel patients regarding premature menopause risk.
HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now
Authors: Schlam Ilana , Swain Sandra M.
Published: May 2021

Human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20–25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.
Dengue emergence in the temperate Argentinian province of Santa Fe, 2009–2020
Authors: López María S. , Jordan Daniela I. , Blatter Evelyn , Walker Elisabet , Gómez Andrea A. , Müller Gabriela V. , Mendicino Diego , Robert Michael A. , Estallo Elizabet L.
Published: May 2021

Dengue virus (DENV) transmission occurs primarily in tropical and subtropical climates, but within the last decade it has extended to temperate regions. Santa Fe, a temperate province in Argentina, has experienced an increase in dengue cases and virus circulation since 2009, with the recent 2020 outbreak being the largest in the province to date. The aim of this work is to describe spatio-temporal fluctuations of dengue cases from 2009 to 2020 in Santa Fe Province. The data presented in this work provide a detailed description of DENV transmission for Santa Fe Province by department. These data are useful to assist in investigating drivers of dengue emergence in Santa Fe Province and for developing a better understanding of the drivers and the impacts of ongoing dengue emergence in temperate regions across the world. This work provides data useful for future studies including those investigating socio-ecological, climatic, and environmental factors associated with DENV transmission, as well as those investigating other variables related to the biology and the ecology of vector-borne diseases.
Analysing wideband absorbance immittance in normal and ears with otitis media with effusion using machine learning
Authors: Grais Emad M. , Wang Xiaoya , Wang Jie , Zhao Fei , Jiang Wen , Cai Yuexin , Zhang Lifang , Lin Qingwen , Yang Haidi
Published: May 2021

Wideband Absorbance Immittance (WAI) has been available for more than a decade, however its clinical use still faces the challenges of limited understanding and poor interpretation of WAI results. This study aimed to develop Machine Learning (ML) tools to identify the WAI absorbance characteristics across different frequency-pressure regions in the normal middle ear and ears with otitis media with effusion (OME) to enable diagnosis of middle ear conditions automatically. Data analysis included pre-processing of the WAI data, statistical analysis and classification model development, and key regions extraction from the 2D frequency-pressure WAI images. The experimental results show that ML tools appear to hold great potential for the automated diagnosis of middle ear diseases from WAI data. The identified key regions in the WAI provide guidance to practitioners to better understand and interpret WAI data and offer the prospect of quick and accurate diagnostic decisions.
Clinical characterization of respiratory large droplet production during common airway procedures using high-speed imaging
Authors: Mueller S. K. , Veltrup R. , Jakubaß B. , Kniesburges S. , Huebner M. J. , Kempfle J. S. , Dittrich S. , Iro H. , Döllinger M.
Published: May 2021

During the COVID-19 pandemic, a significant number of healthcare workers have been infected with SARS-CoV-2. However, there remains little knowledge regarding large droplet dissemination during airway management procedures in real life settings. 12 different airway management procedures were investigated during routine clinical care. A high-speed video camera (1000 frames/second) was for imaging. Quantitative droplet characteristics as size, distance traveled, and velocity were computed. Droplets were detected in 8/12 procedures. The droplet trajectories could be divided into two distinctive patterns (type 1/2). Type 1 represented a ballistic trajectory with higher speed large droplets whereas type 2 represented a random trajectory of slower particles that persisted longer in air. The use of tracheal cannula filters reduced the amount of droplets. Respiratory droplet patterns generated during airway management procedures follow two distinctive trajectories based on the influence of aerodynamic forces. Speaking and coughing produce more droplets than non-invasive ventilation therapy confirming these behaviors as exposure risks. Even large droplets may exhibit patterns resembling the fluid dynamics smaller airborne aerosols that follow the airflow convectively and may place the healthcare provider at risk.
3D free-hand ultrasound to register anatomical landmarks at the pelvis and localize the hip joint center in lean and obese individuals
Authors: Horsak Brian , Schwab Caterine , Durstberger Sebastian , Thajer Alexandra , Greber-Platzer Susanne , Kainz Hans , Jonkers Ilse , Kranzl Andreas
Published: May 2021

3D free-hand ultrasound (3DFUS) is becoming increasingly popular to assist clinical gait analysis because it is cost- and time-efficient and does not expose participants to radiation. The aim of this study was to evaluate its reliability in localizing the anterior superior iliac spine (ASIS) at the pelvis and the hip joint centers (HJC). Additionally, we evaluated its accuracy to get a rough estimation of the potential to use of 3DFUS to segment bony surface. This could offer potential to register medical images to motion capture data in future. To evaluate reliability, a test–retest study was conducted in 16 lean and 19 obese individuals. The locations of the ASIS were determined by manual marker placement (MMP), an instrumented pointer technique (IPT), and with 3DFUS. The HJC location was also determined with 3DFUS. To quantify reliability, intraclass correlation coefficients (ICCs), the standard error of measurement (SEm), among other statistical parameters, were calculated for the identified locations between the test and retest. To assess accuracy, the surface of a human plastic pelvic phantom was segmented with 3DFUS in a distilled water bath in 27 trials and compared to a 3D laser scan of the pelvis. Regarding reliability, the MMP, but especially the IPT showed high reliability in lean (SEm: 2–3 mm) and reduced reliability in obese individuals (SEm: 6–15 mm). Compared to MMP and IPT, 3DFUS presented lower reliability in the lean group (SEm: 2–4 mm vs. 2–8 mm, respectively) but slightly better values in the obese group (SEm: 7–11 mm vs. 6–16 mm, respectively). Correlations between test–retest reliability and torso body fat mass (% of body mass) indicated a moderate to strong relationship for MMP and IPT but only a weak correlation for the 3DFUS approach. The water-bath experiments indicated an acceptable level of 3.5 (1.7) mm of accuracy for 3DFUS in segmenting bone surface. Despite some difficulties with single trials, our data give further rise to the idea that 3DFUS could serve as a promising tool in future to inform marker placement and hip joint center location, especially in groups with higher amount of body fat.
Germination response to water availability in populations of Festuca pallescens along a Patagonian rainfall gradient based on hydrotime model parameters
Authors: López Aldana S. , López D. R. , Arana M. V. , Batlla D. , Marchelli P.
Published: May 2021

Sensitivity to water availability is a key physiological trait for grassland species located in arid and semiarid environments, where successful germination is closely related to rainfall dynamics. Festuca pallescens inhabits diverse environments along a steep precipitation gradient in North Patagonia, thus offering a suitable model for the study of germination behavior in response to water availability. By analyzing germination in nine populations using a hydrotime model approach, we aimed to find within-species variation. Seed population behavior was analyzed under different hydric conditions using hydrotime model parameters (hydrotime, mean base water potential and its standard deviation). We estimated the mean base water potential for F. pallescens (ψb(50) = − 2.79 ± 0.45 MPa), which did not differ significantly between populations. However, the hydrotime parameter (θH) varied markedly, suggesting physiological adaptation to local environments. Higher values of θH were found in populations located at the extremes of the distribution gradient, indicating that germination may be prevented or delayed in conditions that are suboptimal for the species. Since the variation in hydrotime model parameters did not follow a cline, micro-environmental cues may have the greatest influence on the physiological behavior of the species, rather than the macroscale rainfall gradient.
Impact of soil water regimes and partial root-zone drying in field-grown papaya in semi-arid conditions
Authors: Santos Dionei Lima , Coelho Eugênio Ferreira , de Oliveira Rubens Alves , Filgueiras Roberto , da Silva Alves Márcio , Rodrigues Weverton Pereira , Campostrini Eliemar , Sampaio Antônio Hélder Rodrigues , da Silva Reis João Batista Ribeiro , da Cunha Fernando França
Published: May 2021

This study aimed to evaluate in the papaya Tainung genotype, the effects of partial root-zone drying (PRD) technique on soil water regimes by using different frequencies of shifting irrigation-side of plant row and the effects of PRD technique on (1) crop agronomic performance, (2) titratable fruit acidity (TA), (3) total soluble solids (TSS), and TSS/TA ratio. Also, we analyze the spatial dynamic of papaya condition using normalized difference vegetation index (NDVI) from different satellite images. The study was conducted in the semi-arid region of Bahia (BA) and Minas Gerais (MG), Brazil. The combination of 100% (Full irrigation—FU), 50%, and 35% in the irrigation depth (WID) and frequencies of shifting plant-row side irrigation of 0 (Fixed Irrigation—FX), 7, 14, and 21 days were applied. Nine treatments were studied in BA and five in MG. The water available in the soil was reduced to 44% for frequencies of shifting plant-row side irrigation of 7 days, 50% for 14 days, and 85% for 21 days, compared to the soil water availability at field capacity. Partial water deficit in the soil through the PRD technique did not significantly reduce the total root length, effective root depth, and root effective horizontal distance of the papaya Tainung genotype. However, PRD treatments showed leaf abscission, which resulted in reduced leaf area and NDVI values, especially in the MG experiment. Papaya yield and fruit quality were not affected. However, except for PRD 21 35%, irrigation water depth reduced to 50 and 35% under PRD increased crop water productivity (CWP) in papaya plants. Thus, the PRD technique may save 35% of WID using the alternation of lateral shift irrigation of crop row every 7 days under water scarcity in semi-arid regions. The NDVI index was important to compare the papaya canopy vigor between the experimental areas studied. We also confirmed the potential of NDVI to monitor the vigor of papaya canopy, since we could notice the sensibility of NDVI to identify water stress in papaya in higher vapor pressure deficit (VPD) conditions occurred in October 2016 and January 2017 in Bom Jesus da Lapa-BA. Therefore, the PRD strategy can be a useful tool to save water in papaya cultivation under semi-arid conditions.
Contrasting metabolic strategies of two co-occurring deep-sea octocorals
Authors: Rakka M. , Maier S. R. , Van Oevelen D. , Godinho A. , Bilan M. , Orejas C. , Carreiro-Silva M.
Published: May 2021

The feeding biology of deep-sea octocorals remains poorly understood, as attention is more often directed to reef building corals. The present study focused on two common deep-water octocoral species in the Azores Archipelago, Dentomuricea aff. meteor and Viminella flagellum, aiming at determining their ability to exploit different food sources. We adopted an experimental approach, with three different food sources, including live phytoplankton, live zooplankton and dissolved organic matter (DOM), that were artificially enriched with 13C and 15N (C and N tracers). The presence of tracers was subsequently followed in the coral tissue, C respiration and particulate organic C and N (POC and PON) release. In both species, feeding with zooplankton resulted in significantly higher incorporation of tracers in all measured variables, compared to the other food sources, highlighting the importance of zooplankton for major physiological processes. Our results revealed contrasting metabolic strategies between the two species, with D. aff. meteor acquiring higher amounts of prey and allocating higher percentage to respiration and release of POC and PON than V. flagellum. Such metabolic differences can shape species fitness and distributions and have further ecological implications on the ecosystem function of communities formed by different octocoral species.
Extracts from Pulsatilla patens target cancer-related signaling pathways in HeLa cells
Authors: Łaska Grażyna , Maciejewska-Turska Magdalena , Sieniawska Elwira , Świątek Łukasz , Pasco David S. , Balachandran Premalatha
Published: May 2021

The purpose of this study was to determine if a methanolic extract of the Pulsatilla patens (L.) Mill. can inhibit the progression of cancer through the modulation of cancer-related metabolic signaling pathways. We analyzed a panel of 13 inducible luciferase reporter gene vectors which expression is driven by enhancer elements that bind to specific transcription factors for the evaluation of the activity of cancer signaling pathways. The root extract of P. patens exhibited strong inhibition of several signaling pathways in HeLa cells, a cervical cancer cell line, and was found to be the most potent in inhibiting the activation of Stat3, Smad, AP-1, NF-κB, MYC, Ets, Wnt and Hdghog, at a concentration of 40 µg/mL. The methanolic extracts of P. patens enhanced apoptotic death, deregulated cellular proliferation, differentiation, and progression towards the neoplastic phenotype by altering key signaling molecules required for cell cycle progression. This is the first study to report the influence of Pulsatilla species on cancer signaling pathways. Further, our detailed phytochemical analysis of the methanolic extracts of the P. patens allowed to deduce that compounds, which strongly suppressed the growth and proliferation of HeLa cancer cells were mainly triterpenoid saponins accompanied by phenolic acids.
Primary sclerosing cholangitis and the risk of cancer, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of cohort studies
Authors: Aune Dagfinn , Sen Abhijit , Norat Teresa , Riboli Elio , Folseraas Trine
Published: May 2021

A diagnosis of primary sclerosing cholangitis (PSC) has been associated with increased risk of hepatobiliary cancers, colorectal cancer and all-cause mortality in several studies, while associations with cardiovascular disease have been inconsistent. We conducted a systematic review and meta-analysis of published cohort studies on the topic to summarize these associations. PubMed and Embase databases were searched up to January 13th, 2020. Cohort studies on PSC and risk of cancer, cardiovascular disease, or mortality were included. Summary relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated using random effects models. The summary RR (95% CI) comparing persons with PSC to persons without PSC was 584.37 (269.42–1267.51, I2 = 89%, n = 4) for cholangiocarcinoma (CCA), 155.54 (125.34–193.02, I2 = 0%, n = 3) for hepatobiliary cancer, 30.22 (11.99–76.17, I2 = 0%, n = 2) for liver cancer, 16.92 (8.73–32.78, I2 = 88%, n = 4) for gastrointestinal cancer, 7.56 (2.42–23.62, I2 = 0%, n = 3) for pancreatic cancer, 6.10 (4.19–8.87, I2 = 14%, n = 7) for colorectal cancer (CRC), 4.13 (2.99–5.71, I2 = 80%, n = 5) for total cancer, 3.55 (2.94–4.28, I2 = 46%, n = 5) for all-cause mortality, and 1.57 (0.25–9.69, I2 = 79%, n = 2) for cardiovascular disease. Strong positive associations were observed between PSC and risk of CCA, hepatobiliary cancer, liver cancer, gastrointestinal cancer, pancreatic cancer, CRC, total cancer, and all-cause mortality, but not for cardiovascular disease.