bluuebunny/crossref_metadata_2025_split huggingface dataset:
‘Essential Tremor’ Phenotype in FMR1 Premutation/Gray Zone Sibling Series: Exploring Possible Genetic Modifiers
Authors: Loesch Danuta Z. , Duffy David L. , Martin Nicholas G. , Tassone Flora , Atkinson Anna , Storey Elsdon 
Published: March 2021

AbstractFragile X-associated tremor/ataxia syndrome (FXTAS) occurs in carriers of fragile X mental retardation 1 (FMR1) X-linked small CGG expansion (gray zone [GZ] and premutation [PM]) alleles, containing 41–200 repeats. Major features comprise kinetic tremor, gait ataxia, cognitive decline and cerebellar peduncular white matter lesions, but atypical/incomplete FXTAS may occur. We explored the possibility of polygenic effects modifying the FXTAS spectrum phenotypes. We used three motor scales and selected cognitive tests in a series of three males and three females from a single sibship carrying PM or GZ alleles (44 to 75 repeats). The molecular profiles from these siblings were determined by genomewide association study with single-nucleotide polymorphism (SNP) genotyping by Illumina Global Screening Array. Nonparametric linkage analysis was applied and Parkinson’s disease (PD) polygenic risk scores (PRSs) were calculated for all the siblings, based on 107 known risk variants. All male and female siblings manifested similar kinetic tremor phenotypes. In contrast to FXTAS, they showed negligible gait ataxia, and few white matter lesions on MRI. Cognitive functioning was unaffected. Suggestive evidence of linkage to a broad region of the short arm of chromosome 10 was obtained, and median PD PRS for the sibship fell within the top 30% of a sample of over 500,000 UK and Australian controls. The genomewide study results are suggestive of modifying effects of genetic risk loci linked to PD, on the neurological phenotype of FMR1-CGG small expansion carriers, resulting in an oligosymptomatic kinetic tremor seen in FXTAS spectrum, but also consistent with essential tremor.
Direct Estimates of Turbulent Mixing in the Indonesian Archipelago and Its Role in the Transformation of the Indonesian Throughflow Waters
Authors: Nagai Taira , Hibiya Toshiyuki , Syamsudin Fadli 
Published: March 2021

AbstractTurbulent mixing enhanced in the Indonesian Archipelago (IA) is thought to influence the coupled ocean‐climate system through sea surface temperature cooling and water‐mass transformation. The present study describes the first extensive microstructure measurements conducted in the IA in 2019. A total of 120 profiles of turbulent energy dissipation rates showed that strong turbulent mixing was extremely localized in a few narrow tidal straits, where large density overturns and high vertical diffusivity associated with downslope jets were found. Far away from mixing hotspots, in contrast, observed vertical diffusivities were similar to typical open ocean values. Microstructure measurements together with a high‐resolution numerical simulation suggest that significant water‐mass transformation occurred within very short distances, O (10 km), in these narrow tidal straits through not only vertical mixing but also horizontal mixing enhanced by submesoscale topographic eddies.
Frontal Convergence and Vertical Velocity Measured by Drifters in the Alboran Sea
Authors: Tarry Daniel R. , Essink Sebastian , Pascual Ananda , Ruiz Simón , Poulain Pierre‐Marie , Özgökmen Tamay , Centurioni Luca R. , Farrar J. Thomas , Shcherbina Andrey , Mahadevan Amala , D’Asaro Eric 
Published: March 2021

AbstractHorizontal and vertical motions associated with mesoscale (10–100 km) and submesoscale (1–10 km) features, such as fronts, meanders, eddies, and filaments, play a critical role in redistributing physical and biogeochemical properties in the ocean. This study makes use of a multiplatform data set of 82 drifters, a Lagrangian float, and profile timeseries of temperature and salinity, obtained in a ∼1‐m/s semipermanent frontal jet in the Alboran Sea as part of CALYPSO (Coherent Lagrangian Pathways from the Surface Ocean to Interior). Drifters drogued at ∼1‐m and 15‐m depth capture the mesoscale and submesoscale circulation aligning along the perimeter of fronts due to horizontal shear. Clusters of drifters are used to estimate the kinematic properties, such as vorticity and divergence, of the flow by fitting a bivariate plane to the horizontal drifter velocities. Clusters with submesoscale length scales indicate normalized vorticity ζ/f > 1 with Coriolis frequency f and normalized divergence of (1) occurring in patches along the front, with error variance around 10%. By computing divergence from drifter clusters at two different depths, we estimate minimum vertical velocity of (−100 m day−1) in the upper 10 m of the water column. These results are at least twice as large as previous estimates of vertical velocity in the region. Location, magnitude, and timing of the convergence are consistent with behavior of a Lagrangian float subducting in the center of a drifter cluster. These results improve our understanding of frontal subduction and quantify convergence and vertical velocity using Lagrangian tools.
Early probiotic supplementation with B. infantis in breastfed infants leads to persistent colonization at 1 year
Authors: O’Brien Claire E. , Meier Anna K. , Cernioglo Karina , Mitchell Ryan D. , Casaburi Giorgio , Frese Steven A. , Henrick Bethany M. , Underwood Mark A. , Smilowitz Jennifer T. 
Published: March 2021

Abstract
Background
Recent studies have reported a dysfunctional gut microbiome in breastfed infants. Probiotics have been used in an attempt to restore the gut microbiome; however, colonization has been transient, inconsistent among individuals, or has not positively impacted the host’s gut.

Methods
This is a 2-year follow-up study to a randomized controlled trial wherein 7-day-old infants received 1.8 × 1010 colony-forming unit Bifidobacterium longum subsp. infantis (B. infantis) EVC001 (EVC) daily for 21 days or breast milk alone (unsupplemented (UNS)). In the follow-up study, mothers (n = 48) collected infant stool at 4, 6, 8, 10, and 12 months postnatal and completed the health-diet questionnaires.

Results
Fecal B. infantis was 2.5–3.5 log units higher at 6–12 months in the EVC group compared with the UNS group (P < 0.01) and this relationship strengthened with the exclusion of infants who consumed infant formula and antibiotics. Infants in the EVC group had significantly higher Bifidobacteriaceae and lower Bacteroidaceae and Lachnospiraceae (P < 0.05). There were no differences in any health conditions between the two groups.

Conclusions
Probiotic supplementation with B. infantis within the first month postnatal, in combination with breast milk, resulted in stable colonization that persisted until at least 1 year postnatal.

Impact

A dysfunctional gut microbiome in breastfed infants is common in resource-rich nations and associated with an increased risk of immune diseases.

Probiotics only transiently exist in the gut without persistent colonization or altering the gut microbiome.

This is the first study to show that early probiotic supplementation with B. infantis with breast milk results in stable colonization of B. infantis and improvements to the gut microbiome 1 year postnatal.

This study addresses a key gap in the literature whereby probiotics can restore the gut microbiome if biologically selected microorganisms are matched with their specific food in an open ecological niche.
Detection of clustered circulating tumour cells in early breast cancer
Authors: Krol Ilona , Schwab Fabienne D. , Carbone Roberta , Ritter Mathilde , Picocci Sabrina , De Marni Marzia L. , Stepien Grazyna , Franchi Gian M. , Zanardi Andrea , Rissoglio Marco D. , Covelli Alfredo , Guidi Guido , Scarinci Daniele , Castro-Giner Francesc , Mazzarella Luca , Doglioni Claudio , Borghi Francesca , Milani Paolo , Kurzeder Christian , Weber Walter P. , Aceto Nicola 
Published: March 2021

AbstractCirculating tumour cell (CTC) clusters have been proposed to be major players in the metastatic spread of breast cancer, particularly during advanced disease stages. Yet, it is unclear whether or not they manifest in early breast cancer, as their occurrence in patients with metastasis-free primary disease has not been thoroughly evaluated. In this study, exploiting nanostructured titanium oxide-coated slides for shear-free CTC identification, we detect clustered CTCs in the curative setting of multiple patients with early breast cancer prior to surgical treatment, highlighting their presence already at early disease stages. These results spotlight an important aspect of metastasis biology and the possibility to intervene with anti-cluster therapeutics already during the early manifestation of breast cancer.
Retrospective observational study of HER2 immunohistochemistry in borderline breast cancer patients undergoing neoadjuvant therapy, with an emphasis on Group 2 (HER2/CEP17 ratio ≥2.0, HER2 copy number <4.0 signals/cell) cases
Authors: Rakha Emad A. , Miligy Islam M. , Quinn Cecily M. , Provenzano Elena , Shaaban Abeer M. , Marchiò Caterina , Toss Michael S. , Gallagy Grace , Murray Ciara , Walshe Janice , Katayama Ayaka , Eldib Karim , Badr Nahla , Tanchel Bruce , Millican-Slater Rebecca , Purdie Colin , Purnell Dave , Pinder Sarah E. , Ellis Ian O. , Lee Andrew H. S. 
Published: March 2021

Abstract
Background
The ASCO/CAP guidance on HER2 testing in breast cancer (BC) has recently changed. Group 2 tumours with immunohistochemistry score 2+ and HER2/CEP17 ratio ≥2.0 and HER2 copy number <4.0 signals/cell were re-classified as HER2 negative. This study aims to examine the response of Group 2 tumours to neoadjuvant chemotherapy (NACT).

Methods
749 BC cases were identified from 11 institutions. The association between HER2 groups and pathological complete response (pCR) was assessed.

Results
54% of immunohistochemistry HER2 positive (score 3+) BCs showed pCR, compared to 19% of immunohistochemistry 2+ FISH amplified cases. 27% of Group 2 treated with HER2 targeted therapy achieved pCR, compared to 19 and 11% in the combined Groups 1 + 3 and Groups 4 + 5, respectively. No difference in pCR rates was identified between Group 2 and Group 1 or combined Groups 1 + 3. However, Group 2 response rate was higher than Groups 4 + 5 (p = 0.017).

Conclusion
No difference in pCR was detected in tumours with a HER2/CEP17 ratio ≥2.0 and a HER2 score 2+ by IHC when stratified by HER2 gene copy number. Our data suggest that ASCO/CAP HER2 Group 2 carcinomas should be evaluated further with respect to eligibility for HER2 targeted therapy.
Oleandrin, a cardiac glycoside, induces immunogenic cell death via the PERK/elF2α/ATF4/CHOP pathway in breast cancer
Authors: Li Xiaoxi , Zheng Jian , Chen Shi , Meng Fan-dong , Ning Jing , Sun Shu-lan 
Published: March 2021

AbstractChemotherapeutic agents have been linked to immunogenic cell death (ICD) induction that is capable of augmenting anti-tumor immune surveillance. The cardiac glycoside oleandrin, which inhibits Na+/K+-ATPase pump (NKP), has been shown to suppress breast cancer growth via inducing apoptosis. In the present study, we showed that oleandrin treatment triggered breast cancer cell ICD by inducing calreticulin (CRT) exposure on cell surface and the release of high-mobility group protein B1 (HMGB1), heat shock protein 70/90 (HSP70/90), and adenosine triphosphate (ATP). The maturation and activation of dendritic cells (DCs) were increased by co-culturing with the oleandrin-treated cancer cells, which subsequently enhanced CD8+ T cell cytotoxicity. Murine breast cancer cell line EMT6 was engrafted into BALB/c mice, and tumor-bearing mice were administered with oleandrin intraperitoneally every day. Oleandrin inhibited tumor growth and increased tumor infiltrating lymphocytes including DCs and T cells. Furthermore, the differential mRNA expression incurred by oleandrin was investigated by mRNA sequencing and subsequently confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Mechanistically, oleandrin induced endoplasmic reticulum (ER) stress-associated, caspase-independent ICD mainly through PERK/elF2α/ATF4/CHOP pathway. Pharmacological and genetic inhibition of protein kinase R-like ER kinase (PERK) suppressed oleandrin-triggered ICD. Taken together, our findings showed that oleandrin triggered ER stress and induced ICD-mediated immune destruction of breast cancer cells. Oleandrin combined with immune checkpoint inhibitors might improve the efficacy of immunotherapy.
The microbiota is dispensable for the early stages of peripheral regulatory T cell induction within mesenteric lymph nodes
Authors: Wiechers Carolin , Zou Mangge , Galvez Eric , Beckstette Michael , Ebel Maria , Strowig Till , Huehn Jochen , Pezoldt Joern 
Published: March 2021

AbstractIntestinal Foxp3+ regulatory T cell (Treg) subsets are crucial players in tolerance to microbiota-derived and food-borne antigens, and compelling evidence suggests that the intestinal microbiota modulates their generation, functional specialization, and maintenance. Selected bacterial species and microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), have been reported to promote Treg homeostasis in the intestinal lamina propria. Furthermore, gut-draining mesenteric lymph nodes (mLNs) are particularly efficient sites for the generation of peripherally induced Tregs (pTregs). Despite this knowledge, the direct role of the microbiota and their metabolites in the early stages of pTreg induction within mLNs is not fully elucidated. Here, using an adoptive transfer-based pTreg induction system, we demonstrate that neither transfer of a dysbiotic microbiota nor dietary SCFA supplementation modulated the pTreg induction capacity of mLNs. Even mice housed under germ-free (GF) conditions displayed equivalent pTreg induction within mLNs. Further molecular characterization of these de novo induced pTregs from mLNs by dissection of their transcriptomes and accessible chromatin regions revealed that the microbiota indeed has a limited impact and does not contribute to the initialization of the Treg-specific epigenetic landscape. Overall, our data suggest that the microbiota is dispensable for the early stages of pTreg induction within mLNs.
Hyaluronan is a natural and effective immunological adjuvant for protein-based vaccines
Authors: Dalla Pietà Anna , Carpanese Debora , Grigoletto Antonella , Tosi Anna , Dalla Santa Silvia , Pedersen Gabriel Kristian , Christensen Dennis , Meléndez-Alafort Laura , Barbieri Vito , De Benedictis Paola , Pasut Gianfranco , Montagner Isabella Monia , Rosato Antonio 
Published: March 2021

AbstractOne of the main goals of vaccine research is the development of adjuvants that can enhance immune responses and are both safe and biocompatible. We explored the application of the natural polymer hyaluronan (HA) as a promising immunological adjuvant for protein-based vaccines. Chemical conjugation of HA to antigens strongly increased their immunogenicity, reduced booster requirements, and allowed antigen dose sparing. HA-based bioconjugates stimulated robust and long-lasting humoral responses without the addition of other immunostimulatory compounds and proved highly efficient when compared to other adjuvants. Due to its intrinsic biocompatibility, HA allowed the exploitation of different injection routes and did not induce inflammation at the inoculation site. This polymer promoted rapid translocation of the antigen to draining lymph nodes, thus facilitating encounters with antigen-presenting cells. Overall, HA can be regarded as an effective and biocompatible adjuvant to be exploited for the design of a wide variety of vaccines.
Integrated avalanche photodetectors for visible light
Authors: Yanikgonul Salih , Leong Victor , Ong Jun Rong , Hu Ting , Siew Shawn Yohanes , Png Ching Eng , Krivitsky Leonid 
Published: March 2021

AbstractIntegrated photodetectors are essential components of scalable photonics platforms for quantum and classical applications. However, most efforts in the development of such devices to date have been focused on infrared telecommunications wavelengths. Here, we report the first monolithically integrated avalanche photodetector (APD) for visible light. Our devices are based on a doped silicon rib waveguide with a novel end-fire input coupling to a silicon nitride waveguide. We demonstrate a high gain-bandwidth product of 234 ± 25 GHz at 20 V reverse bias measured for 685 nm input light, with a low dark current of 0.12 μA. We also observe open eye diagrams at up to 56 Gbps. This performance is very competitive when benchmarked against other integrated APDs operating in the infrared range. With CMOS-compatible fabrication and integrability with silicon photonic platforms, our devices are attractive for sensing, imaging, communications, and quantum applications at visible wavelengths.
Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway
Authors: Fujino Takeshi , Goyama Susumu , Sugiura Yuki , Inoue Daichi , Asada Shuhei , Yamasaki Satoshi , Matsumoto Akiko , Yamaguchi Kiyoshi , Isobe Yumiko , Tsuchiya Akiho , Shikata Shiori , Sato Naru , Morinaga Hironobu , Fukuyama Tomofusa , Tanaka Yosuke , Fukushima Tsuyoshi , Takeda Reina , Yamamoto Keita , Honda Hiroaki , Nishimura Emi K. , Furukawa Yoichi , Shibata Tatsuhiro , Abdel-Wahab Omar , Suematsu Makoto , Kitamura Toshio 
Published: March 2021

AbstractSomatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.
Axonal chemokine-like Orion induces astrocyte infiltration and engulfment during mushroom body neuronal remodeling
Authors: Boulanger Ana , Thinat Camille , Züchner Stephan , Fradkin Lee G. , Lortat-Jacob Hugues , Dura Jean-Maurice 
Published: March 2021

AbstractThe remodeling of neurons is a conserved fundamental mechanism underlying nervous system maturation and function. Astrocytes can clear neuronal debris and they have an active role in neuronal remodeling. Developmental axon pruning of Drosophila memory center neurons occurs via a degenerative process mediated by infiltrating astrocytes. However, how astrocytes are recruited to the axons during brain development is unclear. Using an unbiased screen, we identify the gene requirement of orion, encoding for a chemokine-like protein, in the developing mushroom bodies. Functional analysis shows that Orion is necessary for both axonal pruning and removal of axonal debris. Orion performs its functions extracellularly and bears some features common to chemokines, a family of chemoattractant cytokines. We propose that Orion is a neuronal signal that elicits astrocyte infiltration and astrocyte-driven axonal engulfment required during neuronal remodeling in the Drosophila developing brain.
Increased autumn and winter precipitation during the Last Glacial Maximum in the European Alps
Authors: Spötl C. , Koltai G. , Jarosch A. H. , Cheng H. 
Published: March 2021

AbstractThe culmination of the glaciers in the European Alps during the Last Glacial Maximum (LGM) is one of the most intensively studied paleoglaciological events, but its trigger and forcing remain incompletely understood. Here, we provide evidence that the timing of this glacier maximum coincided within age uncertainties with a 3100 yr-long interval of subsurface warming (26.6 to 23.5 ka BP) as recorded by an archive preserved in caves, cryogenic carbonates. This interval of sustained permafrost degradation during one of the coldest intervals of the last glacial period calls for a fundamental change in the dry Arctic-style precipitation regime. Instead, heavy snowfall during autumn and early winter led to the accumulation of a seasonal snowpack insulating the ground from the winter chill. Combined with thermal modelling, the data provide compelling evidence that the LGM glacier advance in the Alps was fueled by intensive snowfall late in the year, likely sourced from the Mediterranean Sea.
Reconfigurable electronics by disassembling and reassembling van der Waals heterostructures
Authors: Tao Quanyang , Wu Ruixia , Li Qianyuan , Kong Lingan , Chen Yang , Jiang Jiayang , Lu Zheyi , Li Bailing , Li Wanying , Li Zhiwei , Liu Liting , Duan Xidong , Liao Lei , Liu Yuan 
Published: March 2021

AbstractVan der Waals heterostructures (vdWHs) have attracted tremendous interest owing to the ability to assemble diverse building blocks without the constraints of lattice matching and processing compatibility. However, once assembled, the fabricated vdWHs can hardly be separated into individual building blocks for further manipulation, mainly due to technical difficulties in the disassembling process. Here, we show a method to disassemble the as-fabricated vdWHs into individual building blocks, which can be further reassembled into new vdWHs with different device functionalities. With this technique, we demonstrate reconfigurable transistors from n-type to p-type and back-gate to dual-gate structures through re-stacking. Furthermore, reconfigurable device behaviors from floating gate memory to Schottky diode and reconfigurable anisotropic Raman behaviors have been obtained through layer re-sequencing and re-twisting, respectively. Our results could lead to a reverse engineering concept of disassembled vdWHs electronics in parallel with state-of-the-art vdWHs electronics, offering a general method for multi-functional pluggable electronics and optoelectronics with limited material building blocks.
Robust and flexible platform for directed evolution of yeast genetic switches
Authors: Tominaga Masahiro , Nozaki Kenta , Umeno Daisuke , Ishii Jun , Kondo Akihiko 
Published: March 2021

AbstractA wide repertoire of genetic switches has accelerated prokaryotic synthetic biology, while eukaryotic synthetic biology has lagged in the model organism Saccharomyces cerevisiae. Eukaryotic genetic switches are larger and more complex than prokaryotic ones, complicating the rational design and evolution of them. Here, we present a robust workflow for the creation and evolution of yeast genetic switches. The selector system was designed so that both ON- and OFF-state selection of genetic switches is completed solely by liquid handling, and it enabled parallel screen/selection of different motifs with different selection conditions. Because selection threshold of both ON- and OFF-state selection can be flexibly tuned, the desired selection conditions can be rapidly pinned down for individual directed evolution experiments without a prior knowledge either on the library population. The system’s utility was demonstrated using 20 independent directed evolution experiments, yielding genetic switches with elevated inducer sensitivities, inverted switching behaviours, sensory functions, and improved signal-to-noise ratio (>100-fold induction). The resulting yeast genetic switches were readily integrated, in a plug-and-play manner, into an AND-gated carotenoid biosynthesis pathway.