bluuebunny/crossref_metadata_2025 huggingface dataset:
DA-DRD5 signaling controls colitis by regulating colonic M1/M2 macrophage polarization
Authors: Liu Lu , Wu Yuqing , Wang Bingwei , Jiang Yuying , Lin Lin , Li Xiaoxi , Yang Shuo
Published: May 2021

The decrease of neurotransmitter dopamine (DA) levels in the intestine is closely related to the development of inflammatory bowel disease (IBD). However, the functional relevance and underlying mechanistic basis of the effects of DA signaling on IBD remains unclear. Here, we observed that the DRD5 receptor is highly expressed in colonic macrophages, and the deficiency of DA-DRD5 signaling exacerbated experimental colitis. Moreover, DA-DRD5 signaling can inhibit M1 by negatively regulating NF-κB signaling but promote M2 macrophage polarization through activation of the CREB pathway, respectively. The deficiency of DRD5 signaling increased colonic M1 macrophages but reduced M2 cells during colitis. Additionally, the administration of a D1-like agonist that has a higher affinity to DRD5 can attenuate the colitogenic phenotype of mice. Collectively, these findings provide the first demonstration of DA-DRD5 signaling in colonic macrophages controlling the development of colitis by regulating M1/M2 macrophage polarization.
Direct contribution of skeletal muscle mesenchymal progenitors to bone repair
Authors: Julien Anais , Kanagalingam Anuya , Martínez-Sarrà Ester , Megret Jérome , Luka Marine , Ménager Mickaël , Relaix Frédéric , Colnot Céline
Published: May 2021

Bone regenerates by activation of tissue resident stem/progenitor cells, formation of a fibrous callus followed by deposition of cartilage and bone matrices. Here, we show that mesenchymal progenitors residing in skeletal muscle adjacent to bone mediate the initial fibrotic response to bone injury and also participate in cartilage and bone formation. Combined lineage and single-cell RNA sequencing analyses reveal that skeletal muscle mesenchymal progenitors adopt a fibrogenic fate before they engage in chondrogenesis after fracture. In polytrauma, where bone and skeletal muscle are injured, skeletal muscle mesenchymal progenitors exhibit altered fibrogenesis and chondrogenesis. This leads to impaired bone healing, which is due to accumulation of fibrotic tissue originating from skeletal muscle and can be corrected by the anti-fibrotic agent Imatinib. These results elucidate the central role of skeletal muscle in bone regeneration and provide evidence that skeletal muscle can be targeted to prevent persistent callus fibrosis and improve bone healing after musculoskeletal trauma.
Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma
Authors: Zhang Shaojun , Jiang Vivian Changying , Han Guangchun , Hao Dapeng , Lian Junwei , Liu Yang , Cai Qingsong , Zhang Rongjia , McIntosh Joseph , Wang Ruiping , Dang Minghao , Dai Enyu , Wang Yuanxin , Santos David , Badillo Maria , Leeming Angela , Chen Zhihong , Hartig Kimberly , Bigcal John , Zhou Jia , Kanagal-Shamanna Rashmi , Ok Chi Young , Lee Hun , Steiner Raphael E. , Zhang Jianhua , Song Xingzhi , Nair Ranjit , Ahmed Sairah , Rodriquez Alma , Thirumurthi Selvi , Jain Preetesh , Wagner-Bartak Nicolaus , Hill Holly , Nomie Krystle , Flowers Christopher , Futreal Andrew , Wang Linghua , Wang Michael
Published: May 2021

The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that due to 17q gain, BIRC5/survivin expression is upregulated in resistant MCL tumor cells and targeting BIRC5 results in marked tumor inhibition in preclinical models. In addition, we discover notable differences in the tumor microenvironment including progressive dampening of CD8+ T cells and aberrant cell-to-cell communication networks in refractory MCLs. This study reveals diverse and dynamic tumor and immune programs underlying therapy resistance in MCL.
The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments
Authors: Grieshaber-Bouyer Ricardo , Radtke Felix A. , Cunin Pierre , Stifano Giuseppina , Levescot Anaïs , Vijaykumar Brinda , Nelson-Maney Nathan , Blaustein Rachel B. , Monach Paul A. , Nigrovic Peter A. ,   ImmGen Consortium, Aguilar Oscar , Allan Rhys , Astarita Jilian , Austen K. Frank , Barrett Nora , Baysoy Alev , Benoist Christophe , Brown Brian D. , Buechler Matthew , Buenrostro Jason , Casanova Maria Acebes , Chowdhary Kaitavjeet , Colonna Marco , Crowl Ty , Deng Tianda , Desland Fiona , Dhainaut Maxime , Ding Jiarui , Dominguez Claudia , Dwyer Daniel , Frascoli Michela , Gal-Oz Shani , Goldrath Ananda , Johanson Tim , Jordan Stefan , Kang Joonsoo , Kapoor Varun , Kenigsberg Ephraim , Kim Joel , Kim Ki wook , Kiner Evgeny , Kronenberg Mitchell , Lanier Lewis , Laplace Catherine , Lareau Caleb , Leader Andrew , Lee Jisu , Magen Assaf , Maier Barbara , Maslova Alexandra , Mathis Diane , McFarland Adelle , Merad Miriam , Meunier Etienne , Monach Paul A. , Mostafavi Sara , Muller Soren , Muus Christoph , Ner-Gaon Hadas , Nguyen Quyhn , Novakovsky German , Nutt Stephen , Omilusik Kayla , Ortiz-Lopez Adriana , Paynich Mallory , Peng Vincent , Potempa Marc , Pradhan Rachana , Quon Sara , Ramirez Ricardo , Ramanan Deepshika , Randolph Gwendalyn , Regev Aviv , Rose Samuel A. , Seddu Kumba , Shay Tal , Shemesh Avishai , Shyer Justin , Smilie Christopher , Spidale Nick , Subramanian Ayshwarya , Sylvia Katelyn , Tellier Julie , Turley Shannon , Vijaykumar Brinda , Wagers Amy , Wang Chendi , Wang Peter L. , Wroblewska Aleksandra , Yang Liang , Yim Aldrin , Yoshida Hideyuki
Published: May 2021

Neutrophils are implicated in multiple homeostatic and pathological processes, but whether functional diversity requires discrete neutrophil subsets is not known. Here, we apply single-cell RNA sequencing to neutrophils from normal and inflamed mouse tissues. Whereas conventional clustering yields multiple alternative organizational structures, diffusion mapping plus RNA velocity discloses a single developmental spectrum, ordered chronologically. Termed here neutrotime, this spectrum extends from immature pre-neutrophils, largely in bone marrow, to mature neutrophils predominantly in blood and spleen. The sharpest increments in neutrotime occur during the transitions from pre-neutrophils to immature neutrophils and from mature marrow neutrophils to those in blood. Human neutrophils exhibit a similar transcriptomic pattern. Neutrophils migrating into inflamed mouse lung, peritoneum and joint maintain the core mature neutrotime signature together with new transcriptional activity that varies with site and stimulus. Together, these data identify a single developmental spectrum as the dominant organizational theme of neutrophil heterogeneity.
EMX2-GPR156-Gαi reverses hair cell orientation in mechanosensory epithelia
Authors: Kindt Katie S. , Akturk Anil , Jarysta Amandine , Day Matthew , Beirl Alisha , Flonard Michaela , Tarchini Basile
Published: May 2021

Hair cells detect sound, head position or water movements when their mechanosensory hair bundle is deflected. Each hair bundle has an asymmetric architecture that restricts stimulus detection to a single axis. Coordinated hair cell orientations within sensory epithelia further tune stimulus detection at the organ level. Here, we identify GPR156, an orphan GPCR of unknown function, as a critical regulator of hair cell orientation. We demonstrate that the transcription factor EMX2 polarizes GPR156 distribution, enabling it to signal through Gαi and trigger a 180° reversal in hair cell orientation. GPR156-Gαi mediated reversal is essential to establish hair cells with mirror-image orientations in mouse otolith organs in the vestibular system and in zebrafish lateral line. Remarkably, GPR156-Gαi also instructs hair cell reversal in the auditory epithelium, despite a lack of mirror-image organization. Overall, our work demonstrates that conserved GPR156-Gαi signaling is integral to the framework that builds directional responses into mechanosensory epithelia.
Demonstration of a compact plasma accelerator powered by laser-accelerated electron beams
Authors: Kurz T. , Heinemann T. , Gilljohann M. F. , Chang Y. Y. , Couperus Cabadağ J. P. , Debus A. , Kononenko O. , Pausch R. , Schöbel S. , Assmann R. W. , Bussmann M. , Ding H. , Götzfried J. , Köhler A. , Raj G. , Schindler S. , Steiniger K. , Zarini O. , Corde S. , Döpp A. , Hidding B. , Karsch S. , Schramm U. , Martinez de la Ossa A. , Irman A.
Published: May 2021

Plasma wakefield accelerators are capable of sustaining gigavolt-per-centimeter accelerating fields, surpassing the electric breakdown threshold in state-of-the-art accelerator modules by 3-4 orders of magnitude. Beam-driven wakefields offer particularly attractive conditions for the generation and acceleration of high-quality beams. However, this scheme relies on kilometer-scale accelerators. Here, we report on the demonstration of a millimeter-scale plasma accelerator powered by laser-accelerated electron beams. We showcase the acceleration of electron beams to 128 MeV, consistent with simulations exhibiting accelerating gradients exceeding 100 GV m−1. This miniaturized accelerator is further explored by employing a controlled pair of drive and witness electron bunches, where a fraction of the driver energy is transferred to the accelerated witness through the plasma. Such a hybrid approach allows fundamental studies of beam-driven plasma accelerator concepts at widely accessible high-power laser facilities. It is anticipated to provide compact sources of energetic high-brightness electron beams for quality-demanding applications such as free-electron lasers.
TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration
Authors: Qiao Wei , Wong Karen H. M. , Shen Jie , Wang Wenhao , Wu Jun , Li Jinhua , Lin Zhengjie , Chen Zetao , Matinlinna Jukka P. , Zheng Yufeng , Wu Shuilin , Liu Xuanyong , Lai Keng Po , Chen Zhuofan , Lam Yun Wah , Cheung Kenneth M. C. , Yeung Kelvin W. K.
Published: May 2021

Despite the widespread observations on the osteogenic effects of magnesium ion (Mg2+), the diverse roles of Mg2+ during bone healing have not been systematically dissected. Here, we reveal a previously unknown, biphasic mode of action of Mg2+ in bone repair. During the early inflammation phase, Mg2+ contributes to an upregulated expression of transient receptor potential cation channel member 7 (TRPM7), and a TRPM7-dependent influx of Mg2+ in the monocyte-macrophage lineage, resulting in the cleavage and nuclear accumulation of TRPM7-cleaved kinase fragments (M7CKs). This then triggers the phosphorylation of Histone H3 at serine 10, in a TRPM7-dependent manner at the promoters of inflammatory cytokines, leading to the formation of a pro-osteogenic immune microenvironment. In the later remodeling phase, however, the continued exposure of Mg2+ not only lead to the over-activation of NF-κB signaling in macrophages and increased number of osteoclastic-like cells but also decelerates bone maturation through the suppression of hydroxyapatite precipitation. Thus, the negative effects of Mg2+ on osteogenesis can override the initial pro-osteogenic benefits of Mg2+. Taken together, this study establishes a paradigm shift in the understanding of the diverse and multifaceted roles of Mg2+ in bone healing.
Health and sustainability of glaciers in High Mountain Asia
Authors: Miles Evan , McCarthy Michael , Dehecq Amaury , Kneib Marin , Fugger Stefan , Pellicciotti Francesca
Published: May 2021

Glaciers in High Mountain Asia generate meltwater that supports the water needs of 250 million people, but current knowledge of annual accumulation and ablation is limited to sparse field measurements biased in location and glacier size. Here, we present altitudinally-resolved specific mass balances (surface, internal, and basal combined) for 5527 glaciers in High Mountain Asia for 2000–2016, derived by correcting observed glacier thinning patterns for mass redistribution due to ice flow. We find that 41% of glaciers accumulated mass over less than 20% of their area, and only 60% ± 10% of regional annual ablation was compensated by accumulation. Even without 21stcentury warming, 21% ± 1% of ice volume will be lost by 2100 due to current climatic-geometric imbalance, representing a reduction in glacier ablation into rivers of 28% ± 1%. The ablation of glaciers in the Himalayas and Tien Shan was mostly unsustainable and ice volume in these regions will reduce by at least 30% by 2100. The most important and vulnerable glacier-fed river basins (Amu Darya, Indus, Syr Darya, Tarim Interior) were supplied with >50% sustainable glacier ablation but will see long-term reductions in ice mass and glacier meltwater supply regardless of the Karakoram Anomaly.
Longitudinal in vivo imaging of acute neuropathology in a monkey model of Ebola virus infection
Authors: Schreiber-Stainthorp William , Solomon Jeffrey , Lee Ji Hyun , Castro Marcelo , Shah Swati , Martinez-Orengo Neysha , Reeder Rebecca , Maric Dragan , Gross Robin , Qin Jing , Hagen Katie R. , Johnson Reed F. , Hammoud Dima A.
Published: May 2021

Ebola virus (EBOV) causes neurological symptoms yet its effects on the central nervous system (CNS) are not well-described. Here, we longitudinally assess the acute effects of EBOV on the brain, using quantitative MR-relaxometry, 18F-Fluorodeoxyglucose PET and immunohistochemistry in a monkey model. We report blood–brain barrier disruption, likely related to high cytokine levels and endothelial viral infection, with extravasation of fluid, Gadolinium-based contrast material and albumin into the extracellular space. Increased glucose metabolism is also present compared to the baseline, especially in the deep gray matter and brainstem. This regional hypermetabolism corresponds with mild neuroinflammation, sporadic neuronal infection and apoptosis, as well as increased GLUT3 expression, consistent with increased neuronal metabolic demands. Neuroimaging changes are associated with markers of disease progression including viral load and cytokine/chemokine levels. Our results provide insight into the pathophysiology of CNS involvement with EBOV and may help assess vaccine/treatment efficacy in real time.
A global resource for genomic predictions of antimicrobial resistance and surveillance of Salmonella Typhi at pathogenwatch
Authors: Argimón Silvia , Yeats Corin A. , Goater Richard J. , Abudahab Khalil , Taylor Benjamin , Underwood Anthony , Sánchez-Busó Leonor , Wong Vanessa K. , Dyson Zoe A. , Nair Satheesh , Park Se Eun , Marks Florian , Page Andrew J. , Keane Jacqueline A. , Baker Stephen , Holt Kathryn E. , Dougan Gordon , Aanensen David M.
Published: May 2021

As whole-genome sequencing capacity becomes increasingly decentralized, there is a growing opportunity for collaboration and the sharing of surveillance data within and between countries to inform typhoid control policies. This vision requires free, community-driven tools that facilitate access to genomic data for public health on a global scale. Here we present the Pathogenwatch scheme for Salmonella enterica serovar Typhi (S. Typhi), a web application enabling the rapid identification of genomic markers of antimicrobial resistance (AMR) and contextualization with public genomic data. We show that the clustering of S. Typhi genomes in Pathogenwatch is comparable to established bioinformatics methods, and that genomic predictions of AMR are highly concordant with phenotypic susceptibility data. We demonstrate the public health utility of Pathogenwatch with examples selected from >4,300 public genomes available in the application. Pathogenwatch provides an intuitive entry point to monitor of the emergence and spread of S. Typhi high risk clones.
Electrochemical ammonia synthesis via nitrate reduction on Fe single atom catalyst
Authors: Wu Zhen-Yu , Karamad Mohammadreza , Yong Xue , Huang Qizheng , Cullen David A. , Zhu Peng , Xia Chuan , Xiao Qunfeng , Shakouri Mohsen , Chen Feng-Yang , Kim Jung Yoon , Xia Yang , Heck Kimberly , Hu Yongfeng , Wong Michael S. , Li Qilin , Gates Ian , Siahrostami Samira , Wang Haotian
Published: May 2021

Electrochemically converting nitrate, a widespread water pollutant, back to valuable ammonia is a green and delocalized route for ammonia synthesis, and can be an appealing and supplementary alternative to the Haber-Bosch process. However, as there are other nitrate reduction pathways present, selectively guiding the reaction pathway towards ammonia is currently challenged by the lack of efficient catalysts. Here we report a selective and active nitrate reduction to ammonia on Fe single atom catalyst, with a maximal ammonia Faradaic efficiency of ~ 75% and a yield rate of up to ~ 20,000 μg h−1 mgcat.−1 (0.46 mmol h−1 cm−2). Our Fe single atom catalyst can effectively prevent the N-N coupling step required for N2 due to the lack of neighboring metal sites, promoting ammonia product selectivity. Density functional theory calculations reveal the reaction mechanisms and the potential limiting steps for nitrate reduction on atomically dispersed Fe sites.
Net decrease in spine-surface GluA1-containing AMPA receptors after post-learning sleep in the adult mouse cortex
Authors: Miyamoto Daisuke , Marshall William , Tononi Giulio , Cirelli Chiara
Published: May 2021

The mechanisms by which sleep benefits learning and memory remain unclear. Sleep may further strengthen the synapses potentiated by learning or promote broad synaptic weakening while protecting the newly potentiated synapses. We tested these ideas by combining a motor task whose consolidation is sleep-dependent, a marker of synaptic AMPA receptor plasticity, and repeated two-photon imaging to track hundreds of spines in vivo with single spine resolution. In mouse motor cortex, sleep leads to an overall net decrease in spine-surface GluA1-containing AMPA receptors, both before and after learning. Molecular changes in single spines during post-learning sleep are correlated with changes in performance after sleep. The spines in which learning leads to the largest increase in GluA1 expression have a relative advantage after post-learning sleep compared to sleep deprivation, because sleep weakens all remaining spines. These results are obtained in adult mice, showing that sleep-dependent synaptic down-selection also benefits the mature brain.
Single-cell lipidomics with high structural specificity by mass spectrometry
Authors: Li Zishuai , Cheng Simin , Lin Qiaohong , Cao Wenbo , Yang Jing , Zhang Minmin , Shen Aijun , Zhang Wenpeng , Xia Yu , Ma Xiaoxiao , Ouyang Zheng
Published: May 2021

Single-cell analysis is critical to revealing cell-to-cell heterogeneity that would otherwise be lost in ensemble analysis. Detailed lipidome characterization for single cells is still far from mature, especially when considering the highly complex structural diversity of lipids and the limited sample amounts available from a single cell. We report the development of a general strategy enabling single-cell lipidomic analysis with high structural specificity. Cell fixation is applied to retain lipids in the cell during batch treatments prior to single-cell analysis. In addition to tandem mass spectrometry analysis revealing the class and fatty acyl-chain for lipids, batch photochemical derivatization and single-cell droplet treatment are performed to identify the C=C locations and sn-positions of lipids, respectively. Electro-migration combined with droplet-assisted electrospray ionization enables single-cell mass spectrometry analysis with easy operation but high efficiency in sample usage. Four subtypes of human breast cancer cells are correctly classified through quantitative analysis of lipid C=C location or sn-position isomers in ~160 cells. Most importantly, the single-cell deep lipidomics strategy successfully discriminates gefitinib-resistant cells from a population of wild-type human lung cancer cells (HCC827), highlighting its unique capability to promote precision medicine.
Efficient 3D printing via photooxidation of ketocoumarin based photopolymerization
Authors: Zhao Xiaoyu , Zhao Ye , Li Ming-De , Li Zhong’an , Peng Haiyan , Xie Tao , Xie Xiaolin
Published: May 2021

Photopolymerization-based three-dimensional (3D) printing can enable customized manufacturing that is difficult to achieve through other traditional means. Nevertheless, it remains challenging to achieve efficient 3D printing due to the compromise between print speed and resolution. Herein, we report an efficient 3D printing approach based on the photooxidation of ketocoumarin that functions as the photosensitizer during photopolymerization, which can simultaneously deliver high print speed (5.1 cm h−1) and high print resolution (23 μm) on a common 3D printer. Mechanistically, the initiating radical and deethylated ketocoumarin are both generated upon visible light exposure, with the former giving rise to rapid photopolymerization and high print speed while the latter ensuring high print resolution by confining the light penetration. By comparison, the printed feature is hard to identify when the ketocoumarin encounters photoreduction due to the increased lateral photopolymerization. The proposed approach here provides a viable solution towards efficient additive manufacturing by controlling the photoreaction of photosensitizers during photopolymerization.
IL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques
Authors: Harper Justin , Huot Nicolas , Micci Luca , Tharp Gregory , King Colin , Rascle Philippe , Shenvi Neeta , Wang Hong , Galardi Cristin , Upadhyay Amit A. , Villinger Francois , Lifson Jeffrey , Silvestri Guido , Easley Kirk , Jacquelin Beatrice , Bosinger Steven , Müller-Trutwin Michaela , Paiardini Mirko
Published: May 2021

Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy, nonpathogenic infections in natural hosts, such African green monkeys, are characterized by a lack of gut microbial translocation and robust secondary lymphoid natural killer cell responses resulting in an absence of chronic inflammation and limited SIV dissemination in lymph node B-cell follicles. Here we report, using the pathogenic model of antiretroviral therapy-treated, SIV-infected rhesus macaques that sequential interleukin-21 and interferon alpha therapy generate terminally differentiated blood natural killer cells (NKG2a/clowCD16+) with potent human leukocyte antigen-E-restricted activity in response to SIV envelope peptides. This is in contrast to control macaques, where less differentiated, interferon gamma-producing natural killer cells predominate. The frequency and activity of terminally differentiated NKG2a/clowCD16+natural killer cells correlates with a reduction of replication-competent SIV in lymph node during antiretroviral therapy and time to viral rebound following analytical treatment interruption. These data demonstrate that African green monkey-like natural killer cell differentiation profiles can be rescued in rhesus macaques to promote viral clearance in tissues.
A universal strategy towards high–energy aqueous multivalent–ion batteries
Authors: Tang Xiao , Zhou Dong , Zhang Bao , Wang Shijian , Li Peng , Liu Hao , Guo Xin , Jaumaux Pauline , Gao Xiaochun , Fu Yongzhu , Wang Chengyin , Wang Chunsheng , Wang Guoxiu
Published: May 2021

Rechargeable multivalent metal (e.g., Ca, Mg or, Al) batteries are ideal candidates for large–scale electrochemical energy storage due to their intrinsic low cost. However, their practical application is hampered by the low electrochemical reversibility, dendrite growth at the metal anodes, sluggish multivalent–ion kinetics in metal oxide cathodes and, poor electrode compatibility with non–aqueous organic–based electrolytes. To circumvent these issues, here we report various aqueous multivalent–ion batteries comprising of concentrated aqueous gel electrolytes, sulfur–containing anodes and, high-voltage metal oxide cathodes as alternative systems to the non–aqueous multivalent metal batteries. This rationally designed aqueous battery chemistry enables satisfactory specific energy, favorable reversibility and improved safety. As a demonstration model, we report a room–temperature calcium-ion/sulfur| |metal oxide full cell with a specific energy of 110 Wh kg–1 and remarkable cycling stability. Molecular dynamics modeling and experimental investigations reveal that the side reactions could be significantly restrained through the suppressed water activity and formation of a protective inorganic solid electrolyte interphase. The unique redox chemistry of the multivalent–ion system is also demonstrated for aqueous magnesium–ion/sulfur||metal oxide and aluminum–ion/sulfur||metal oxide full cells.
Polymer-free corticosteroid dimer implants for controlled and sustained drug delivery
Authors: Battiston Kyle , Parrag Ian , Statham Matthew , Louka Dimitra , Fischer Hans , Mackey Gillian , Daley Adam , Gu Fan , Baldwin Emily , Yang Bingqing , Muirhead Ben , Hicks Emily Anne , Sheardown Heather , Kalachev Leonid , Crean Christopher , Edelman Jeffrey , Santerre J. Paul , Naimark Wendy
Published: May 2021

Polymeric drug carriers are widely used for providing temporal and/or spatial control of drug delivery, with corticosteroids being one class of drugs that have benefitted from their use for the treatment of inflammatory-mediated conditions. However, these polymer-based systems often have limited drug-loading capacity, suboptimal release kinetics, and/or promote adverse inflammatory responses. This manuscript investigates and describes a strategy for achieving controlled delivery of corticosteroids, based on a discovery that low molecular weight corticosteroid dimers can be processed into drug delivery implant materials using a broad range of established fabrication methods, without the use of polymers or excipients. These implants undergo surface erosion, achieving tightly controlled and reproducible drug release kinetics in vitro. As an example, when used as ocular implants in rats, a dexamethasone dimer implant is shown to effectively inhibit inflammation induced by lipopolysaccharide. In a rabbit model, dexamethasone dimer intravitreal implants demonstrate predictable pharmacokinetics and significantly extend drug release duration and efficacy (>6 months) compared to a leading commercial polymeric dexamethasone-releasing implant.
Hox dosage contributes to flight appendage morphology in Drosophila
Authors: Paul Rachel , Giraud Guillaume , Domsch Katrin , Duffraisse Marilyne , Marmigère Frédéric , Khan Soumen , Vanderperre Solene , Lohmann Ingrid , Stoks Robby , Shashidhara L. S. , Merabet Samir
Published: May 2021

Flying insects have invaded all the aerial space on Earth and this astonishing radiation could not have been possible without a remarkable morphological diversification of their flight appendages. Here, we show that characteristic spatial expression profiles and levels of the Hox genes Antennapedia (Antp) and Ultrabithorax (Ubx) underlie the formation of two different flight organs in the fruit fly Drosophila melanogaster. We further demonstrate that flight appendage morphology is dependent on specific Hox doses. Interestingly, we find that wing morphology from evolutionary distant four-winged insect species is also associated with a differential expression of Antp and Ubx. We propose that variation in the spatial expression profile and dosage of Hox proteins is a major determinant of flight appendage diversification in Drosophila and possibly in other insect species during evolution.
Cells/colony motion of oral keratinocytes determined by non-invasive and quantitative measurement using optical flow predicts epithelial regenerative capacity
Authors: Hoshikawa Emi , Sato Taisuke , Haga Kenta , Suzuki Ayako , Kobayashi Ryota , Tabeta Koichi , Izumi Kenji
Published: May 2021

Cells/colony motion determined by non-invasive, quantitative measurements using the optical flow (OF) algorithm can indicate the oral keratinocyte proliferative capacity in early-phase primary cultures. This study aimed to determine a threshold for the cells/colony motion index to detect substandard cell populations in a subsequent subculture before manufacturing a tissue-engineered oral mucosa graft and to investigate the correlation with the epithelial regenerative capacity. The distinctive proliferating pattern of first-passage [passage 1 (p1)] cells reveals the motion of p1 cells/colonies, which can be measured in a non-invasive, quantitative manner using OF with fewer full-screen imaging analyses and cell segmentations. Our results demonstrate that the motion index lower than 40 μm/h reflects cellular damages by experimental metabolic challenges although this value shall only apply in case of our culture system. Nonetheless, the motion index can be used as the threshold to determine the quality of cultured cells while it may be affected by any different culture conditions. Because the p1 cells/colony motion index is correlated with epithelial regenerative capacity, it is a reliable index for quality control of oral keratinocytes.
Author Correction: Novel diagnostic and therapeutic techniques reveal changed metabolic profiles in recurrent focal segmental glomerulosclerosis
Authors: Müller-Deile Janina , Sarau George , Kotb Ahmed M. , Jaremenko Christian , Rolle-Kampczyk Ulrike E. , Daniel Christoph , Kalkhof Stefan , Christiansen Silke H. , Schiffer Mario
Published: May 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Long-term conservation agriculture and best nutrient management improves productivity and profitability coupled with soil properties of a maize–chickpea rotation
Authors: Pooniya Vijay , Zhiipao R. R. , Biswakarma Niraj , Jat S. L. , Kumar Dinesh , Parihar C. M. , Swarnalakshmi K. , Lama Achal , Verma A. K. , Roy Debasish , Das Kajal , Majumdar K. , Satyanarayana T. , Jat R. D. , Ghasal P. C. , Ram Hardev , Jat Rajkumar , Nath Amlan
Published: May 2021

Conservation agriculture (CA)-based practices have been promoted and recouped, as they hold the potential to enhance farm profits besides a consistent improvement in soil properties. A 7 years' field experiment consisting of three crop establishment practices viz., zero-till flatbed (ZTFB), permanent beds (PNB), conventional system (CT) along with the three-nutrient management; nutrient expert-based application (NE), recommended fertilization (RDF), and farmers’ fertilizer practice (FFP), was carried out from 2013 to 2020. The CA-based practices (ZTFB/PNB) produced 13.9–17.6% greater maize grain-equivalent yield (MGEY) compared to the CT, while NE and RDF had 10.7–20% greater MGEY than the FFP. PNB and ZTFB gave 28.8% and 24% additional net returns than CT, while NE and RDF had 22.8% and 17.4% greater returns, respectively over FFP. PNB and ZTFB had 2.3–4.1% (0.0–0.20 m soil layers) lower bulk density than the CT. Furthermore, microbial biomass carbon (MBC) increased by 8–19% (0.0–0.50 m soil layers) in ZTFB/PNB over the CT, and by 7.6–11.0% in NE/RDF over FFP. Hence, CA-based crop establishment coupled with the NE or RDF could enhance the yields, farm profits, soil properties of the maize–chickpea rotation, thereby, could sustain production in the long run.
CRISPR-mediated mutations in the ABC transporter gene ABCA2 confer pink bollworm resistance to Bt toxin Cry2Ab
Authors: Fabrick Jeffrey A. , LeRoy Dannialle M. , Mathew Lolita G. , Wu Yidong , Unnithan Gopalan C. , Yelich Alex J. , Carrière Yves , Li Xianchun , Tabashnik Bruce E.
Published: May 2021

Crops genetically engineered to produce insecticidal proteins from Bacillus thuringiensis (Bt) have many benefits and are important globally for managing insect pests. However, the evolution of pest resistance to Bt crops reduces their benefits. Understanding the genetic basis of such resistance is needed to better monitor, manage, and counter pest resistance to Bt crops. Previous work shows that resistance to Bt toxin Cry2Ab is associated with mutations in the gene encoding the ATP-binding cassette protein ABCA2 in lab- and field-selected populations of the pink bollworm (Pectinophora gossypiella), one of the world’s most destructive pests of cotton. Here we used CRISPR/Cas9 gene editing to test the hypothesis that mutations in the pink bollworm gene encoding ABCA2 (PgABCA2) can cause resistance to Cry2Ab. Consistent with this hypothesis, introduction of disruptive mutations in PgABCA2 in a susceptible strain of pink bollworm increased the frequency of resistance to Cry2Ab and facilitated creation of a Cry2Ab-resistant strain. All Cry2Ab-resistant individuals tested in this study had disruptive mutations in PgABCA2. Overall, we found 17 different disruptive mutations in PgABCA2 gDNA and 26 in PgABCA2 cDNA, including novel mutations corresponding precisely to single-guide (sgRNA) sites used for CRISPR/Cas9. Together with previous results, these findings provide the first case of practical resistance to Cry2Ab where evidence identifies a specific gene in which disruptive mutations can cause resistance and are associated with resistance in field-selected populations.
Mouse primary microglia respond differently to LPS and poly(I:C) in vitro
Authors: He Yingbo , Taylor Natalie , Yao Xiang , Bhattacharya Anindya
Published: May 2021

Microglia, CNS resident innate immune cells, respond strongly to activation of TLR3 and TLR4, which recognize viral dsRNA poly(I:C) and bacterial endotoxin LPS, respectively. However, few studies have thoroughly and parallelly compared functional phenotypes and downstream mechanisms between LPS- and poly(I:C)-exposed primary microglia. Here, we investigated the responses of mouse primary microglia upon LPS and poly(I:C) stimulation by detecting various phenotypes ranging from morphology, proliferation, secretion, chemotaxis, to phagocytosis. Furthermore, we explored their sequential gene expression and the downstream signal cascades. Interestingly, we found that the microglial activation pattern induced by LPS was distinguished from that induced by poly(I:C). Regarding microglial morphology, LPS caused an ameboid-like shape while poly(I:C) induced a bushy shape. Microglial proliferation was also facilitated by LPS but not by poly(I:C). In addition, LPS and poly(I:C) modulated microglial chemotaxis and phagocytosis differently. Furthermore, genome-wide analysis provided gene-level support to these functional differences, which may be associated with NF-κb and type I interferon pathways. Last, LPS- and poly(I:C)-activated microglia mediated neurotoxicity in a co-culture system. This study extends our understanding of TLR roles in microglia and provides insights into selecting proper inflammatory microglial models, which may facilitate identification of new targets for therapeutic application.
A study of the correlations between IVIM-DWI parameters and the histologic differentiation of hepatocellular carcinoma
Authors: Zhou Yi , Yang Gang , Gong Xue-Qin , Tao Yun-Yun , Wang Ran , Zheng Jing , Yang Cui , Peng Juan , Yang Lin , Li Jing-Dong , Zhang Xiao-Ming
Published: May 2021

The present study aimed to investigate the value of intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) in the preoperative prediction of the histologic differentiation of hepatocellular carcinoma (HCC). Seventy HCC patients were scanned with a 3.0 T magnetic resonance scanner. The values of apparent diffusion coefficient (ADC), slow apparent diffusion coefficient (D), fast apparent diffusion coefficient (D*), and the fraction of the fast apparent diffusion coefficient (f) were measured. Analysis of variance was used to compare the differences in parameters between groups with different degrees of histologic differentiation. p < 0.05 was considered statistically significant. Receiver operating characteristic (ROC) curves were used to analyse the efficacy of IVIM-DWI parameters for predicting the histologic differentiation of HCC. The ADC and D values for well, moderately and poorly differentiated HCC were 1.35 ± 0.17 × 10−3 mm2/s, 1.16 ± 0.17 × 10−3 mm2/s, 0.98 ± 0.21 × 10−3 mm2/s, and 1.06 ± 0.15 × 10−3 mm2/s, 0.88 ± 0.16 × 10−3 mm2/s, 0.76 ± 0.18 × 10−3 mm2/s, respectively, and all differences were significant. The D* and f values of the three groups were 32.87 ± 14.70 × 10−3 mm2/s, 41.68 ± 17.90 × 10−3 mm2/s, 34.54 ± 18.60 × 10−3 mm2/s and 0.22 ± 0.07, 0.23 ± 0.08, 0.18 ± 0.07, respectively, with no significant difference. When the cut-off values of ADC and D were 1.25 × 10−3 mm2/s and 0.97 × 10−3 mm2/s, respectively, their diagnostic sensitivities and specificities for distinguishing well differentiated HCC from moderately differentiated and poorly differentiated HCC were 73.3%, 85.5%, 86.7%, and 78.2%, and their areas under the ROC curve were 0.821 and 0.841, respectively. ADC and D values can be used preoperatively to predict the degree of histologic differentiation in HCC, and the D value has better diagnostic value.
Identification of a PadR-type regulator essential for intracellular pathogenesis of Burkholderia pseudomallei
Authors: McMillan Ian A. , Norris Michael H. , Zarzycki-Siek Jan , Heacock-Kang Yun , Sun Zhenxin , Borlee Bradley R. , Hoang Tung T.
Published: May 2021

Burkholderia pseudomallei (Bp) is the causative agent of melioidosis, a disease endemic to the tropics. Melioidosis manifests in various ways ranging from acute skin lesions to pneumonia and, in rare cases, infection of the central nervous system. Bp is a facultative intracellular pathogen and it can infect various cell types. The Bp intracellular lifecycle has been partially elucidated and is highly complex. Herein, we have identified a transcriptional regulator, BP1026B_II1198, that is differentially expressed as Bp transits through host cells. A deletion mutant of BP1026B_II1198 was attenuated in RAW264.7 cell and BALB/c mouse infection. To further characterize the function of this transcriptional regulator, we endeavored to determine the regulon of BP1026B_II1198. RNA-seq analysis showed the global picture of genes regulated while ChIP-seq analysis identified two specific BP1026B_II1198 binding regions on chromosome II. We investigated the transposon mutants of these genes controlled by BP1026B_II1198 and confirmed that these genes contribute to pathogenesis in RAW264.7 murine macrophage cells. Taken together, the data presented here shed light on the regulon of BP1026B_II1198 and its role during intracellular infection and highlights an integral portion of the highly complex regulation network of Bp during host infection.
Outer membrane and phospholipid composition of the target membrane affect the antimicrobial potential of first- and second-generation lipophosphonoxins
Authors: Látrová Klára , Havlová Noemi , Večeřová Renata , Pinkas Dominik , Bogdanová Kateřina , Kolář Milan , Fišer Radovan , Konopásek Ivo , Do Pham Duy Dinh , Rejman Dominik , Mikušová Gabriela
Published: May 2021

Lipophosphonoxins (LPPOs) are small modular synthetic antibacterial compounds that target the cytoplasmic membrane. First-generation LPPOs (LPPO I) exhibit an antimicrobial activity against Gram-positive bacteria; however they do not exhibit any activity against Gram-negatives. Second-generation LPPOs (LPPO II) also exhibit broadened activity against Gram-negatives. We investigated the reasons behind this different susceptibility of bacteria to the two generations of LPPOs using model membranes and the living model bacteria Bacillus subtilis and Escherichia coli. We show that both generations of LPPOs form oligomeric conductive pores and permeabilize the bacterial membrane of sensitive cells. LPPO activity is not affected by the value of the target membrane potential, and thus they are also active against persister cells. The insensitivity of Gram-negative bacteria to LPPO I is probably caused by the barrier function of the outer membrane with LPS. LPPO I is almost incapable of overcoming the outer membrane in living cells, and the presence of LPS in liposomes substantially reduces their activity. Further, the antimicrobial activity of LPPO is also influenced by the phospholipid composition of the target membrane. A higher proportion of phospholipids with neutral charge such as phosphatidylethanolamine or phosphatidylcholine reduces the LPPO permeabilizing potential.
The implication of autoantibodies in early diagnosis and monitoring of plasmonic photothermal therapy in the treatment of feline mammary carcinoma
Authors: El-Rasikh Asmaa M. , Farghali Haithem A. M. , Abdelrahman Hisham A. , Elgaffary Mostafa , Abdelmalek Shaymaa , Emam Ibrahim A. , Ghoneim Magdy A. , Selim Salah A.
Published: May 2021

Feline mammary carcinoma (FMC) shows great similarities to human breast cancer in the cellular and molecular levels. So, in cats as in humans, the role of immune responses is indicated to detect and follow up the development of tumors. As a new breast cancer therapeutic approach, Plasmonic Photothermal Therapy (PPTT) is an effective localized treatment for canine and feline mammary-carcinoma. Its systemic effect has not been inquired yet and needs many studies to hypothesis how the PPTT eradicates tumor cells. In this study, it is the first time to detect (P53, PCNA, MUC-1, and C-MYC) feline autoantibodies (AAbs), study the relationship between PCNA AAbs and mammary-tumors, and investigate the effect of PPTT on the humoral immune response of cats with mammary-carcinoma through detection of AAbs level before, during, and after the treatment. The four-AAbs panel was evaluated in serum of normal and clinically diagnosed cats with mammary tumors using Enzyme-Linked Immunosorbent Assay. The panel showed 100% specificity and 93.7% sensitivity to mammary tumors. The panel was evaluated in PPTT monotherapy, mastectomy monotherapy, and combination therapy. PPTT monotherapy decreased AAbs level significantly while mastectomy monotherapy and combination therapy had a nonsignificant effect on AAbs level.
Altered mapping of sound frequency to cochlear place in ears with endolymphatic hydrops provide insight into the pitch anomaly of diplacusis
Authors: Guinan J. J. , Lefler S. M. , Buchman C. A. , Goodman S. S. , Lichtenhan J. T.
Published: May 2021

A fundamental property of mammalian hearing is the conversion of sound pressure into a frequency-specific place of maximum vibration along the cochlear length, thereby creating a tonotopic map. The tonotopic map makes possible systematic frequency tuning across auditory-nerve fibers, which enables the brain to use pitch to separate sounds from different environmental sources and process the speech and music that connects us to people and the world. Sometimes a tone has a different pitch in the left and right ears, a perceptual anomaly known as diplacusis. Diplacusis has been attributed to a change in the cochlear frequency-place map, but the hypothesized abnormal cochlear map has never been demonstrated. Here we assess cochlear frequency-place maps in guinea-pig ears with experimentally-induced endolymphatic hydrops, a hallmark of Ménière’s disease. Our findings are consistent with the hypothesis that diplacusis is due to an altered cochlear map. Map changes can lead to altered pitch, but the size of the pitch change is also affected by neural synchrony. Our data show that the cochlear frequency-place map is not fixed but can be altered by endolymphatic hydrops. Map changes should be considered in assessing hearing pathologies and treatments.
Effect of physical activity levels on oncological breast surgery recovery: a prospective cohort study
Authors: Klein Ifat , Kalichman Leonid , Chen Noy , Susmallian Sergio
Published: May 2021

After breast cancer (BC) surgery, women may experience a physical decline. The effect of physical activity (PA) on the course of recovery after BC surgery has not yet been thoroughly examined. To analyze the impact of physical activity performed by women undergoing breast cancer surgery on measures of function, range of motion, and self-efficacy. A prospective study was carried out in 157 patients who underwent surgery for BC between October 2018 and April 2019, divided into four groups according to the intensity of PA with 6 months follow-up. 50 sedentary patients and 107 active patients were enrolled; the mean age was 52.6. Women who performed physical activity, moderate to vigorous, demonstrated lower function disabilities (QuickDASH 2.22) compared with inactivity or light physical activity (QuickDASH 7.0, p < 0.001), with better shoulder flexion (159.0° vs. 150.7°, p = 0.007) and abduction (159.5° vs. 152.2°, p = 0.008). Higher PA levels, displayed in higher self-efficacy reports (9.5 vs. 8.8, p = 0.002), and return to prior job status (0.005). The PA level does not influence pain at one, three and 6 months postoperatively (p = 0.278, p = 0.304 and p = 0.304 respectively). High PA levels increase the risk of axillary web syndrome (p = 0.041), although, it reduces the incidence of chronic pain (p = 0.007). Women who practice physical activity recover better from BC surgery than sedentary women. The higher the intensity and frequency of training, the better the results. Vigorous activity cause axillary web syndrome, despite, it has a beneficial effect on lowering the rate of chronic pain.
The effect of increased channel interaction on speech perception with cochlear implants
Authors: Goehring Tobias , Archer-Boyd Alan W. , Arenberg Julie G. , Carlyon Robert P.
Published: May 2021

Cochlear implants (CIs) are neuroprostheses that partially restore hearing for people with severe-to-profound hearing loss. While CIs can provide good speech perception in quiet listening situations for many, they fail to do so in environments with interfering sounds for most listeners. Previous research suggests that this is due to detrimental interaction effects between CI electrode channels, limiting their function to convey frequency-specific information, but evidence is still scarce. In this study, an experimental manipulation called spectral blurring was used to increase channel interaction in CI listeners using Advanced Bionics devices with HiFocus 1J and MS electrode arrays to directly investigate its causal effect on speech perception. Instead of using a single electrode per channel as in standard CI processing, spectral blurring used up to 6 electrodes per channel simultaneously to increase the overlap between adjacent frequency channels as would occur in cases with severe channel interaction. Results demonstrated that this manipulation significantly degraded CI speech perception in quiet by 15% and speech reception thresholds in babble noise by 5 dB when all channels were blurred by a factor of 6. Importantly, when channel interaction was increased just on a subset of electrodes, speech scores were mostly unaffected and were only significantly degraded when the 5 most apical channels were blurred. These apical channels convey information up to 1 kHz at the apical end of the electrode array and are typically located at angular insertion depths of about 250 up to 500°. These results confirm and extend earlier findings indicating that CI speech perception may not benefit from deactivating individual channels along the array and that efforts should instead be directed towards reducing channel interaction per se and in particular for the most-apical electrodes. Hereby, causal methods such as spectral blurring could be used in future research to control channel interaction effects within listeners for evaluating compensation strategies.