bluuebunny/crossref_metadata_2025 huggingface dataset:
Cartilage Viability with Interpolated Skin Flaps: An Experimental Study
Authors: Park Stephen S. , White Gregory J. , Cook Ted A. , Wang Tom A. , Kessler Stephen , Cohen James I.
Published: September 2022

Although composite cartilage grafts are often used in conjunction with a midline forehead flap to repair full‐thickness nasal defects, the timing of pedicle division, which optimizes cartilage viability, has yet to be determined. A rabbit animal model was designed to investigate this question. The skin flap pedicle was divided at 0 days, 4 days, 3 weeks, 6 weeks, and 10 weeks in each of five groups of five animals. Although early pedicle division led to partial skin flap necrosis, the cartilage grafts tolerated this ischemic period better. Cartilage viability was approximately 70% and did not differ significantly between the five groups. It is concluded that a larger composite graft and better definition of the skin flap's critical period are needed to determine optimum timing for pedicle division in this animal model.
Middle Ear Mucin Glycoprotein: Purification and Interaction with Nontypable Haemophilus Influenzae and Moraxella Catarrhalis
Authors: Reddy Molakola S. , Murphy Timothy F. , Faden Howard S. , Bernstein Joel M.
Published: September 2022

Nontypable Haemophilus influenzae and Moraxella catarrhalis are important pathogens in children and adults. The mechanisms of their adherence to the epithelial cell surface and colonization are not clear. For the pathogen to adhere to the epithelial cell, it must first attach to and penetrate the mucus barrier. Mucin glycoproteins of the mucus layer generally are thought to be involved in bacterial attachment. To understand the precise mechanisms of middle ear mucin‐bacterial interactions, we used an overlay binding assay with a highly purified middle ear mucin and outer membrane proteins of both nontypable H. influenzae and M. catarrhalis. Outer membrane proteins P2 and P5 were identified as the major components that mediate the binding between nontypable H. influenzae and human middle ear mucin. Moreover, the 57 kDa protein, CD, of the outer membrane protein of M. catarrhalis was found to be the only protein binding human middle ear mucin. Finally, it appears that a protein‐oligosaccharide interaction is responsible for binding because asialo‐mucin does not bind to either of the bacteria. Knowledge of the specific bacterial‐mucin interaction may provide an understanding of the bacterial‐epithelial cell colonization. Conversely, comprehension of this interaction between bacteria and purified mucin may be a strategy to prevent colonization of potential pathogens that cause otitis media and sinusitis in children.
New Developments in the Diagnosis of Kartagener's Syndrome
Authors: Teknos Theodoros N. , Metson Ralph , Chasse Thomas , Balercia Giancarlo , Dickersin G. Richard
Published: September 2022

Kartagener's syndrome is characterized by the clinical triad of bronchitis, sinusitis, and situs inversus. An inherited ultrastructural defect results in ciliary immotility with impaired mucociliary clearance throughout the pulmonary and sinonasal passages. Until recently, the diagnosis of Kartagener's syndrome was made on the basis of a qualitative decrease in the number of dynein arms and subjective abnormalities in other ciliary components on electron microscopy. New investigations, however, have defined objective methods of diagnosis on the basis of quantitative ciliary measurements. The use of these methods in a series of 17 cases of suspected ciliary immotility resulted in a reversal of diagnosis in 6 cases (35%) that previously were considered normal. These results suggest that the prevalence of inherited ciliary dyskinesias is much greater than currently is recognized. The early identification and treatment of individuals with these disorders could lead to a reduction in irreversible sinus and pulmonary pathologic conditions with improved long‐term survival.
Endoscopically Introduced Expandable Stents in Laryngotracheal Stenosis: The Jury is Still Out
Authors: Hanna Ehab , Eliachar Isaac
Published: September 2022

A new technique using endoscopically introduced, expandable stents for the management of upper airway stenosis is presented. Evaluation of this technique in the canine model forms the basis of this pilot study. Stenosis was surgically induced in a controlled fashion by resection of cartilage from the anterior cricoid arch and tracheal wall to reduce the airway diameter by approximately 50%. A period of 8 weeks was allowed for complete healing and maturation of the surgical stenosis. This was followed by endoscopic introduction of expandable titanium‐mesh stents. The stents were then balloon‐inflated to dilate the stenotic region. Airway patency was assessed clinically, radiologically, and endoscopically, before expansion and at 4 and 8 weeks after expansion. This assessment was followed by euthanasia of the animals and gross examination of the expanded stenotic segments. In general, the stents were well tolerated with adequate expansion of the airway. In some instances granulation tissue formation was noted around the stents. This was less pronounced when stents coated with Tecoflex (Advanced Surgical Intervention Co., San Clemente, Calif.) were used. This is probably because of their “inert” nature, which induces less tissue reaction. A literature review of the subject is presented. The significance of this endoscopic modality for management of upper airway stenosis is discussed, and the indications, alternatives, potential pitfalls, and complications are depicted.
Diagnosing and Treating Pediatric Allergy
Authors: Cook Paul R. , Herr Timothy M. , Highfill Gary
Published: September 2022

Allergy is a significant problem in as much as 60% of patients seeking care at an otolaryngologist's office. This raises the issue of the most effective means of diagnosing allergy, especially in pediatric patients, who often may not tolerate skin testing. The RAST and CAP (Pharmacia) tests have been shown to be quite comparable with skin testing in diagnosing allergy. This study was undertaken to assess the effectiveness of treatment of children with allergies who had undergone in vitro testing. This was done by obtaining subjective symptom scores both before and after treatment. These were obtained from patients with different in vitro results, including some with negative testing. Overall, 77 of 155 mailed questionnaires were returned. Results showed overall improvement of 38.81 points in 12 symptoms (p = 0.001; n = 62). Each symptom was rated on a visual scale of 1 to 10. A small portion of the patient population received surgical treatment (tympanostomy tube placement with or without adenoidectomy) in addition to medical treatment and avoidance. These patients did not have significantly higher pretreatment scores and did not have a higher improvement rate for all symptoms. We believe this study shows the validity of in vitro testing and treatment of allergy in children.
Instability of a quantum vortex by twist perturbation
Authors: Foresti Matteo , Ricca Renzo L.
Published: September 2022

In this paper, we determine the instability effects of a phase twist superposed on a quantum vortex defect governed by the Gross–Pitaevskii equation. For this, we consider the modified form of the equation in two cases: when a uniform phase twist is present everywhere in the condensate, and when the defect is subject to a localized phase twist confined to the defect healing region. In the first case, we show that a secondary, new defect is produced as manifestation of an Aharonov–Bohm type effect. In the second case, we prove that due to energy minimization, the defect changes its configurational energy by converting localized twist to writhe. This mechanism, typical of classical elastic systems, is shown to occur also in quantum defects, and it may find useful applications in science and technology.
Introduction: the issue of duplicates
Authors: Heumann Ina , MacKinney Anne Greenwood , Buschmann Rainer
Published: September 2022

The permanent preservation of objects in global custodianship is a captivating ideal that informs countless museums’ corporate identities and governs collection guidelines as well as politics. Recent research has challenged the alleged perpetuity of collections and collected items, revealing their coherence as fragile and dependent on historically, politically and culturally specific conditions. Duplicates offer an instructive point of entry to explore the idea of collection permanence, museum politics, and the mobility of museum objects. The history of duplicates, moreover, comprises a constellation of practises, concepts and debates that can be found in various forms throughout the intertwined histories of natural-scientific, ethnographic and artistic collections. This history, however, has rarely been questioned or explored. By introducing the issue of duplicates, this paper opens up a discussion that not only connects different forms of collections, but also situates the history of collecting institutions across the disciplinary spectrum within broader political, economic and epistemic frameworks.
ΤΙΘΑΙΒΩΣΣΟΥΣΙ ΜΕΛΙΣΣΑΙ (HOMER,ODYSSEY13.106)
Authors: Nikolaev Alexander
Published: September 2022

This article examines the verbτιθαιβώσσω, a Homeric hapax legomenon of unknown meaning and etymology: it reviews its use in Hellenistic poetry and strives to provide a contextually plausible meaning for the verb (‘to sting’), as well as for the related adjectiveθιβρός(‘stinging, mordant, piquant’). It argues thatτιθαιβώσσωis etymologically related to Latinfīgere‘insert, pierce’,fībula‘pin’, Lithuaniandíegti‘to poke, sting’, and Tocharian Btsākā- ‘to bite’.
Aerodynamic analysis for a bat-like robot with a deformable flexible wing
Authors: Duan Bosong , Guo Chuangqiang , Liu Hong
Published: September 2022

Due to the efficient and flexible flight ability of bats, bat-like robots have become the focus of research in the field of bionic robots. Aerodynamic calculation is an important part of the research field of bat-like robot, which is the basis of the structure design and flight controller design of bat-like robot. However, due to the complex flight mechanism of bats, there is no mature theoretical method to calculate the flight aerodynamic force of bat-like robots. To solve this problem, this paper takes the membrane of a bat-like robot as the research object and analyzes in detail the effects of wing folding and unfolding and flexible deformation of the membrane on the chord length, passive torsion angle and relative velocity. Based on quasi-steady state model and blade element method, a set of aerodynamic calculation method for flexible deformed wing is established. In order to verify the effectiveness of the proposed method, the theoretical calculation results and the results of the fluid-structure interaction simulation are compared and analyzed under various working conditions. The two results are in good agreement under each working condition, and the errors are all within reasonable range, which proves the effectiveness of the method. This study can provide a theoretical basis for rational structure design and precise flight control of bat-like robot.
Seamless and intuitive control of a powered prosthetic leg using deep neural network for transfemoral amputees
Authors: Kim Minjae , Simon Ann M. , Hargrove Levi J.
Published: September 2022

Powered prosthetic legs are becoming a promising option for amputee patients. However, developing safe, robust, and intuitive control strategies for powered legs remains one of the greatest challenges. Although a variety of control strategies have been proposed, creating and fine-tuning the system parameters is time-intensive and complicated when more activities need to be restored. In this study, we developed a deep neural network (DNN) model that facilitates seamless and intuitive gait generation and transitions across five ambulation modes: level-ground walking, ascending/descending ramps, and ascending/descending stairs. The combination of latent and time sequence features generated the desired impedance parameters within the ambulation modes and allowed seamless transitions between ambulation modes. The model was applied to the open-source bionic leg and tested on unilateral transfemoral users. It achieved the overall coefficient of determination of 0.72 with the state machine-based impedance parameters in the offline testing session. In addition, users were able to perform in-laboratory ambulation modes with an overall success rate of 96% during the online testing session. The results indicate that the DNN model is a promising candidate for subject-independent and tuning-free prosthetic leg control for transfemoral amputees.
Tracking Climate Through Ship Exhaust
Authors: Basilio Humberto
Published: September 2022

International regulations have reduced aerosol pollutants released from ships. Now, researchers want to use ship tracks to better understand the ambiguous effects that cleaner air has on climate.
Neurodevelopmental outcomes of extremely preterm infants fed an exclusive human milk-based diet versus a mixed human milk + bovine milk-based diet: a multi-center study
Authors: Hair Amy B. , Patel Aloka L. , Kiechl-Kohlendorfer Ursula , Kim Jae H. , Schanler Richard J. , Hawthorne Keli M. , Itriago Elena , Abrams Steven A. , Blanco Cynthia L.
Published: September 2022

Objective

The objective of this multi-center study was to compare, in infants ≤1250 g birth weight (BW) with neurodevelopmental assessment at 18–22 months of corrected age (CA), whether their neurodevelopmental outcomes differed based on exposure to an exclusive human milk-based (HUM) or to a bovine milk-based fortifier and/or preterm formula (BOV).

Study Design

Retrospective multi-center cohort study of infants undergoing neurodevelopmental assessment as to whether HUM or BOV exposure related to differences in outcomes of infants at 18–22 months CA, using the Bayley Scales of Infant Development III (BSID-III). BSID-III cognitive, language, and motor scores were adjusted for BW, sex, study site, and necrotizing enterocolitis.

Results

252 infants from 6 centers were included. BSID-III cognitive scores were higher in the HUM group (96.5 ± 15.1 vs 89.6 ± 14.1, adjusted p = 0.0001). Mean BSID-III language scores were 85.5 ± 15.0 in HUM and 82.2 ± 14.1 in BOV (adjusted p = 0.09). Mean BSID-III motor scores were 92.9 ± 11.7 in HUM and 91.4 ± 14.6 in BOV (adjusted p = 0.32).

Conclusion

In this cohort of infants undergoing neurodevelopmental assessment, infants receiving HUM diet had significantly higher cognitive BSID-III scores at 18–22 months CA. Further investigation is needed of this potential for HUM to positively influence infant cognitive outcomes.
Influence of protocol scan on choroidal vascularity measurements: a spectralis optical coherence tomography study
Authors: Iovino Claudio , Melillo Paolo , Capriuoli Paolo , Vupparaboina Kiran Kumar , Testa Francesco , Chhablani Jay , Simonelli Francesca
Published: September 2022

Objectives

To compare choroidal vascularity index (CVI) measurements using the automated image binarization algorithm in healthy subjects with two Spectralis spectral-domain optical coherence tomography (SD-OCT) protocol scans.

Methods

Sixty-nine eyes of 69 healthy volunteers were included in this cross-sectional prospective study. Two subsequent horizontal 20°line scans passing through the fovea were acquired with enhanced-depth imaging mode with high speed (HS) and high resolution (HR) protocol scans. CVI and its subcomponents were measured with the previously validated automated algorithm. Differences between choroidal measurements obtained with HS and HR protocol scans were evaluated with t-test and Bland & Altman plots.

Results

A total of 33 male (47.8%) and 36 female (52.2%) subjects with a mean age of 35.1 ± 13.4 years were included. Overall, HS protocol scan was associated with significant lower values of total choroidal area (−0.047 mm2) and stromal choroidal area (−0.036 mm2), and a significant greater value of CVI (+0.010%) if compared to HR protocol. Luminal choroidal area was lower when calculated with the HS protocol, although it did not reach significance. To compare the two different protocols, the number of pixels should be multiplied for 3.87 ×5.73 when the CVI is measured on a HR OCT b scan and 3.87 ×11.46 for the HS OCT b scan.

Conclusions

HS and HR acquisition modes significantly influence CVI and its subcomponents values measured with the automated software. However, adopting the scale factors can minimize the differences between the two protocol scans.
Activation of the human insulin receptor by non-insulin-related peptides
Authors: Kirk Nicholas S. , Chen Qi , Wu Yingzhe Ginger , Asante Anastasia L. , Hu Haitao , Espinosa Juan F. , Martínez-Olid Francisco , Margetts Mai B. , Mohammed Faiz A. , Kiselyov Vladislav V. , Barrett David G. , Lawrence Michael C.
Published: September 2022

The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in turn effects trans-activation of the intracellular tyrosine kinase domains and downstream signalling. Of particular therapeutic interest is whether insulin receptor signalling can be replicated by molecules other than insulin. Here, we present single-particle cryoEM structures that show how a 33-mer polypeptide unrelated to insulin can cross-link two sites on the receptor surface and direct the receptor into a signalling-active conformation. The 33-mer polypeptide engages the receptor by two helical binding motifs that are each potentially mimicable by small molecules. The resultant conformation of the receptor is distinct from—but related to—those in extant three-dimensional structures of the insulin-complexed receptor. Our findings thus illuminate unexplored pathways for controlling the signalling of the insulin receptor as well as opportunities for development of insulin mimetics.
Lesion environments direct transplanted neural progenitors towards a wound repair astroglial phenotype in mice
Authors: O’Shea T. M. , Ao Y. , Wang S. , Wollenberg A. L. , Kim J. H. , Ramos Espinoza R. A. , Czechanski A. , Reinholdt L. G. , Deming T. J. , Sofroniew M. V.
Published: September 2022

Neural progenitor cells (NPC) represent potential cell transplantation therapies for CNS injuries. To understand how lesion environments influence transplanted NPC fate in vivo, we derived NPC expressing a ribosomal protein-hemagglutinin tag (RiboTag) for transcriptional profiling of transplanted NPC. Here, we show that NPC grafted into uninjured mouse CNS generate cells that are transcriptionally similar to healthy astrocytes and oligodendrocyte lineages. In striking contrast, NPC transplanted into subacute CNS lesions after stroke or spinal cord injury in mice generate cells that share transcriptional, morphological and functional features with newly proliferated host astroglia that restrict inflammation and fibrosis and isolate lesions from adjacent viable neural tissue. Our findings reveal overlapping differentiation potentials of grafted NPC and proliferating host astrocytes; and show that in the absence of other interventions, non-cell autonomous cues in subacute CNS lesions direct the differentiation of grafted NPC towards a naturally occurring wound repair astroglial phenotype.
The transcriptional coactivator RUVBL2 regulates Pol II clustering with diverse transcription factors
Authors: Wang Hui , Li Boyuan , Zuo Linyu , Wang Bo , Yan Yan , Tian Kai , Zhou Rong , Wang Chenlu , Chen Xizi , Jiang Yongpeng , Zheng Haonan , Qin Fangfei , Zhang Bin , Yu Yang , Liu Chao-Pei , Xu Yanhui , Gao Juntao , Qi Zhi , Deng Wulan , Ji Xiong
Published: September 2022

RNA polymerase II (Pol II) apparatuses are compartmentalized into transcriptional clusters. Whether protein factors control these clusters remains unknown. In this study, we find that theATPase-associated with diverse cellularactivities (AAA + ) ATPase RUVBL2 co-occupies promoters with Pol II and various transcription factors. RUVBL2 interacts with unphosphorylated Pol II in chromatin to promote RPB1 carboxy-terminal domain (CTD) clustering and transcription initiation. Rapid depletion of RUVBL2 leads to a decrease in the number of Pol II clusters and inhibits nascent RNA synthesis, and tethering RUVBL2 to an active promoter enhances Pol II clustering at the promoter. We also identify target genes that are directly linked to the RUVBL2-Pol II axis. Many of these genes are hallmarks of cancers and encode proteins with diverse cellular functions. Our results demonstrate an emerging activity for RUVBL2 in regulating Pol II cluster formation in the nucleus.
Understanding water transport through graphene-based nanochannels via experimental control of slip length
Authors: Wen Xinyue , Foller Tobias , Jin Xiaoheng , Musso Tiziana , Kumar Priyank , Joshi Rakesh
Published: September 2022

The water transport along graphene-based nanochannels has gained significant interest. However, experimental access to the influence of defects and impurities on transport poses a critical knowledge gap. Here, we investigate the water transport of cation intercalated graphene oxide membranes. The cations act as water-attracting impurities on the channel walls. Via water transport experiments, we show that the slip length of the nanochannels decay exponentially with the hydrated diameter of the intercalated cations, confirming that water transport is governed by the interaction between water molecules and the impurities on the channel wall. The exponential decay of slip length approximates non-slip conditions. This offers experimental support for the use of the Hagen-Poiseuille equation in graphene-based nanochannels, which was previously only confirmed by simulations. Our study gives valuable feedback to theoretical predictions of the water transport along graphene-based channels with water-attracting impurities.
Functional connectivity of the cortico-subcortical sensorimotor loop is modulated by the severity of nigrostriatal dopaminergic denervation in Parkinson’s Disease
Authors: Quarantelli Mario , Quattrone Andrea , Sarica Alessia , Cicone Francesco , Cascini Giuseppe Lucio , Quattrone Aldo
Published: September 2022

To assess if the severity of nigrostriatal innervation loss affects the functional connectivity (FC) of the sensorimotor cortico-striato-thalamic-cortical loop (CSTCL) in Parkinson’s Disease (PD), Resting-State functional MRI and 18F-DOPA PET data, simultaneously acquired on a hybrid PET/MRI scanner, were retrospectively analyzed in 39 PD and 16 essential tremor patients. Correlations between posterior Putamen DOPA Uptake (pPDU) and the FC of the main CSTCL hubs were assessed separately in the two groups, analyzing the differences between the two groups by a group-by-pPDU interaction analysis of the resulting clusters’ FC. Unlike in essential tremor, in PD patients pPDU correlated inversely with the FC of the thalamus with the sensorimotor cortices, and of the postcentral gyrus with the dorsal cerebellum, and directly with the FC of pre- and post-central gyri with both the superior and middle temporal gyri and the paracentral lobule, and of the caudate with the superior parietal cortex. The interaction analysis confirmed the significance of the difference between the two groups in these correlations. In PD patients, the post-central cortex FC, in the clusters correlating directly with pPDU, negatively correlated with both UPDRS motor examination score and Hoehn and Yahr stage, independent of the pPDU, suggesting that these FC changes contribute to motor impairment. In PD, nigrostriatal innervation loss correlates with a decrease in the FC within the sensorimotor network and between the sensorimotor network and the superior temporal cortices, possibly contributing to motor impairment, and with a strengthening of the thalamo-cortical FC, that may represent ineffective compensatory phenomena.
Extending the spectrum of fully integrated photonics to submicrometre wavelengths
Authors: Tran Minh A. , Zhang Chong , Morin Theodore J. , Chang Lin , Barik Sabyasachi , Yuan Zhiquan , Lee Woonghee , Kim Glenn , Malik Aditya , Zhang Zeyu , Guo Joel , Wang Heming , Shen Boqiang , Wu Lue , Vahala Kerry , Bowers John E. , Park Hyundai , Komljenovic Tin
Published: September 2022

Integrated photonics has profoundly affected a wide range of technologies underpinning modern society1–4. The ability to fabricate a complete optical system on a chip offers unrivalled scalability, weight, cost and power efficiency5,6. Over the last decade, the progression from pure III–V materials platforms to silicon photonics has significantly broadened the scope of integrated photonics, by combining integrated lasers with the high-volume, advanced fabrication capabilities of the commercial electronics industry7,8. Yet, despite remarkable manufacturing advantages, reliance on silicon-based waveguides currently limits the spectral window available to photonic integrated circuits (PICs). Here, we present a new generation of integrated photonics by directly uniting III–V materials with silicon nitride waveguides on Si wafers. Using this technology, we present a fully integrated PIC at photon energies greater than the bandgap of silicon, demonstrating essential photonic building blocks, including lasers, amplifiers, photodetectors, modulators and passives, all operating at submicrometre wavelengths. Using this platform, we achieve unprecedented coherence and tunability in an integrated laser at short wavelength. Furthermore, by making use of this higher photon energy, we demonstrate superb high-temperature performance and kHz-level fundamental linewidths at elevated temperatures. Given the many potential applications at short wavelengths, the success of this integration strategy unlocks a broad range of new integrated photonics applications.
PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells
Authors: Codarri Deak Laura , Nicolini Valeria , Hashimoto Masao , Karagianni Maria , Schwalie Petra C. , Lauener Laura , Varypataki Eleni Maria , Richard Marine , Bommer Esther , Sam Johannes , Joller Stefanie , Perro Mario , Cremasco Floriana , Kunz Leo , Yanguez Emilio , Hüsser Tamara , Schlenker Ramona , Mariani Marisa , Tosevski Vinko , Herter Sylvia , Bacac Marina , Waldhauer Inja , Colombetti Sara , Gueripel Xavier , Wullschleger Stephan , Tichet Melanie , Hanahan Douglas , Kissick Haydn T. , Leclair Stephane , Freimoser-Grundschober Anne , Seeber Stefan , Teichgräber Volker , Ahmed Rafi , Klein Christian , Umaña Pablo
Published: September 2022

Expansion and differentiation of antigen-experienced PD-1+TCF-1+ stem-like CD8+ T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade1–4. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of ‘better effector’ CD8+ T cells similar to those generated in an acute infection5. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed6–10. Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8+ T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.
Visualizing translation dynamics at atomic detail inside a bacterial cell
Authors: Xue Liang , Lenz Swantje , Zimmermann-Kogadeeva Maria , Tegunov Dimitry , Cramer Patrick , Bork Peer , Rappsilber Juri , Mahamid Julia
Published: September 2022

Translation is the fundamental process of protein synthesis and is catalysed by the ribosome in all living cells1. Here we use advances in cryo-electron tomography and sub-tomogram analysis2,3 to visualize the structural dynamics of translation inside the bacterium Mycoplasma pneumoniae. To interpret the functional states in detail, we first obtain a high-resolution in-cell average map of all translating ribosomes and build an atomic model for the M. pneumoniae ribosome that reveals distinct extensions of ribosomal proteins. Classification then resolves 13 ribosome states that differ in their conformation and composition. These recapitulate major states that were previously resolved in vitro, and reflect intermediates during active translation. On the basis of these states, we animate translation elongation inside native cells and show how antibiotics reshape the cellular translation landscapes. During translation elongation, ribosomes often assemble in defined three-dimensional arrangements to form polysomes4. By mapping the intracellular organization of translating ribosomes, we show that their association into polysomes involves a local coordination mechanism that is mediated by the ribosomal protein L9. We propose that an extended conformation of L9 within polysomes mitigates collisions to facilitate translation fidelity. Our work thus demonstrates the feasibility of visualizing molecular processes at atomic detail inside cells.
LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity
Authors: Krishnamurty Akshay T. , Shyer Justin A. , Thai Minh , Gandham Vineela , Buechler Matthew B. , Yang Yeqing Angela , Pradhan Rachana N. , Wang Amber W. , Sanchez Patricia L. , Qu Yan , Breart Beatrice , Chalouni Cécile , Dunlap Debra , Ziai James , Elstrott Justin , Zacharias Neelie , Mao Weiguang , Rowntree Rebecca K. , Sadowsky Jack , Lewis Gail D. , Pillow Thomas H. , Nabet Barzin Y. , Banchereau Romain , Tam Lucinda , Caothien Roger , Bacarro Natasha , Roose-Girma Merone , Modrusan Zora , Mariathasan Sanjeev , Müller Sören , Turley Shannon J.
Published: September 2022

Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15)1–3. However, the molecular signals that underlie the development of LRRC15+ cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptor type 2 signalling in healthy dermatopontin+ universal fibroblasts is essential for the development of cancer-associated LRRC15+ myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15–diphtheria toxin receptor knock-in mice to selectively deplete LRRC15+ CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8+ T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFβ-dependent LRRC15+ CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8+ T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15+ myofibroblasts may improve patient survival and response to immunotherapy.
Awake perception is associated with dedicated neuronal assemblies in the cerebral cortex
Authors: Filipchuk Anton , Schwenkgrub Joanna , Destexhe Alain , Bathellier Brice
Published: September 2022

Neural activity in the sensory cortex combines stimulus responses and ongoing activity, but it remains unclear whether these reflect the same underlying dynamics or separate processes. In the present study, we show in mice that, during wakefulness, the neuronal assemblies evoked by sounds in the auditory cortex and thalamus are specific to the stimulus and distinct from the assemblies observed in ongoing activity. By contrast, under three different anesthetics, evoked assemblies are indistinguishable from ongoing assemblies in the cortex. However, they remain distinct in the thalamus. A strong remapping of sensory responses accompanies this dynamic state change produced by anesthesia. Together, these results show that the awake cortex engages dedicated neuronal assemblies in response to sensory inputs, which we suggest is a network correlate of sensory perception.
Healthcare workers’ self-regulatory eating behaviours are associated with being stress-free during the Covid-19 lockdown in Singapore
Authors: Huang Zhongwei , Tan Pei Ting , Kua Zaylea , Ong Li Jiuen , Hamzah Fadzil Bin Mohamed , Tan Benedict
Published: September 2022

Our study sought to examine the impact of the pandemic and the Circuit-breaker (CB) measures on dietary behaviours of healthcare workers (HCW). In addition, the association between self-regulatory eating behaviours and psychological stress was explored. Our study employed a cross-sectional anonymous survey that examined the demographics, dietary habits, self-regulatory eating behaviours (SR) and their association to stress levels of healthcare workers (HCWs) before and during the Circuit Breaker (CB) in Singapore. The survey was conducted over four weeks from May 17 to June 18, 2020. Snowball sampling was performed in the final week. A total of 707 participants took part in the survey. Due to the CB measures and modifications of work scope and work areas, there were significant changes in their dietary behaviors before CB versus during the CB period (n = 707), with many reducing the intake of vegetables (p = 0.018) while increasing their intake of unhealthy food choices such as canned drinks (p = 0.002), convenience food (p ≤ 0.001) and alcoholic drinks (p = 0.034). Before the CB period, 91.8% (602/656) of participants who intended to have a healthy diet were classified in medium-to-high SR groups whereas during the CB period, 87.7% (575/656) were in medium-to-high SR groups and the difference was statistically significant (p = 0.011). Nurses, administrative staff, HCWs of Chinese and Indian ethnicities, staff who did not complete university education and those who did not have domestic helpers were more likely to have reduced SR. Importantly, amongst participants who intended to have a healthy diet, 70.9% displayed no change or improved eating habits and showed medium-to-high levels of SR during CB. Participants with no changes in SR were 2.11 times more likely to be stress-free as compared to those who had deteriorated SR (OR 2.11 95% CI 1.27–3.48, p = 0.004). Due to CB measures and work modifications, dietary behaviours of HCWs deteriorated with increased intake of unhealthy food choices. HCWs who maintain their self-regulatory eating behaviour are more likely to be stress-free. Short screening questionnaires based on SR changes should be developed and explored as surveillance tools for assessment of HCWs’ general well-being such that personalized interventions to vulnerable groups of workers could be implemented effectively on the ground.
Multiparameter analysis of timelapse imaging reveals kinetics of megakaryocytic erythroid progenitor clonal expansion and differentiation
Authors: Scanlon Vanessa M. , Thompson Evrett N. , Lawton Betty R. , Kochugaeva Maria , Ta Kevinminh , Mayday Madeline Y. , Xavier-Ferrucio Juliana , Kang Elaine , Eskow Nicole M. , Lu Yi-Chien , Kwon Nayoung , Laumas Anisha , Cenci Matthew , Lawrence Kalyani , Barden Katie , Larsuel Shannon T. , Reed Fiona E. , Peña-Carmona Gabriela , Ubbelohde Ashley , Lee June P. , Boobalan Shakthi , Oppong Yvette , Anderson Rachel , Maynard Colby , Sahirul Kaylie , Lajeune Callista , Ivathraya Varsha , Addy Tiffany , Sanchez Patricia , Holbrook Colin , Van Ho Andrew Tri , Duncan James S. , Blau Helen M. , Levchenko Andre , Krause Diane S.
Published: September 2022

Single-cell assays have enriched our understanding of hematopoiesis and, more generally, stem and progenitor cell biology. However, these single-end-point approaches provide only a static snapshot of the state of a cell. To observe and measure dynamic changes that may instruct cell fate, we developed an approach for examining hematopoietic progenitor fate specification using long-term (> 7-day) single-cell time-lapse imaging for up to 13 generations with in situ fluorescence staining of primary human hematopoietic progenitors followed by algorithm-assisted lineage tracing. We analyzed progenitor cell dynamics, including the division rate, velocity, viability, and probability of lineage commitment at the single-cell level over time. We applied a Markov probabilistic model to predict progenitor division outcome over each generation in culture. We demonstrated the utility of this methodological pipeline by evaluating the effects of the cytokines thrombopoietin and erythropoietin on the dynamics of self-renewal and lineage specification in primary human bipotent megakaryocytic-erythroid progenitors (MEPs). Our data support the hypothesis that thrombopoietin and erythropoietin support the viability and self-renewal of MEPs, but do not affect fate specification. Thus, single-cell tracking of time-lapse imaged colony-forming unit assays provides a robust method for assessing the dynamics of progenitor self-renewal and lineage commitment.
An ultrasound-induced wireless power supply based on AlN piezoelectric micromachined ultrasonic transducers
Authors: Rong Zhicong , Zhang Menglun , Ning Yuan , Pang Wei
Published: September 2022

Wireless power transfer is one of the enabling technologies for powering implantable biomedical devices. Biocompatibility and CMOS compatibility of wireless power transfer devices are highly desired due to safety and footprint concerns. Toward implantable applications, this paper presents an ultrasound-induced wireless power supply based on AlN piezoelectric micromachined ultrasonic transducer (PMUT). The wireless power supply integrates wireless power transfer, power management and energy storage functions. The PMUT array is used as a passive wireless power receiver, followed by electrical impedance matching networks and a voltage multiplier for efficient power transmission and rectification. The output power intensity of the wireless receiver reaches 7.36 μW/mm2with an incident ultrasound power below the FDA safety limit. The output power of the wireless power supply reaches 18.8 μW and a 100-μF capacitor is fully charged to 3.19 V after power management, which are sufficient to power many low-power implantable biomedical devices such as for neural electrical stimulation, biosensors and intrabody communication applications. The wireless power supply is implemented in a PCB with a diameter of 1 cm. With biocompatibility and CMOS compatibility of AlN thin film compared to commonly used PZT, the proposed solution paves the way for safer and ultraminiaturized wireless power supplies with further development incorporating all the functions on a monolithic chip in the future.
Effect of processing parameters on texture and variant selection of as-built 300 maraging steel processed by laser powder bed fusion
Authors: Eres-Castellanos Adriana , Santana Ana , De-Castro David , Jimenez Jose Antonio , Rementeria Rosalia , Capdevila Carlos , Caballero Francisca G.
Published: September 2022

Among the materials that might be manufactured with laser powder bed fusion (LPBF), one can highlight maraging steels, with excellent weldability, strength and fracture toughness. However, the effects of the processing parameters and the mechanisms governing the as-built texture are not clear yet. A recent publication showed a low texture index in the prior austenite, in contrast to other alloys subjected to LPBF with the same strategy. Authors suggested several hypotheses, although no conclusions were drawn. This work aims to investigate these findings by using a 300 maraging steel processed under different conditions, i.e. different printer, powder layer thickness and laser emission mode. To do so, X-Ray Diffraction, Electron Backscattered Diffraction and Scanning Electron Microscopy have been used. Results show that the heat treatment intrinsic to the LPBF process does not affect the prior austenite grains, whose texture and morphology remain unchanged throughout the process. Also, for the studied ranges, the microstructure texture is not related to the powder layer thickness or to the laser emission mode, although it could be affected by the laser power or the scan strategy. Finally, a low degree of variant selection has been observed, where the selected variants are those that contribute to a martensite cubic rotated texture.
Attomolar sensitivity microRNA detection using real-time digital microarrays
Authors: Ekiz Kanik Fulya , Celebi Iris , Sevenler Derin , Tanriverdi Kahraman , Lortlar Ünlü Nese , Freedman Jane E. , Ünlü M. Selim
Published: September 2022

MicroRNAs (miRNAs) are a family of noncoding, functional RNAs. With recent developments in molecular biology, miRNA detection has attracted significant interest, as hundreds of miRNAs and their expression levels have shown to be linked to various diseases such as infections, cardiovascular disorders and cancers. A powerful and high throughput tool for nucleic acid detection is the DNA microarray technology. However, conventional methods do not meet the demands in sensitivity and specificity, presenting significant challenges for the adaptation of miRNA detection for diagnostic applications. In this study, we developed a highly sensitive and multiplexed digital microarray using plasmonic gold nanorods as labels. For proof of concept studies, we conducted experiments with two miRNAs, miRNA-451a (miR-451) and miRNA-223-3p (miR-223). We demonstrated improvements in sensitivity in comparison to traditional end-point assays that employ capture on solid phase support, by implementing real-time tracking of the target molecules on the sensor surface. Particle tracking overcomes the sensitivity limitations for detection of low-abundance biomarkers in the presence of low-affinity but high-abundance background molecules, where endpoint assays fall short. The absolute lowest measured concentration was 100 aM. The measured detection limit being well above the blank samples, we performed theoretical calculations for an extrapolated limit of detection (LOD). The dynamic tracking improved the extrapolated LODs from femtomolar range to $$\sim$$
∼
 10 attomolar (less than 1300 copies in 0.2 ml of sample) for both miRNAs and the total incubation time was decreased from 5 h to 35 min.
Hand dexterity, daily functioning and health-related quality of life in kidney transplant recipients
Authors: Knobbe Tim J. , Kremer Daan , Eisenga Michele F. , Corpeleijn Eva , Annema Coby , Spikman Joke M. ,   Transplantlines Investigators, Annema Coby , Bakker Stephan J. L. , Berger Stefan P. , Blokzijl Hans , Bodewes Frank , de Boer Marieke T. , Damman Kevin , de Borst Martin H. , Diepstra Arjan , Dijkstra Gerard , Douwes Rianne M. , Eisenga Michele F. , Erasmus Michiel E. , Tji Gan C. , Gomes Neto Antonio W. , Grootjans Heleen , Hak Eelko , Rebecca Heiner-Fokkema M. , Hepkema Bouke G. , Klont Frank , Knobbe Tim J. , Kremer Daan , Leuvenink Henri G. D. , Lexmond Willem S. , de Meijer Vincent E. , Niesters Hubert G. M. , van Pelt L. Joost , Pol Robert J. , Porte Robert J. , Ranchor Adelita V. , Sanders Jan Stephan F. , Schutten Joëlle C. , Siebelink Marion J. , Slart Riemer J. H. J. A. , Casper Swarte J. , Timens Wim , Touw Daan J. , van den Heuvel Marius C. , van Leer-Buter Coretta C. , van Londen Marco , Verschuuren Erik A. M. , Vos Michel J. , Weersma Rinse K. , Navis Gerjan , Berger Stefan P. , Bakker Stephan J. L.
Published: September 2022

Impaired interplay between sensory and motor function may be an important, often overlooked cause of the decreased daily functioning and impaired health-related quality of life (HRQoL) of kidney transplant recipients (KTR). We assessed this interplay using a hand dexterity test, and investigated its potential associations with daily functioning and HRQoL among KTR enrolled at the TransplantLines Biobank and Cohort Study. A total of 309 KTR (58% male, mean age 56 ± 13 years) at median 4 [IQR: 1–11] years after transplantation were included. Impaired hand dexterity, as defined by a test performance slower than the 95th percentile of an age- and sex-specific reference population, was observed in 71 (23%) KTR. Worse hand dexterity was independently associated with worse performance on almost all measures of physical capacity, activities of daily living and societal participation. Finally, hand dexterity was independently associated with physical HRQoL (standardized beta − 0.22, 95%CI − 0.34 to − 0.09, P < 0.001). In conclusion, impaired interplay between sensory and motor function, as assessed by hand dexterity, is prevalent among KTR. In addition, poor hand dexterity was associated with impaired daily functioning and limited physical HRQoL. Impaired interplay between sensory and motor function may be therefore an important, hitherto overlooked, phenomenon in KTR.
Synthesis, biological evaluation, and molecular modeling studies of new benzoxazole derivatives as PARP-2 inhibitors targeting breast cancer
Authors: El-Ghobashy Nadeen M. , El-Sayed Selwan M. , Shehata Ihsan A. , El-Ashmawy Mahmoud B.
Published: September 2022

Many benzoxazole-based and similar scaffolds were reported to have wide-range of anticancer activities. In this study, four series of benzoxazole derivatives were designed by combining benzoxazole scaffold with different amines via a reversed phenyl amide linker to produce the compounds of series A, B and C. A fourth new hybrid of benzoxazole with 1,2,3 triazole ring (series D) was also designed. The designed compounds were synthesized and screened for their anti-breast cancer activity against MDA-MB-231 and MCF-7 cell lines using MTT assay. The most potent cytotoxic compounds; 11–14, 21, 22, 25–27 were further evaluated for their in vitro PARP-2 enzyme inhibition. Compounds 12 and 27 proved to be the most active PARP-2 inhibitors with IC50 values of 0.07 and 0.057 µM, respectively. Compounds 12 and 27 caused cell cycle arrest in mutant MCF-7 cell line at G2/M and G1/S phase, respectively and they possessed significant apoptosis-promoting activity. Docking results of compounds 12 and 27 into PARP-2 pocket demonstrated binding interactions comparable to those of olaparib. Their predicted pharmacokinetic parameters and oral bioavailability appeared to be appropriate. Collectively, it could be concluded that compounds 12 and 27 are promising anti-breast cancer agents that act as PARP-2 inhibitors with potent apoptotic activity.