bluuebunny/crossref_metadata_2025 huggingface dataset:
Low Femoral Tunnel Widening Incidence Rate After ACL Reconstruction Using Patellar Tendon Graft with Press-Fit Fixation
Authors: Tátrai Miklós , Halasi Tamás , Tállay András , Tátrai Annamária , Pavlik Attila
Published: February 2023

Background

Femoral tunnel widening after ACL reconstruction is a common phenomenon. We hypothesized that using a patellar tendon graft with a press-fit fixation technique without any fixation device reduces the incidence of femoral tunnel widening.

Methods

This study was conducted on 467 patients with ACL surgery between 2003 and 2015. Two hundred and nineteen of them had an ACL surgery with patellar tendon (PT) graft, and two hundred and forty-eight of them with hamstring tendon (HS). Exclusion criteria were history of previous ACL reconstruction of either knee, multiple ligament injury, or evidence of osteoarthritis on radiographs. The femoral tunnels were measured on the anteroposterior (ap) and lateral radiographs 6 months after the operation. Two independent orthopedic surgeons measured all radiographs twice and recorded the tunnel widenings. We hypothesized that using an implant-free press-fit technique with PT graft can reduce the femoral tunnel widening incidence rate.

Results

The mean incidence rate of the tunnel widening in the HS group was, on the AP and the lateral femoral views, 88% (n = 217) and 83% (n = 205), while in the PT group, 17% (n = 37) and 2% (n = 4), respectively. There was a significant difference both on AP and lateral radiographs (HS vs. PT: fem. AP: 89% vs. 17% p < 0.001; HS vs. PT: fem. lat: 84% vs. 2% p < 0.001).

Conclusion

The femoral tunnel widening incidence rate during an ACL reconstruction is significantly less when using PT tendon with femoral press-fit fixation than when using HT tendon with suspensory fixation method.
“Watch and wait” strategy after neoadjuvant chemoradiotherapy in rectal cancer: opportunities and challenges
Authors: Yang Yong , Huang An , Sun Zhuang , Hong Hao-peng , Kim Nam KYu , Gu Jin
Published: February 2023

The "watch and wait" (W&W) strategy has been widely used in rectal cancer patients who have achieved clinical complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT), which can save them from surgery and improve their quality of life. However, this strategy also has many unsolved practical problems, including the improvement of cCR/pCR rate, the search for efficient predictors, the standard follow-up and the methods of rescue surgery, etc. Larger sample size and more standardized clinical trials are still needed to obtain credible evidence. Therefore, we must rationally view the cCR after nCRT for middle and low rectal cancer, understand the risk of W&W strategy, and make a reasonable choice. It is particularly important to emphasize that we should actively carry out prospective multi-center clinical trials to produce high-level evidence suitable for Chinese characteristics, so that more rectal cancer patients can benefit from nCRT.
Adult Onset Langerhans Cell Histiocytosis: Clinical Characteristics and Treatment Outcomes
Authors: Arslan Davulcu Eren , Soyer Nur , Demirci Zühal , Güneş Ajda , Vural Filiz , Şahin Fahri , Töbü Mahmut , Kamer Serra , Hekimgil Mine , Saydam Güray
Published: February 2023

Purpose

Langerhans cell histiocytosis (LCH) is a rare disease that can affect all tissues and organs. Our study evaluated the clinical characteristics and treatment outcomes of adult-onset LCH patients in a tertiary center.

Materials and Methods

Adult patients diagnosed with LCH were retrospectively evaluated. Their initial symptoms, stratification according to disease involvement, treatment details, treatment responses, and overall and progression-free survival (PFS) were analyzed.

Results

Thirty-three patients were included. There were 21 single system LCH, 10 multisystem LCH, and 2 pulmonary LCH patients. Patients with single system unifocal involvement were successfully treated with local therapies such as surgery and radiotherapy. Most of the multisystem LCH patients and patients with single system multifocal involvement were treated with systemic chemotherapy. Cladribine was the first choice in 10 out of 11 patients who received chemotherapy. Among all patients, the overall response rate (ORR) was 97%. Among those who had cladribine in the first-line the ORR was 81%. All these patients achieved a complete remission and were alive at the last visit. The median follow-up was 38 (range, 2–183) months. The median PFS has not yet been reached. Ten-year PFS was 90.9%.

Conclusion

Besides successful local treatments with surgery and radiotherapy, our study provides information for front-line cladribine treatment.
Delius and his Music
Authors: Lee-Browne Martin , Guinery Paul , Elder Mark
Published: February 2023

The first comprehensive study of the music of Frederick Delius (1862-1934), from his earliest pieces up to his final compositions, with background information and a complete list of works.
Consumption and Culture in Sixteenth-Century Ireland
Authors: Flavin Susan
Published: February 2023

A detailed study of changing patterns of consumption, showing how these related to wider political, social and economic developments.
Feminism and gender in thinking about extraterrestrial intelligence
Authors: Szocik Konrad , Abylkasymova Rakhat
Published: February 2023

In this paper, we offer an outline of a feminist approach to considering the issue of extraterrestrial intelligence (ETI). Dominant ways of discussing ETI, particularly first-contact scenarios and protocols, are characterized by what feminism terms male bias. As with other cultural texts and disciplines, ETI studies can also be enriched by a feminist perspective. In this paper, we propose two possible applications of a feminist approach to considering ETI, such as using feminist categories to analyse our discourse about ETI, as well as understanding ETI in terms of sex and gender. We also propose a vision of ETI as genderless.
Key Role of Arctic Sea‐Ice in Subseasonal Reversal of Early and Late Winter PM2.5 Concentration Anomalies Over the North China Plain
Authors: An Xiadong , Chen Wen , Ma Tianjiao , Aru Hasi , Cai Qingyu , Li Chun , Sheng Lifang
Published: February 2023

The PM2.5 (fine particulate matter with diameter ≤2.5 μm) concentration anomalies over the North China Plain (NCP) in early and late winter sometimes show a subseasonal reversal, which brings a great challenge for precise control of air pollution, and mechanisms are not well understood. This paper reveals the key role of the Barents Sea sea‐ice in this reversal. In early winter, a negative Scandinavian‐like pattern causes an anticyclonic anomaly over Northeast Asia and thus leads to the positive PM2.5 concentration anomaly over the NCP. In addition, anomalous warm advection associated with the positive North Atlantic Oscillation‐like pattern accelerates winter sea‐ice loss in the Barents Sea, especially in late winter, which increases the surface turbulent heating flux. These heating causes a negative Polar/Eurasian‐like pattern that induces a cyclonic anomaly over Northeast Asia and eventually leads to a negative PM2.5 concentration anomaly over the NCP in late winter. Vice versa.
When Will the Unprecedented 2022 Summer Heat Waves in Yangtze River Basin Become Normal in a Warming Climate?
Authors: Ma Feng , Yuan Xing
Published: February 2023

Yangtze River basin (YZB) experienced record‐breaking heat in the summer of 2022. Here, we focused on daytime‐nighttime compound heat waves, and used the magnitude index that considers both duration and intensity to investigate the risk of the 2022 extreme heat. The magnitude of heatwaves in 2022 was much larger than the historical average level, which was estimated as a 1‐in‐64‐year event over 1979–2014 climate. Without mitigation efforts (SSP585), the record‐breaking heat would emerge as normal during 2050s, and would affect ∼70% of land and projected population in the basin before global mean temperature change reaches 3°C. Such an emergence could be progressively delayed and impacts could be reduced under lower warming levels. The affected area would be 60% lesser at 2°C warming, and the emergence could be avoided by limiting warming to 1.5°C. Our results call for urgent mitigation efforts for reducing the risk of compound heat extremes.
Low‐Altitude UAV Imaging Accurately Quantifies Eelgrass Wasting Disease From Alaska to California
Authors: Yang Bo , Hawthorne Timothy L. , Aoki Lillian , Beatty Deanna S. , Copeland Tyler , Domke Lia K. , Eckert Ginny L. , Gomes Carla P. , Graham Olivia J. , Harvell C. Drew , Hovel Kevin A. , Hessing‐Lewis Margot , Harper Leah , Mueller Ryan S. , Rappazzo Brendan , Reshitnyk Luba , Stachowicz John J. , Tomas Fiona , Duffy J. Emmett
Published: February 2023

Declines in eelgrass, an important and widespread coastal habitat, are associated with wasting disease in recent outbreaks on the Pacific coast of North America. This study presents a novel method for mapping and predicting wasting disease using Unoccupied Aerial Vehicle (UAV) with low‐altitude autonomous imaging of visible bands. We conducted UAV mapping and sampling in intertidal eelgrass beds across multiple sites in Alaska, British Columbia, and California. We designed and implemented a UAV low‐altitude mapping protocol to detect disease prevalence and validated against in situ results. Our analysis revealed that green leaf area index derived from UAV imagery was a strong and significant (inverse) predictor of spatial distribution and severity of wasting disease measured on the ground, especially for regions with extensive disease infection. This study highlights a novel, efficient, and portable method to investigate seagrass disease at landscape scales across geographic regions and conditions.
Survival in hematological malignancies in the Nordic countries through a half century with correlation to treatment
Authors: Hemminki Kari , Hemminki Janne , Försti Asta , Sud Amit
Published: February 2023

Studies of survival in hematological malignancies (HMs) have generally shown an improvement over time, although most of these studies are limited by a short follow-up period. Using the NORDCAN database with data from Denmark, Finland, Norway and Sweden, we follow periodic increases in relative survival in seven HMs through half a century up to 2015–2019. Five-year survival improved in all seven HMs, reaching 90% for Hodgkin lymphoma (HL), myeloproliferative neoplasias and chronic lymphocytic leukemia (CLL), 60% for multiple myeloma (MM) and chronic myeloid leukemias (CMLs), 50% for the myelodysplastic syndromes and 30% for acute myeloid leukemia (AML). Improvements in survival over 50 years ranged from 20% to more than 50% units across the different HMs. The likely reasons for such progress include earlier diagnoses, improved risk stratification and advances in treatment. We observed differing temporal trends in improvements in survival. The gradual increases observed in HL, CLL and AML highlight the impact of optimization of existing therapies and improvements in diagnostics and risk stratification, whereas the rapid increases observed in the CMLs and MM highlight the impact of novel therapies. Recent therapeutic advances may further improve survival in HMs where survival remains low such as in AML.
Current pain management practices for preterm infants with necrotizing enterocolitis: a European survey
Authors: ten Barge Judith A. , van den Bosch Gerbrich E. , Meesters Naomi J. , Allegaert Karel , Arribas Cristina , Cavallaro Giacomo , Garrido Felipe , Raffaeli Genny , Vermeulen Marijn J. , Simons Sinno H. P. ,   on behalf of the ESPR Special Interest Group for Neonatal Pain and the NEC Pain Study Group
Published: February 2023

Background

Necrotizing enterocolitis (NEC) is a highly painful intestinal complication in preterm infants that requires adequate pain management to prevent short- and long-term effects of neonatal pain. There is a lack of international guidelines for pain management in NEC patients. Therefore, this study aims to describe current pain management for NEC patients in European neonatal intensive care units (NICUs).

Methods

An online survey was designed and conducted to assess current practices in pain management for NEC patients in European NICUs. The survey was distributed via neonatal societies, digital platforms, and professional contacts.

Results

Out of the 259 responding unique European NICUs from 36 countries, 61% had a standard protocol for analgesic therapy, 73% assessed pain during NEC, and 92% treated NEC patients with intravenous analgosedatives. There was strong heterogeneity in the used pain scales and initial analgesic therapy, which mainly included acetaminophen (70%), fentanyl (56%), and/or morphine (49%). A third of NICU representatives considered their pain assessment adequate, and half considered their analgesic therapy adequate for NEC patients.

Conclusions

Various pain scales and analgesics are used to treat NEC patients in European NICUs. Our results provide the first step towards an international guideline to improve pain management for NEC patients.

Impact

This study provides an overview of current pain management practices for infants with necrotizing enterocolitis (NEC) in European neonatal intensive care units.

Choice of pain assessment tools, analgosedatives, and dosages vary considerably among NICUs and countries.

A third of NICU representatives were satisfied with their current pain assessment practices and half of NICU representatives with their analgesic therapy practices in NEC patients in their NICU.

The results of this survey may provide a first step towards developing a European pain management consensus guideline for patients with NEC.
Single-cell RNA sequencing in orthopedic research
Authors: Wang Tao , Wang Ling , Zhang Liping , Long Yubin , Zhang Yingze , Hou Zhiyong
Published: February 2023

Although previous RNA sequencing methods have been widely used in orthopedic research and have provided ideas for therapeutic strategies, the specific mechanisms of some orthopedic disorders, including osteoarthritis, lumbar disc herniation, rheumatoid arthritis, fractures, tendon injuries, spinal cord injury, heterotopic ossification, and osteosarcoma, require further elucidation. The emergence of the single-cell RNA sequencing (scRNA-seq) technique has introduced a new era of research on these topics, as this method provides information regarding cellular heterogeneity, new cell subtypes, functions of novel subclusters, potential molecular mechanisms, cell-fate transitions, and cell‒cell interactions that are involved in the development of orthopedic diseases. Here, we summarize the cell subpopulations, genes, and underlying mechanisms involved in the development of orthopedic diseases identified by scRNA-seq, improving our understanding of the pathology of these diseases and providing new insights into therapeutic approaches.
Minimally invasive selective caries removal: a clinical guide
Authors: Lim Zi En , Duncan Henry F. , Moorthy Advan , McReynolds David
Published: February 2023

An evolving understanding of the carious process, along with new research in adhesive restorative materials, has led to a more conservative, minimally invasive and biologically-based approach to managing dental carious lesions. The growing volume of literature has also demonstrated prognostic success in the selective caries excavation technique, subsequently preventing excessive tooth structure removal and injury to the dentine-pulp complex, which maintains pulp vitality and improves the long-term prognosis of the tooth. However, at present, there remains a limited volume of high-quality evidence to support selective caries removal, which subsequently could partly explain some resistance to its use in clinical practice. This clinical technique guide aims to demonstrate the management of carious lesions of moderate-to-deep depth in permanent teeth based on current minimally invasive dental literature.
Potential links between the microbiota and T cell immunity determine the tumor cell fate
Authors: Mohseni Amir Hossein , Taghinezhad-S Sedigheh , Casolaro Vincenzo , Lv Zhongwei , Li Dan
Published: February 2023

The central role of the microbiota as a pivotal factor regulating anti-tumor immune responses has recently been appreciated. Increasing evidence has put a spotlight on the connection of microbiota to T cells, by showing impaired effector and/or memory responses in germ-free (GF) mice or in the presence of dysbiotic communities, and association with tumor growth and overall survival (OS). These observations also have significant implications for anti-tumor therapy and vaccination, suggesting that the communication between T cells and the microbiota involves soluble mediators (microbiota-derived metabolites) that influence various functions of T cells. In addition, there is growing appreciation of the role of bacterial translocation into the peritumoral milieu from the intestinal tract, as well as of locally developed tumor microbial communities, spatially separated from the gut microbiota, in shaping the tumor microbiome. Collectively, these findings have added new support to the idea that tonic inputs mirroring the existence of tumor microbiome could regulate the function of tumor-infiltrating T cells and tissue-resident memory T (TRM) cells. In this review, we focus on recent advances and aspects of these active areas of investigation and provide a comprehensive overview of the unique mechanisms that play a pivotal role in the regulation of anti-tumor immunity by the microbiota, some of which could be of particular relevance for addressing problems caused by tumor heterogeneity. It is our hope that this review will provide a theoretical foundation for future investigations in this area.
MLKL signaling regulates macrophage polarization in acute pancreatitis through CXCL10
Authors: Peng Cheng , Tu Guangping , Wang Jiale , Wang Yilin , Wu Peng , Yu Li , Li Zhiqiang , Yu Xiao
Published: February 2023

Acute pancreatitis (AP) is a disease characterized by local and systemic inflammation with an increasing incidence worldwide. Receptor-interacting serine/threonine protein kinase 3 (RIPK3), mixed-lineage kinase domain-like protein (MLKL), and innate immune cell macrophages have been reported to be involved in the pathogenesis of AP. However, the mechanisms by which RIPK3 and MLKL regulate pancreatic injury, as well as the interactions between injured pancreatic acinar cells and infiltrating macrophages in AP, remain poorly defined. In the present study, experimental pancreatitis was induced in C57BL/6J, Ripk3-/- and Mlkl-/- mice by cerulein plus lipopolysaccharide in vivo, and primary pancreatic acinar cells were also isolated to uncover cellular mechanisms during cerulein stimulation in vitro. The results showed that MLKL and its phosphorylated protein p-MLKL were upregulated in the pancreas of the mouse AP model and cerulein-treated pancreatic acinar cells, independent of its canonical upstream molecule Ripk3, and appeared to function in a cell death-independent manner. Knockout of Mlkl attenuated AP in mice by reducing the polarization of pancreatic macrophages toward the M1 phenotype, and this protective effect was partly achieved by reducing the secretion of CXCL10 from pancreatic acinar cells, whereas knockout of Ripk3 did not. In vitro neutralization of CXCL10 impaired the pro-M1 ability of the conditioned medium of cerulein-treated pancreatic acinar cells, whereas in vivo neutralization of CXCL10 reduced the polarization of pancreatic macrophages toward M1 and the severity of AP in mice. These findings suggested that targeting the MLKL-CXCL10-macrophage axis might be a promising strategy for the treatment of AP.
CD11c+ microglia promote white matter repair after ischemic stroke
Authors: Jia Junqiu , Zheng Lili , Ye Lei , Chen Jian , Shu Shu , Xu Siyi , Bao Xinyu , Xia Shengnan , Liu Renyuan , Xu Yun , Zhang Meijuan
Published: February 2023

Ischemic stroke leads to white matter damage and neurological deficits. However, the characteristics of white matter injury and repair after stroke are unclear. Additionally, the precise molecular communications between microglia and white matter repair during the stroke rehabilitation phase remain elusive. In this current study, MRI DTI scan and immunofluorescence staining were performed to trace white matter and microglia in the mouse transient middle cerebral artery occlusion (tMCAO) stroke model. We found that the most serious white matter damage was on Day 7 after the ischemic stroke, then it recovered gradually from Day 7 to Day 30. Parallel to white matter recovery, we observed that microglia centered around the damaged myelin sheath and swallowed myelin debris in the ischemic areas. Then, microglia of the ischemic hemisphere were sorted by flow cytometry for RNA sequencing and subpopulation analysis. We found that CD11c+ microglia increased from Day 7 to Day 30, demonstrating high phagocytotic capabilities, myelin-supportive genes, and lipid metabolism associated genes. CD11c+ microglia population was partly depleted by the stereotactic injecting of rAAV2/6M-taCasp3 (rAAV2/6M-CMV-DIO-taCasp3-TEVp) into CD11c-cre mice. Selective depletion of CD11c+ microglia disrupted white matter repair, oligodendrocyte maturation, and functional recovery after stroke by Rotarod test, Adhesive Removal test, and Morris Water Maze test. These findings suggest that spontaneous white matter repair occurs after ischemic stroke, while CD11c+ microglia play critical roles in this white matter restorative progress.
Impaired hepatic autophagy exacerbates hepatotoxin induced liver injury
Authors: Byrnes Katherine , Bailey Niani Tiaye , Baral Kamal , Mercer Arissa , Joshi Spandan , Wahby Nickol , Rorison Tyler , Liu Gang , Yin Xiao-Ming , Khambu Bilon
Published: February 2023

Hepatotoxins activate the hepatic survival pathway, but it is unclear whether impaired survival pathways contribute to liver injury caused by hepatotoxins. We investigated the role of hepatic autophagy, a cellular survival pathway, in cholestatic liver injury driven by a hepatotoxin. Here we demonstrate that hepatotoxin contained DDC diet impaired autophagic flux, resulting in the accumulation of p62-Ub-intrahyaline bodies (IHBs) but not the Mallory Denk-Bodies (MDBs). An impaired autophagic flux was associated with a deregulated hepatic protein-chaperonin system and significant decline in Rab family proteins. Additionally, p62-Ub-IHB accumulation activated the NRF2 pathway rather than the proteostasis-related ER stress signaling pathway and suppressed the FXR nuclear receptor. Moreover, we demonstrate that heterozygous deletion of Atg7, a key autophagy gene, aggravated the IHB accumulation and cholestatic liver injury. Conclusion: Impaired autophagy exacerbates hepatotoxin-induced cholestatic liver injury. The promotion of autophagy may represent a new therapeutic approach for hepatotoxin-induced liver damage.
Recent progress with one-dimensional metal halide perovskites: from rational synthesis to optoelectronic applications
Authors: Duan Dawei , Ge Chuangye , Rahaman Md Zahidur , Lin Chun-Ho , Shi Yumeng , Lin Haoran , Hu Hanlin , Wu Tom
Published: February 2023

Metal halide perovskites can be readily synthesized, they exhibit tunable physical properties and excellent performance, and they are heavily studied optoelectronic materials. Compared to the typical three-dimensional perovskites, morphological-level one-dimensional (1D) nanostructures enable charge transport and photon propagation with low exciton binding energies and long charge-carrier diffusion lengths, while molecular-level 1D nanostructures exhibit good compositional and structural flexibilities, highly tunable bandgaps, strong quantum confinement effects, and excellent ambient stabilities. The 1D natures of these emerging halide perovskites enhance the performance of optoelectronic devices. Herein, we highlight recent progress realized in the syntheses and characterizations of both morphological- and molecular-level 1D halide perovskites with tunable structures, compositions, and properties, as well as their photovoltaic, light-emission, and photodetection applications. In addition, current challenges, future prospects, and promising research directions are discussed to provide guidance in advancing the field of 1D perovskites.
Up-to-fivefold reverberating waves through the Earth’s center and distinctly anisotropic innermost inner core
Authors: Phạm Thanh-Son , Tkalčić Hrvoje
Published: February 2023

Probing the Earth’s center is critical for understanding planetary formation and evolution. However, geophysical inferences have been challenging due to the lack of seismological probes sensitive to the Earth’s center. Here, by stacking waveforms recorded by a growing number of global seismic stations, we observe up-to-fivefold reverberating waves from selected earthquakes along the Earth’s diameter. Differential travel times of these exotic arrival pairs, hitherto unreported in seismological literature, complement and improve currently available information. The inferred transversely isotropic inner-core model contains a ~650-km thick innermost ball with P-wave speeds ~4% slower at ~50° from the Earth’s rotation axis. In contrast, the inner core’s outer shell displays much weaker anisotropy with the slowest direction in the equatorial plane. Our findings strengthen the evidence for an anisotropically-distinctive innermost inner core and its transition to a weakly anisotropic outer shell, which could be a fossilized record of a significant global event from the past.
The usherin mutation c.2299delG leads to its mislocalization and disrupts interactions with whirlin and VLGR1
Authors: Tebbe Lars , Mwoyosvi Maggie L. , Crane Ryan , Makia Mustafa S. , Kakakhel Mashal , Cosgrove Dominic , Al-Ubaidi Muayyad R. , Naash Muna I.
Published: February 2023

Usher syndrome (USH) is the leading cause of combined deafness-blindness with type 2 A (USH2A) being the most common form. Knockout models of USH proteins, like the Ush2a-/- model that develops a late-onset retinal phenotype, failed to mimic the retinal phenotype observed in patients. Since patient’s mutations result in the expression of a mutant protein and to determine the mechanism of USH2A, we generated and evaluated an usherin (USH2A) knock-in mouse expressing the common human disease-mutation, c.2299delG. This mouse exhibits retinal degeneration and expresses a truncated, glycosylated protein which is mislocalized to the photoreceptor inner segment. The degeneration is associated with a decline in retinal function, structural abnormalities in connecting cilium and outer segment and mislocaliztion of the usherin interactors very long G-protein receptor 1 and whirlin. The onset of symptoms is significantly earlier compared to Ush2a-/-, proving expression of mutated protein is required to recapitulate the patients’ retinal phenotype.
Complex-tensor theory of simple smectics
Authors: Paget Jack , Mazza Marco G. , Archer Andrew J. , Shendruk Tyler N.
Published: February 2023

Matter self-assembling into layers generates unique properties, including structures of stacked surfaces, directed transport, and compact area maximization that can be highly functionalized in biology and technology. Smectics represent the paradigm of such lamellar materials — they are a state between fluids and solids, characterized by both orientational and partial positional ordering in one layering direction, making them notoriously difficult to model, particularly in confining geometries. We propose a complex tensor order parameter to describe the local degree of lamellar ordering, layer displacement and orientation of the layers for simple, lamellar smectics. The theory accounts for both dislocations and disclinations, by regularizing singularities within defect cores and so remaining continuous everywhere. The ability to describe disclinations and dislocation allows this theory to simulate arrested configurations and inclusion-induced local ordering. This tensorial theory for simple smectics considerably simplifies numerics, facilitating studies on the mesoscopic structure of topologically complex systems.
Spatially confined protein assembly in hierarchical mesoporous metal-organic framework
Authors: Wang Xiaoliang , He Lilin , Sumner Jacob , Qian Shuo , Zhang Qiu , O’Neill Hugh , Mao Yimin , Chen Chengxia , Al-Enizi Abdullah M. , Nafady Ayman , Ma Shengqian
Published: February 2023

Immobilization of biomolecules into porous materials could lead to significantly enhanced performance in terms of stability towards harsh reaction conditions and easier separation for their reuse. Metal-Organic Frameworks (MOFs), offering unique structural features, have emerged as a promising platform for immobilizing large biomolecules. Although many indirect methods have been used to investigate the immobilized biomolecules for diverse applications, understanding their spatial arrangement in the pores of MOFs is still preliminary due to the difficulties in directly monitoring their conformations. To gain insights into the spatial arrangement of biomolecules within the nanopores. We used in situ small-angle neutron scattering (SANS) to probe deuterated green fluorescent protein (d-GFP) entrapped in a mesoporous MOF. Our work revealed that GFP molecules are spatially arranged in adjacent nanosized cavities of MOF-919 to form “assembly” through adsorbate-adsorbate interactions across pore apertures. Our findings, therefore, lay a crucial foundation for the identification of proteins structural basics under confinement environment of MOFs.
Citrullination modulates antigen processing and presentation by revealing cryptic epitopes in rheumatoid arthritis
Authors: Curran Ashley M. , Girgis Alexander A. , Jang Yura , Crawford Jonathan D. , Thomas Mekha A. , Kawalerski Ryan , Coller Jeff , Bingham Clifton O. , Na Chan Hyun , Darrah Erika
Published: February 2023

Cryptic peptides, hidden from the immune system under physiologic conditions, are revealed by changes to MHC class II processing and hypothesized to drive the loss of immune tolerance to self-antigens in autoimmunity. Rheumatoid arthritis (RA) is an autoimmune disease characterized by immune responses to citrullinated self-antigens, in which arginine residues are converted to citrullines. Here, we investigate the hypothesis that citrullination exposes cryptic peptides by modifying protein structure and proteolytic cleavage. We show that citrullination alters processing and presentation of autoantigens, resulting in the generation of a unique citrullination-dependent repertoire composed primarily of native sequences. This repertoire stimulates T cells from RA patients with anti-citrullinated protein antibodies more robustly than controls. The generation of this unique repertoire is achieved through altered protease cleavage and protein destabilization, rather than direct presentation of citrulline-containing epitopes, suggesting a novel paradigm for the role of protein citrullination in the breach of immune tolerance in RA.
Gasdermin-D activation promotes NLRP3 activation and host resistance to Leishmania infection
Authors: de Sá Keyla S. G. , Amaral Luana A. , Rodrigues Tamara S. , Ishimoto Adriene Y. , de Andrade Warrison A. C. , de Almeida Leticia , Freitas-Castro Felipe , Batah Sabrina S. , Oliveira Sergio C. , Pastorello Mônica T. , Fabro Alexandre T. , Zamboni Dario S.
Published: February 2023

Intracellular parasites from the Leishmania genus cause Leishmaniasis, a disease affecting millions of people worldwide. NLRP3 inflammasome is key for disease outcome, but the molecular mechanisms upstream of the inflammasome activation are still unclear. Here, we demonstrate that despite the absence of pyroptosis, Gasdermin-D (GSDMD) is active at the early stages of Leishmania infection in macrophages, allowing transient cell permeabilization, potassium efflux, and NLRP3 inflammasome activation. Further, GSDMD is processed into a non-canonical 25 kDa fragment. Gsdmd–/– macrophages and mice exhibit less NLRP3 inflammasome activation and are highly susceptible to infection by several Leishmania species, confirming the role of GSDMD for inflammasome-mediated host resistance. Active NLRP3 inflammasome and GSDMD are present in skin biopsies of patients, demonstrating activation of this pathway in human leishmaniasis. Altogether, our findings reveal that Leishmania subverts the normal functions of GSDMD, an important molecule to promote inflammasome activation and immunity in Leishmaniasis.
Asymmetric activity of NetrinB controls laterality of the Drosophila brain
Authors: Lapraz F. , Boutres C. , Fixary-Schuster C. , De Queiroz B. R. , Plaçais P. Y. , Cerezo D. , Besse F. , Préat T. , Noselli S.
Published: February 2023

Left-Right (LR) asymmetry of the nervous system is widespread across animals and is thought to be important for cognition and behaviour. But in contrast to visceral organ asymmetry, the genetic basis and function of brain laterality remain only poorly characterized. In this study, we performed RNAi screening to identify genes controlling brain asymmetry in Drosophila. We found that the conserved NetrinB (NetB) pathway is required for a small group of bilateral neurons to project asymmetrically into a pair of neuropils (Asymmetrical Bodies, AB) in the central brain in both sexes. While neurons project unilaterally into the right AB in wild-type flies, netB mutants show a bilateral projection phenotype and hence lose asymmetry. Developmental time course analysis reveals an initially bilateral connectivity, eventually resolving into a right asymmetrical circuit during metamorphosis, with the NetB pathway being required just prior symmetry breaking. We show using unilateral clonal analysis that netB activity is required specifically on the right side for neurons to innervate the right AB. We finally show that loss of NetB pathway activity leads to specific alteration of long-term memory, providing a functional link between asymmetrical circuitry determined by NetB and animal cognitive functions.
Phonon-driven intra-exciton Rabi oscillations in CsPbBr3 halide perovskites
Authors: Nguyen Xuan Trung , Winte Katrin , Timmer Daniel , Rakita Yevgeny , Ceratti Davide Raffaele , Aharon Sigalit , Ramzan Muhammad Sufyan , Cocchi Caterina , Lorke Michael , Jahnke Frank , Cahen David , Lienau Christoph , De Sio Antonietta
Published: February 2023

Coupling electromagnetic radiation with matter, e.g., by resonant light fields in external optical cavities, is highly promising for tailoring the optoelectronic properties of functional materials on the nanoscale. Here, we demonstrate that even internal fields induced by coherent lattice motions can be used to control the transient excitonic optical response in CsPbBr3 halide perovskite crystals. Upon resonant photoexcitation, two-dimensional electronic spectroscopy reveals an excitonic peak structure oscillating persistently with a 100-fs period for up to ~2 ps which does not match the frequency of any phonon modes of the crystals. Only at later times, beyond 2 ps, two low-frequency phonons of the lead-bromide lattice dominate the dynamics. We rationalize these findings by an unusual exciton-phonon coupling inducing off-resonant 100-fs Rabi oscillations between 1s and 2p excitons driven by the low-frequency phonons. As such, prevailing models for the electron-phonon coupling in halide perovskites are insufficient to explain these results. We propose the coupling of characteristic low-frequency phonon fields to intra-excitonic transitions in halide perovskites as the key to control the anharmonic response of these materials in order to establish new routes for enhancing their optoelectronic properties.
Fundamental limits to learning closed-form mathematical models from data
Authors: Fajardo-Fontiveros Oscar , Reichardt Ignasi , De Los Ríos Harry R. , Duch Jordi , Sales-Pardo Marta , Guimerà Roger
Published: February 2023

Given a finite and noisy dataset generated with a closed-form mathematical model, when is it possible to learn the true generating model from the data alone? This is the question we investigate here. We show that this model-learning problem displays a transition from a low-noise phase in which the true model can be learned, to a phase in which the observation noise is too high for the true model to be learned by any method. Both in the low-noise phase and in the high-noise phase, probabilistic model selection leads to optimal generalization to unseen data. This is in contrast to standard machine learning approaches, including artificial neural networks, which in this particular problem are limited, in the low-noise phase, by their ability to interpolate. In the transition region between the learnable and unlearnable phases, generalization is hard for all approaches including probabilistic model selection.
Noncanonical amino acids as doubly bio-orthogonal handles for one-pot preparation of protein multiconjugates
Authors: Wang Yong , Zhang Jingming , Han Boyang , Tan Linzhi , Cai Wenkang , Li Yuxuan , Su Yeyu , Yu Yutong , Wang Xin , Duan Xiaojiang , Wang Haoyu , Shi Xiaomeng , Wang Jing , Yang Xing , Liu Tao
Published: February 2023

Genetic encoding of noncanonical amino acid (ncAA) for site-specific protein modification has been widely applied for many biological and therapeutic applications. To efficiently prepare homogeneous protein multiconjugates, we design two encodable noncanonical amino acids (ncAAs), 4-(6-(3-azidopropyl)-s-tetrazin-3-yl) phenylalanine (pTAF) and 3-(6-(3-azidopropyl)-s-tetrazin-3-yl) phenylalanine (mTAF), containing mutually orthogonal and bioorthogonal azide and tetrazine reaction handles. Recombinant proteins and antibody fragments containing the TAFs can easily be functionalized in one-pot reactions with combinations of commercially available fluorophores, radioisotopes, PEGs, and drugs in a plug-and-play manner to afford protein dual conjugates to assess combinations of tumor diagnosis, image-guided surgery, and targeted therapy in mouse models. Furthermore, we demonstrate that simultaneously incorporating mTAF and a ketone-containing ncAA into one protein via two non-sense codons allows preparation of a site-specific protein triconjugate. Our results demonstrate that TAFs are doubly bio-orthogonal handles for efficient and scalable preparation of homogeneous protein multiconjugates.
Visible light-exposed lignin facilitates cellulose solubilization by lytic polysaccharide monooxygenases
Authors: Kommedal Eirik G. , Angeltveit Camilla F. , Klau Leesa J. , Ayuso-Fernández Iván , Arstad Bjørnar , Antonsen Simen G. , Stenstrøm Yngve , Ekeberg Dag , Gírio Francisco , Carvalheiro Florbela , Horn Svein J. , Aachmann Finn Lillelund , Eijsink Vincent G. H.
Published: February 2023

Lytic polysaccharide monooxygenases (LPMOs) catalyze oxidative cleavage of crystalline polysaccharides such as cellulose and are crucial for the conversion of plant biomass in Nature and in industrial applications. Sunlight promotes microbial conversion of plant litter; this effect has been attributed to photochemical degradation of lignin, a major redox-active component of secondary plant cell walls that limits enzyme access to the cell wall carbohydrates. Here, we show that exposing lignin to visible light facilitates cellulose solubilization by promoting formation of H2O2 that fuels LPMO catalysis. Light-driven H2O2 formation is accompanied by oxidation of ring-conjugated olefins in the lignin, while LPMO-catalyzed oxidation of phenolic hydroxyls leads to the required priming reduction of the enzyme. The discovery that light-driven abiotic reactions in Nature can fuel H2O2-dependent redox enzymes involved in deconstructing lignocellulose may offer opportunities for bioprocessing and provides an enzymatic explanation for the known effect of visible light on biomass conversion.
A thousand-genome panel retraces the global spread and adaptation of a major fungal crop pathogen
Authors: Feurtey Alice , Lorrain Cécile , McDonald Megan C. , Milgate Andrew , Solomon Peter S. , Warren Rachael , Puccetti Guido , Scalliet Gabriel , Torriani Stefano F. F. , Gout Lilian , Marcel Thierry C. , Suffert Frédéric , Alassimone Julien , Lipzen Anna , Yoshinaga Yuko , Daum Christopher , Barry Kerrie , Grigoriev Igor V. , Goodwin Stephen B. , Genissel Anne , Seidl Michael F. , Stukenbrock Eva H. , Lebrun Marc-Henri , Kema Gert H. J. , McDonald Bruce A. , Croll Daniel
Published: February 2023

Human activity impacts the evolutionary trajectories of many species worldwide. Global trade of agricultural goods contributes to the dispersal of pathogens reshaping their genetic makeup and providing opportunities for virulence gains. Understanding how pathogens surmount control strategies and cope with new climates is crucial to predicting the future impact of crop pathogens. Here, we address this by assembling a global thousand-genome panel of Zymoseptoria tritici, a major fungal pathogen of wheat reported in all production areas worldwide. We identify the global invasion routes and ongoing genetic exchange of the pathogen among wheat-growing regions. We find that the global expansion was accompanied by increased activity of transposable elements and weakened genomic defenses. Finally, we find significant standing variation for adaptation to new climates encountered during the global spread. Our work shows how large population genomic panels enable deep insights into the evolutionary trajectory of a major crop pathogen.
The cofactor-dependent folding mechanism of Drosophila cryptochrome revealed by single-molecule pulling experiments
Authors: Foroutannejad Sahar , Good Lydia L. , Lin Changfan , Carter Zachariah I. , Tadesse Mahlet G. , Lucius Aaron L. , Crane Brian R. , Maillard Rodrigo A.
Published: February 2023

The link between cofactor binding and protein activity is well-established. However, how cofactor interactions modulate folding of large proteins remains unknown. We use optical tweezers, clustering and global fitting to dissect the folding mechanism of Drosophila cryptochrome (dCRY), a 542-residue protein that binds FAD, one of the most chemically and structurally complex cofactors in nature. We show that the first dCRY parts to fold are independent of FAD, but later steps are FAD-driven as the remaining polypeptide folds around the cofactor. FAD binds to largely unfolded intermediates, yet with association kinetics above the diffusion-limit. Interestingly, not all FAD moieties are required for folding: whereas the isoalloxazine ring linked to ribitol and one phosphate is sufficient to drive complete folding, the adenosine ring with phosphates only leads to partial folding. Lastly, we propose a dCRY folding model where regions that undergo conformational transitions during signal transduction are the last to fold.
Chiral electrocatalysts eclipse water splitting metrics through spin control
Authors: Vadakkayil Aravind , Clever Caleb , Kunzler Karli N. , Tan Susheng , Bloom Brian P. , Waldeck David H.
Published: February 2023

Continual progress in technologies that rely on water splitting are often hampered by the slow kinetics associated with the oxygen evolution reaction (OER). Here, we show that the efficiency of top-performing catalysts can be improved, beyond typical thermodynamic considerations, through control over reaction intermediate spin alignment during electrolysis. Spin alignment is achieved using the chiral induced spin selectivity (CISS) effect and the improvement in OER manifests as an increase in Faradaic efficiency, decrease in reaction overpotential, and change in the rate determining step for chiral nanocatalysts over compositionally analogous achiral nanocatalysts. These studies illustrate that a defined spatial orientation of the nanocatalysts is not necessary to exhibit spin selectivity and therefore represent a viable platform for employing the transformative role of chirality in other reaction pathways and processes.
Spintronic leaky-integrate-fire spiking neurons with self-reset and winner-takes-all for neuromorphic computing
Authors: Wang Di , Tang Ruifeng , Lin Huai , Liu Long , Xu Nuo , Sun Yan , Zhao Xuefeng , Wang Ziwei , Wang Dandan , Mai Zhihong , Zhou Yongjian , Gao Nan , Song Cheng , Zhu Lijun , Wu Tom , Liu Ming , Xing Guozhong
Published: February 2023

Neuromorphic computing using nonvolatile memories is expected to tackle the memory wall and energy efficiency bottleneck in the von Neumann system and to mitigate the stagnation of Moore’s law. However, an ideal artificial neuron possessing bio-inspired behaviors as exemplified by the requisite leaky-integrate-fire and self-reset (LIFT) functionalities within a single device is still lacking. Here, we report a new type of spiking neuron with LIFT characteristics by manipulating the magnetic domain wall motion in a synthetic antiferromagnetic (SAF) heterostructure. We validate the mechanism of Joule heating modulated competition between the Ruderman–Kittel–Kasuya–Yosida interaction and the built-in field in the SAF device, enabling it with a firing rate up to 17 MHz and energy consumption of 486 fJ/spike. A spiking neuron circuit is implemented with a latency of 170 ps and power consumption of 90.99 μW. Moreover, the winner-takes-all is executed with a current ratio >104 between activated and inhibited neurons. We further establish a two-layer spiking neural network based on the developed spintronic LIFT neurons. The architecture achieves 88.5% accuracy on the handwritten digit database benchmark. Our studies corroborate the circuit compatibility of the spintronic neurons and their great potential in the field of intelligent devices and neuromorphic computing.
Theoretical and experimental analysis of circularly polarized luminescence spectrophotometers for artifact-free measurements using a single CCD camera
Authors: Baguenard Bruno , Bensalah-Ledoux Amina , Guy Laure , Riobé François , Maury Olivier , Guy Stéphan
Published: February 2023

Circularly polarized luminescence (CPL) is a fast growing research field as a complementary chiroptical spectroscopy alternative to the conventional circular dichroism or in the quest of devices producing circularly polarized light for different applications. Because chiroptical signals are generally lower than 0.1%, conventional chiral spectroscopies rely on polarization time modulation requiring step-by-step wavelength scanning and a long acquisition time. High throughput controls motivated the development of CPL spectrophotometers using cameras as detectors and space polarization splitting. However, CPL measurements imposes careful precautions to minimize the numerous artifacts arising from experimental imperfections. Some previous work used complex calibration procedure to this end. Here we present a rigorous Mueller analysis of an instrument based on polarizations space splitting. We show that by using one camera and combining spatial and temporal separation through two switchable circular polarization encoding arms we can record accurate CPL spectra without the need of any calibration. The measurements robustness and their fast acquisition times are exemplified on different chiral emitters.
Mid-infrared cross-comb spectroscopy
Authors: Liu Mingchen , Gray Robert M. , Costa Luis , Markus Charles R. , Roy Arkadev , Marandi Alireza
Published: February 2023

Dual-comb spectroscopy has been proven beneficial in molecular characterization but remains challenging in the mid-infrared region due to difficulties in sources and efficient photodetection. Here we introduce cross-comb spectroscopy, in which a mid-infrared comb is upconverted via sum-frequency generation with a near-infrared comb of a shifted repetition rate and then interfered with a spectral extension of the near-infrared comb. We measure CO2absorption around 4.25 µm with a 1-µm photodetector, exhibiting a 233-cm−1instantaneous bandwidth, 28000 comb lines, a single-shot signal-to-noise ratio of 167 and a figure of merit of 2.4 × 106Hz1/2. We show that cross-comb spectroscopy can have superior signal-to-noise ratio, sensitivity, dynamic range, and detection efficiency compared to other dual-comb-based methods and mitigate the limits of the excitation background and detector saturation. This approach offers an adaptable and powerful spectroscopic method outside the well-developed near-IR region and opens new avenues to high-performance frequency-comb-based sensing with wavelength flexibility.