bluuebunny/crossref_metadata_2025 huggingface dataset:
Side-by-Side Comparison of uPAR-Targeting Optical Imaging Antibodies and Antibody Fragments for Fluorescence-Guided Surgery of Solid Tumors
Authors: Baart Victor M. , van Manen Labrinus , Bhairosingh Shadhvi S. , Vuijk Floris A. , Iamele Luisa , de Jonge Hugo , Scotti Claudia , Resnati Massimo , Cordfunke Robert A. , Kuppen Peter J. K. , Mazar Andrew P. , Burggraaf Jacobus , Vahrmeijer Alexander L. , Sier Cornelis F. M.
Published: October 2021

Purpose

Radical resection is paramount for curative oncological surgery. Fluorescence-guided surgery (FGS) aids in intraoperative identification of tumor-positive resection margins. This study aims to assess the feasibility of urokinase plasminogen activator receptor (uPAR) targeting antibody fragments for FGS in a direct comparison with their parent IgG in various relevant in vivo models.

Procedures

Humanized anti-uPAR monoclonal antibody MNPR-101 (uIgG) was proteolytically digested into F(ab’)2 and Fab fragments named uFab2 and uFab. Surface plasmon resonance (SPR) and cell assays were used to determine in vitro binding before and after fluorescent labeling with IRDye800CW. Mice bearing subcutaneous HT-29 human colonic cancer cells were imaged serially for up to 120 h after fluorescent tracer administration. Imaging characteristics and ex vivo organ biodistribution were further compared in orthotopic pancreatic ductal adenocarcinoma (BxPc-3-luc2), head-and-neck squamous cell carcinoma (OSC-19-luc2-GFP), and peritoneal carcinomatosis (HT29-luc2) models using the clinical Artemis fluorescence imaging system.

Results

Unconjugated and conjugated uIgG, uFab2, and uFab specifically recognized uPAR in the nanomolar range as determined by SPR and cell assays. Subcutaneous tumors were clearly identifiable with tumor-to-background ratios (TBRs) > 2 after 72 h for uIgG-800F and 24 h for uFab2-800F and uFab-800F. For the latter two, mean fluorescence intensities (MFIs) dipped below predetermined threshold after 72 h and 36 h, respectively. Tumors were easily identified in the orthotopic models with uIgG-800F consistently having the highest MFIs and uFab2-800F and uFab-800F having similar values. In biodistribution studies, kidney and liver fluorescence approached tumor fluorescence after uIgG-800F administration and surpassed tumor fluorescence after uFab2-800F or uFab-800F administration, resulting in interference in the abdominal orthotopic mouse models.

Conclusions

In a side-by-side comparison, FGS with uPAR-targeting antibody fragments compared with the parent IgG resulted in earlier tumor visualization at the expense of peak fluorescence intensity.
How trade can drive inclusive and sustainable food system outcomes in food deficit low-income countries
Authors: van Berkum Siemen
Published: October 2021

Recent decades have seen food markets and value chains become increasingly global—a trend that creates challenges as well as opportunities for food systems. Positive trade effects on food security are not always self-evident in food deficit low-income countries. Moreover, whereas international trade may also be used to balance regional differences in climate change impacts and biodiversity, trade can exacerbate environmental challenges associated with food production, land use and climate change. This article argues that, for trade to drive inclusive and sustainable growth of nutritious food production in food deficit low-income countries, policies and investments in these countries must focus on three key priorities: 1) diversifying production and markets to increase resilience to external shocks; 2) enhancing competitiveness and improving market access for local farmers and SMEs, and 3) incorporating externalities in international trade. The latter requires collective international action.
Revealing morphological characteristics of Goniodorididae genera (Mollusca: Nudibranchia)
Authors: Paz-Sedano Sofia , Díaz-Agras Guillermo , Gosliner Terrence M. , Pola Marta
Published: October 2021

Detailed knowledge of the anatomy of the species is an essential element in taxonomic studies, since it allows the comparison and differentiation of separate groups of taxa. It becomes especially important when considering type species, as the subsequent identification of the species that compose the taxa is based on its characteristics, considered common in the group. However, despite its relevance, there are still numerous species without detailed descriptions, being especially significant among invertebrates. The family Goniodorididae is a little-known group of nudibranchs that includes eight recognized genera:Okenia,Goniodoris,Ancula,Lophodoris,Spahria,Trapania,GoniodoridellaandMurphydoris. Several of their species are not completely described, including type species, and the systematics of the family is still unclear. Here we study in detail the external morphology and internal anatomy of the type species of five of the eight Goniodorididae genera using microcomputed tomography and scanning electron microscopy. We include the speciesOkenia elegans,Goniodoris nodosa,Ancula gibbosa,Goniodoridella savignyiandMurphydoris singaporensisas well as one species ofTrapania,T. graeffei. We describe for the first time the detailed internal anatomy of the type speciesGoniodoridella savignyi. The diagnostic features of each genus are compared, and a preliminary framework is shown to clarify their systematics and identifications.
The influence of palm oil additives on the pour point and wax deposition tendencies of Chenor crude oil
Authors: Ragunathan Thevaruban , Wood Colin D. , Husin Hazlina
Published: October 2021

One of the major concerns during the production of crude oil especially in tropical waters is the deposition of wax on to the walls of the pipeline. This is due to the low seabed temperatures which can be below the wax appearance temperature (WAT) which leads to wax depositing out through molecular diffusion. Currently, there are many methods to prevent and remedy wax deposition but most of these solutions pose a serious environmental threat and are expensive to produce. Hence, this research investigated the use of an organic and cheaper alternative by utilizing synthetic fatty acid esters such as oleic acid which has shown promising results in reducing the pour point of waxy crude oils. The solution that was used was of palm oil origin, crude palm oil (CPO) and crude palm kernel oil (CPKO) and was subsequently compared with the pour point depressant and wax inhibition efficiency of the current industry used inhibitors utilizing the SETA Pour Point and Cloud Point as well as the cold finger apparatus. It was observed that the palm oil inhibitors were highly effective at 1 wt.% due to the high composition of oleic acid present portraying a similar result to Triethanolamine (TEA) while Ethylene Vinyl Acetate (EVA) performed best at low concentration of 0.1 wt.% but deteriorates significantly as the concentration increases due to the polar end agglomerating among itself.
Vitiligo and tumor response in a patient with amelanotic melanoma undergoing nivolumab treatment
Authors: Furune Satoshi , Kondo Chiaki , Takano Yuko , Shimokata Tomoya , Sugishita Mihoko , Mitsuma Ayako , Maeda Osamu , Ando Yuichi
Published: October 2021

Vitiligo, an acquired depigmenting disorder of the skin that reacts against normal melanocytes, sometimes occurs as an immune-related adverse event in the treatment of melanoma with immune checkpoint inhibitors. It has been known that the occurrence of vitiligo is associated with a favorable therapeutic response in patients with melanoma, but it is not yet clear whether the association also applies to amelanotic melanoma, a minor subtype of melanoma with little or no melanin pigmentation. We report a patient with amelanotic melanoma of the esophagus who responded well to nivolumab treatment. Shortly after the tumor response, vitiligo was found on the patient’s forearms. This case suggests that the occurrence of vitiligo is associated with a favorable response to nivolumab treatment for amelanotic melanoma.
Association between coronavirus cases and seasonal climatic variables in Mediterranean European Region, evidence by panel data regression
Authors: Alsayed A. R. M.
Published: October 2021

The coronavirus pandemic is one of the most fast-spreading diseases in the history, and the transmission of this virus has crossed rapidly over the whole world. In this study, we intend to detect the effect of temperature, precipitation, and wind speed on the Coronavirus infected cases throughout climate seasons for the whole year of epidemic starting from February 20, 2020 to February 19, 2021 with considering data patterns of each season separately; winter, spring, summer, autumn, in Mediterranean European regions, whereas those are located at the similar temperature zone in southern Europe. We apply the panel data approach by considering the developed robust estimation of clustered standard error which leads to achieving high forecasting accuracy. The main finding supports that temperature and wind speed have significant influence in reducing the Coronavirus cases at the beginning of this epidemic particularly in the first-winter, spring, and early summer, but they have very weak effects in the autumn and second-winter. Therefore, it is important to take into account the changes throughout seasons, and to consider other indirect factors which influence the virus transmission. This finding could lead to significant contributions to policymakers in European Union and European Commission Environment to limit the Coronavirus transmissions. As the Mediterranean region becomes more crowded for tourism purposes particularly in the summer season.
Stability result of a suspension bridge Problem with time-varying delay and time-varying weight
Authors: Mukiawa Soh Edwin
Published: October 2021

In this paper, we study a plate equation as a model for a suspension bridge with time-varying delay and time-varying weights. Under some conditions on the delay and weight functions, we establish a stability result for the associated energy functional. The present work extends and generalizes some similar results in the case of wave or plate equations.
What Factors Lead to Racial Disparities in Outcomes After Total Knee Arthroplasty?
Authors: Hu Daniel A. , Hu James B. , Lee Ariel , Rubenstein William J. , Hwang Kevin M. , Ibrahim Said A. , Kuo Alfred C.
Published: October 2021

Total knee arthroplasty (TKA) is one of the most commonly performed, major elective surgeries in the USA. African American TKA patients on average experience worse clinical outcomes than whites, including lower improvements in patient-reported outcomes and higher rates of complications, hospital readmissions, and reoperations. The mechanisms leading to these racial health disparities are unclear, but likely involve patient, provider, healthcare system, and societal factors. Lower physical and mental health at baseline, lower social support, provider bias, lower rates of health insurance coverage, higher utilization of lower quality hospitals, and systemic racism may contribute to the inferior outcomes that African Americans experience. Limited evidence suggests that improving the quality of surgical care can offset these factors and lead to a reduction in outcome disparities.
Remarks on Parabolicity in a One-Dimensional Interdiffusion Model with the Vegard Rule
Authors: Sapa Lucjan , Bożek Bogusław , Danielewski Marek
Published: October 2021

Until 1948 the interdiffusion theory was based on the Onsager phenomenology, namely thermodynamics of irreversible processes, and a drift was not included. Its main limitation is practical impossibility of the experimental as well as theoretical determination of mobilities (diffusivities) in multicomponent systems ($$r > 2$$

r
>
2

). After experimental discovery of the drift by Smigelskas and Kirkendall (Trans AIME 171:130–142, 1947), Darken (Trans AIME 175:184–201, 1948) formulated his famous model for the binary system. Consequently, the bi-velocity approach dominates interdiffusion studies (e.g. in more than 500 papers in 2020). In this paper, we consider the diffusional transport in a one-dimensional r-component solid solution. The model is expressed by the nonlinear system of strongly coupled evolution differential equations with initial and nonlinear coupled boundary conditions. We present a non-trivial proof of a theorem called the criterion of parabolicity, which implies the generalized parabolicity condition formulated without a proof in our previous works. This condition is a key in the proofs of our previous theorems on existence, uniqueness and properties of global weak solutions of the differential problem studied. The criterion of parabolicity works if diffusion coefficients are not too dispersed, and it is true in many physical systems. The numerical simulations consistent with real experiments for which our criterion works are given.
Intralogistik im Zeitalter des digitalen Wandels: Arbeitsanforderungen und psychische Beanspruchung in der Kommissionierung am Beispiel eines Unternehmens aus dem E-Commerce-Bereich
Authors: Rinkenauer Gerhard , Reiser Julian Elias , Renker Johanna , Kretschmer Veronika
Published: October 2021

Der E‑Commerce-Bereich erfährt aufgrund der Digitalisierung einen kontinuierlichen Aufschwung in der Logistik. Der Mensch bleibt vor dem Hintergrund der mehrheitlich manuell ausgeführten Tätigkeiten eine entscheidende Ressource im Lager, die es, mit besonderem Blick auf den demografischen Wandel, zu halten und zu integrieren gilt. Im Beitrag werden die Befragungsergebnisse einer Feldstudie mit dem Fokus auf den Bereich der Kommissionierung, die bei einem großen Versandhändler durchgeführt wurde, exemplarisch beschrieben und mit Befragungsergebnissen von anderen Betrieben verglichen. In Anlehnung an das Anforderungs-Ressourcen-Modell werden neben den Zielgrößen Arbeitsfähigkeit, Arbeitszufriedenheit und Gesundheit, Stressoren, Herausforderungen und Ressourcen beleuchtet. Die Ergebnisse deuten darauf hin, dass sich Stressoren und Arbeitsressourcen in etwa ausgleichen, auch wenn sich z. B. Arbeitszufriedenheit und Gesundheit lediglich auf einem mittleren Niveau befinden. Vor allem die Autonomie der Beschäftigten birgt noch Handlungsbedarf. Die digitale Transformation wird als Chance gesehen, den Handlungs- und Entscheidungsspielraum zu erweitern.

Praktische Relevanz: Die operative Logistik birgt aufgrund der manuell geprägten Tätigkeiten und der vorgegebenen Prozesse eine Vielzahl an Arbeitsanforderungen, die zu psychischer Fehlbeanspruchungen und langfristig zu Störungen oder Erkrankungen führen können. Zur Kompensation der Stressoren ist die Erweiterung von arbeitsbedingten Ressourcen notwendig. Die Digitalisierung wird als Chance gesehen, diese auszubauen.
Microwave-assisted combustion to produce benzene polycarboxylic acids as molecular markers for biochar identification and quantification
Authors: Glaser Bruno , Guenther Marie , Maennicke Heike , Bromm Tobias
Published: October 2021

Biochar is a promising carbon dioxide removal (CDR) technology for climate change mitigation. Current procedures for its determination are lengthy, labor-intensive, and difficult to conduct. Benzene polycarboxylic acids (BPCA) are the most promising molecular markers for identification and quantification of biochar and its quality as they specifically represent the stable polyaromatic backbone of biochar. Therefore, using the BPCA method, its stability and, thus, its C sequestration potential could be used for CDR accounting. The current BPCA method relies on a specific high-pressure digestion apparatus, which is not available around the world. Therefore, the aims of the present work were (i) to compare the conventional high-pressure nitric acid oxidation with a microwave-assisted digestion technique and optimize the oxidation conditions in such a way that previous results are comparable with future ones, and (ii) to significantly reduce the digestion time of soil samples of 8 h and to develop a suitable routine method that produces comparable and reproducible results. For this purpose, soil and control sample series were prepared for different temperature–time-program. Obtained results were compared with the values of the conventional method both for individual samples and for the whole dataset separately. To ensure the representativeness of the results, in addition to various soil samples with different properties, we included two reference materials into our data set, one without biochar (wheat flour) and a biochar sample. Our results showed that conventional nitric acid oxidation in the BPCA determination at 170 °C and 8 h can be substituted by digestion in a microwave reaction system (CEM Mars6) at 190 °C and 1 h. Our results further showed that this condition needs to be strictly matched, because, otherwise, over- or underestimation of biochar quantity and/or quality will be the consequence. The goal of a less time-consuming BPCA extraction from soil samples was achieved by reducing the extraction time from 8 to 1 h using the microwave-assisted method. However, one disadvantage of the new method is that five times more sample material and chemicals are needed for further BPCA analysis, compared to the original method.
A survey of intestinal helminths in domestic dogs in a human–animal–environmental interface: the Oloisukut Conservancy, Narok County, Kenya
Authors: Mulinge E. , Zeyhle E. , Mpario J. , Mugo M. , Nungari L. , Ngugi B. , Sankale B. , Gathura P. , Magambo J. , Kachani M.
Published: October 2021

Dogs living in a domestic–wildlife interface can serve as reservoirs and sentinels of parasites shared among humans, domestic animals and wildlife. In Kenya, the epidemiology of intestinal parasites of dogs and their role as reservoirs of zoonoses is poorly understood, especially in domestic–wildlife interfaces. This study aimed to determine the occurrence of intestinal helminths in domestic dogs in the Oloisukut Conservancy. One hundred dog faecal samples were collected per rectum and examined microscopically following zinc chloride flotation and formal-ether concentration techniques. Genotyping of helminths was achieved by nested polymerase chain reaction of NADH dehydrogenase subunit 1, cytochrome oxidase 1 and partial sequencing. Nine genera were detected by microscopy in 65 (65%) dog faecal samples from 54/76 (71.05%) households. The most frequent helminths were hookworm (39%), Spirometra spp. (17%), taeniids (13%), Toxocara spp. (10%), Trichuris spp. (10%), Spirocerca lupi (5%), Physaloptera spp. (2%), Dipylidium caninum (1%) and Strongyloides spp. (1%). Ancylostoma caninum was the only hookworm species detected in dogs, while Taenia serialis and Taenia madoquae were detected in four and one faecal samples, respectively. This study reports for the first time the molecular detection of the cestodes Spirometra theileri, D. caninum and Mesocestoides sp. in dogs in Kenya. The presence of zoonotic helminths in dogs indicates that the residents of this conservancy are exposed to public health risks. The helminths reported here confirm the interaction of domestic dogs with wildlife. An integrated control programme involving the medical, veterinary and wildlife conservation professionals is needed to avert transmission of infectious diseases to humans, domestic animals and wildlife.
On bucket increasing trees, clustered increasing trees and increasing diamonds
Authors: Kuba Markus , Panholzer Alois
Published: October 2021

In this work we analyse bucket increasing tree families. We introduce two simple stochastic growth processes, generating random bucket increasing trees of size n, complementing the earlier result of Mahmoud and Smythe (1995, Theoret. Comput. Sci.144 221–249.) for bucket recursive trees. On the combinatorial side, we define multilabelled generalisations of the tree families d-ary increasing trees and generalised plane-oriented recursive trees. Additionally, we introduce a clustering process for ordinary increasing trees and relate it to bucket increasing trees. We discuss in detail the bucket size two and present a bijection between such bucket increasing tree families and certain families of graphs called increasing diamonds, providing an explanation for phenomena observed by Bodini et al. (2016, Lect. Notes Comput. Sci.9644 207–219.). Concerning structural properties of bucket increasing trees, we analyse the tree parameter
$K_n$
. It counts the initial bucket size of the node containing label n in a tree of size n and is closely related to the distribution of node types. Additionally, we analyse the parameters descendants of label j and degree of the bucket containing label j, providing distributional decompositions, complementing and extending earlier results (Kuba and Panholzer (2010), Theoret. Comput. Sci.411(34–36) 3255–3273.).
Decadal Variations in Hydroxy Fatty Acids Over Chichijima Island in the North Pacific: Long‐Term Seasonal Variability in Plant and Microbial Markers
Authors: Bikkina Poonam , Kawamura Kimitaka , Bikkina Srinivas , Yamaguchi Hayato
Published: October 2021

To understand the sources and transport pathways of organic compounds associated with soil microbes and higher plant waxes in the East Asian outflow, we assessed source‐specific tracers such as α‐, β‐ and ω‐hydroxy fatty acids (FAs) in remote marine aerosols collected at Chichijima Island in the western North Pacific (WNP) during 2001–2003. Molecular distributions of hydroxy FAs are characterized by strong even‐carbon numbered predominance, indicating biogenic sources. Hydroxy FAs showed a strong seasonality with higher loadings during winter/spring than summer/autumn. Cluster analysis of backward air mass trajectories, satellite‐based fire counts and dust extinction data reveal an impact of the East Asian outflow over the WNP in winter/spring. In the spring, there are larger relative abundances of short‐chain β‐hydroxy C10‐C18 FAs (a proxy for soil microbes), consistent with the higher loadings of non‐sea‐salt Ca2+ (dust tracer). The molecular distributions of β‐hydroxy FAs in spring are in agreement with those of the reference materials of Chinese loess (CJ‐1) and simulated Asian mineral dust (CJ‐2), suggesting their probable sources in East Asia. A comparison of relative abundances of short‐chain β‐hydroxy C10‐C18 FAs and long‐chain ω‐hydroxy C20‐C32 FAs (a proxy for higher plant metabolites) in Chichijima aerosols between this (2001–2003) and previous (1990–1993) studies have unveiled an increment of 20% and 30%, respectively. Such an increase was likely caused by the changes in source strength on a decadal‐scale and warrants further investigation. Furthermore, cluster analysis of trajectories and the overall distributions of hydroxy FAs between both datasets have shown their similar provenance in winter/spring.
Remote Work May Be Keeping Some Cities’ Air Cleaner
Authors: Dzombak Rebecca
Published: October 2021

Widespread remote work may have kept air pollution lower than pre-COVID-19 lockdown levels even though restrictions were lifted in 2020, a new study finds.
Thin Current Sheet Behind the Dipolarization Front
Authors: Nakamura R. , Baumjohann W. , Nakamura T. K. M. , Panov E. V. , Schmid D. , Varsani A. , Apatenkov S. , Sergeev V. A. , Birn J. , Nagai T. , Gabrielse C. , André M. , Burch J. L. , Carr C. , Dandouras I. S. , Escoubet C. P. , Fazakerley A. N. , Giles B. L. , Le Contel O. , Russell C. T. , Torbert R. B.
Published: October 2021

We report a unique conjugate observation of fast flows and associated current sheet disturbances in the near‐Earth magnetotail by MMS (Magnetospheric Multiscale) and Cluster preceding a positive bay onset of a small substorm at ∼14:10 UT, September 8, 2018. MMS and Cluster were located both at X ∼ −14 RE. A dipolarization front (DF) of a localized fast flow was detected by Cluster and MMS, separated in the dawn‐dusk direction by ∼4 RE, almost simultaneously. Adiabatic electron acceleration signatures revealed from the comparison of the energy spectra confirm that both spacecraft encounter the same DF. We analyzed the change in the current sheet structure based on multi‐scale multi‐point data analysis. The current sheet thickened during the passage of DF, yet, temporally thinned subsequently associated with another flow enhancement centered more on the dawnward side of the initial flow. MMS and Cluster observed intense perpendicular and parallel current in the off‐equatorial region mainly during this interval of the current sheet thinning. Maximum field‐aligned currents both at MMS and Cluster are directed tailward. Detailed analysis of MMS data showed that the intense field‐aligned currents consisted of multiple small‐scale intense current layers accompanied by enhanced Hall‐currents in the dawn‐dusk flow‐shear region. We suggest that the current sheet thinning is related to the flow bouncing process and/or to the expansion/activation of reconnection. Based on these mesoscale and small‐scale multipoint observations, 3D evolution of the flow and current‐sheet disturbances was inferred preceding the development of a substorm current wedge.
Augmenting Traditional Networks With Data Buys Can Support Science, as Well as Operations
Authors: Gannon J. L. , Lugaz N.
Published: October 2021

Key Points

A data buy is where an entity purchases access to a set of data or a data stream, instead of operating the sensors themselves

Efficiency and cost are factors that drive this kind of data access over the more traditional methods of running a network

As data buys evolve, new solutions will need to be developed for public access to data archives that do not compromise operational integrity
Influences of Dead‐End Pores in Porous Media on Viscous Fingering Instabilities and Cleanup of NAPLs in Miscible Displacements
Authors: Yuan Qingwang , Ma Zhiwei , Wang Jinjie , Zhou Xiang
Published: October 2021

Improving the understanding of mechanisms involved in a low miscible displacement efficiency is significant for a wide spectrum of applications in subsurface from environment such as groundwater remediation and sequestration to energy extraction such as enhanced oil recovery and geothermal recovery. Two key limiting factors to the efficiency are viscous fingering (VF) instability and dead‐end pores in porous media. Previous research on VF simply assumes all pores are well connected and fluids can be mobilized by convection. However, fluids trapped in dead‐end pores, such as nonaqueous phase liquids (NAPLs) in groundwater remediation, are inaccessible to convection, resulting in even less efficient displacements. Instead of the classic convection‐diffusion/dispersion equation, in this work, we use a fundamentally different capacitance model to incorporate the mass transfer between two pore types in miscible displacements. The hybrid pseudospectral and high‐order finite difference methods are employed to solve the governing equations in a fixed reference frame for simulating the flow dynamics. We found that the viscous fingering instabilities in well‐connected pore network led to an unstable, nonuniform distribution of trapped NAPLs in dead‐end pores network. Different with a traditional view that NAPLs are easily cleaned up, our study indicates the existence of dead‐end pores results in an inefficient cleanup of NAPLs in swept area because of the slow mass transfer of trapped NAPLs between two pore types. A simple model is developed to accurately predict the NAPL concentration behind finger trailing front, which has not been previously examined. Six flow regimes, four of which are new, are then identified.
A highly annotated database of genes associated with platinum resistance in cancer
Authors: Huang Dongqing , Savage Sara R. , Calinawan Anna P. , Lin Chenwei , Zhang Bing , Wang Pei , Starr Timothy K. , Birrer Michael J. , Paulovich Amanda G.
Published: October 2021

Platinum-based chemotherapy, including cisplatin, carboplatin, and oxaliplatin, is prescribed to 10-20% of all cancer patients. Unfortunately, platinum resistance develops in a significant number of patients and is a determinant of clinical outcome. Extensive research has been conducted to understand and overcome platinum resistance, and mechanisms of resistance can be categorized into several broad biological processes, including (1) regulation of drug entry, exit, accumulation, sequestration, and detoxification, (2) enhanced repair and tolerance of platinum-induced DNA damage, (3) alterations in cell survival pathways, (4) alterations in pleiotropic processes and pathways, and (5) changes in the tumor microenvironment. As a resource to the cancer research community, we provide a comprehensive overview accompanied by a manually curated database of the >900 genes/proteins that have been associated with platinum resistance over the last 30 years of literature. The database is annotated with possible pathways through which the curated genes are related to platinum resistance, types of evidence, and hyperlinks to literature sources. The searchable, downloadable database is available online at http://ptrc-ddr.cptac-data-view.org.
Mitochondrial morphology is associated with respiratory chain uncoupling in autism spectrum disorder
Authors: Frye Richard E. , Lionnard Loïc , Singh Indrapal , Karim Mohammad A. , Chajra Hanane , Frechet Mathilde , Kissa Karima , Racine Victor , Ammanamanchi Amrit , McCarty Patrick John , Delhey Leanna , Tippett Marie , Rose Shannon , Aouacheria Abdel
Published: October 2021

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is associated with unique changes in mitochondrial metabolism, including elevated respiration rates and morphological alterations. We examined electron transport chain (ETC) complex activity in fibroblasts derived from 18 children with ASD as well as mitochondrial morphology measurements in fibroblasts derived from the ASD participants and four typically developing controls. In ASD participants, symptoms severity was measured by the Social Responsiveness Scale and Aberrant Behavior Checklist. Mixed-model regression demonstrated that alterations in mitochondrial morphology were associated with both ETC Complex I+III and IV activity as well as the difference between ETC Complex I+III and IV activity. The subgroup of ASD participants with relative elevation in Complex IV activity demonstrated more typical mitochondrial morphology and milder ASD related symptoms. This study is limited by sample size given the invasive nature of obtaining fibroblasts from children. Furthermore, since mitochondrial function is heterogenous across tissues, the result may be specific to fibroblast respiration. Previous studies have separately described elevated ETC Complex IV activity and changes in mitochondrial morphology in cells derived from children with ASD but this is the first study to link these two findings in mitochondrial metabolism. The association between a difference in ETC complex I+III and IV activity and normal morphology suggests that mitochondrial in individuals with ASD may require ETC uncoupling to function optimally. Further studies should assess the molecular mechanisms behind these unique metabolic changes.

Trial registration:Protocols used in this study were registered in clinicaltrials.gov as NCT02000284 and NCT02003170.
RETRACTED ARTICLE: METTL3 improves cardiomyocyte proliferation upon myocardial infarction via upregulating miR-17-3p in a DGCR8-dependent manner
Authors: Zhao Kun , Yang Chuanxi , Zhang Jing , Sun Wei , Zhou Bin , Kong Xiangqing , Shi Jing
Published: October 2021

Myocardial infarction (MI), one of the most severe types of heart
attack, exerts a strong negative effect on heart muscle by causing a massive and
rapid loss of cardiomyocytes. However, the existing therapies do little to improve
cardiac regeneration. Due to the role of methyltransferase-like 3 (METTL3) in the
physiological proliferation of cardiomyocytes, we aimed to determine whether METTL3
could also promote cardiomyocyte proliferation under pathological conditions and to
elucidate the underlying mechanism. The effects of METTL3 on cardiomyocyte
proliferation and apoptosis were investigated in an in vivo rat model of MI and in
an in vitro model of neonatal rat cardiomyocytes (NRCMs) exposed to hypoxia. We
found that METTL3 expression was downregulated in hypoxia-exposed NRCMs and
MI-induced rats. Furthermore, METTL3 pretreatment enhanced cardiomyocyte
proliferation and inhibited cardiomyocyte apoptosis under hypoxic or MI conditions,
and silencing METTL3 had the opposite effects. Additionally, METTL3 overexpression
upregulated miR-17-3p expression. The miR-17-3p agomir mimicked the
pro-proliferative and antiapoptotic effects of METTL3 in hypoxia-exposed cells or
rats with MI, while the miR-17-3p antagomir blocked these effects. Additionally,
pretreatment with the RNA-binding protein DGCR8 also hampered the protective role of
METTL3 in hypoxia-exposed cells. Overall, the current study indicated that METTL3
could improve cardiomyocyte proliferation and subsequently ameliorate MI in rats by
upregulating proliferation-related miR-17-3p in a DGCR8-dependent
pri-miRNA-processing manner.
Characterization of SARS-CoV-2-specific humoral immunity and its potential applications and therapeutic prospects
Authors: Zheng Jiaxin , Deng Yingying , Zhao Zhenyu , Mao Binli , Lu Mengji , Lin Yong , Huang Ailong
Published: October 2021

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing pandemic that poses a great threat to human health worldwide. As the humoral immune response plays essential roles in disease occurrence and development, understanding the dynamics and characteristics of virus-specific humoral immunity in SARS-CoV-2-infected patients is of great importance for controlling this disease. In this review, we summarize the characteristics of the humoral immune response after SARS-CoV-2 infection and further emphasize the potential applications and therapeutic prospects of SARS-CoV-2-specific humoral immunity and the critical role of this immunity in vaccine development. Notably, serological antibody testing based on the humoral immune response can guide public health measures and control strategies; however, it is not recommended for population surveys in areas with very low prevalence. Existing evidence suggests that asymptomatic individuals have a weaker immune response to SARS-CoV-2 infection, whereas SARS-CoV-2-infected children have a more effective humoral immune response than adults. The correlations between antibody (especially neutralizing antibody) titers and protection against SARS-CoV-2 reinfection should be further examined. In addition, the emergence of cross-reactions among different coronavirus antigens in the development of screening technology and the risk of antibody-dependent enhancement related to SARS-CoV-2 vaccination should be given further attention.
Exposure to 16 h of normobaric hypoxia induces ionic edema in the healthy brain
Authors: Biller Armin , Badde Stephanie , Heckel Andreas , Guericke Philipp , Bendszus Martin , Nagel Armin M. , Heiland Sabine , Mairbäurl Heimo , Bärtsch Peter , Schommer Kai
Published: October 2021

Following prolonged exposure to hypoxic conditions, for example, due to ascent to high altitude, stroke, or traumatic brain injury, cerebral edema can develop. The exact nature and genesis of hypoxia-induced edema in healthy individuals remain unresolved. We examined the effects of prolonged, normobaric hypoxia, induced by 16 h of exposure to simulated high altitude, on healthy brains using proton, dynamic contrast enhanced, and sodium MRI. This dual approach allowed us to directly measure key factors in the development of hypoxia-induced brain edema: (1) Sodium signals as a surrogate of the distribution of electrolytes within the cerebral tissue and (2) Ktransas a marker of blood–brain–barrier integrity. The measurements point toward an accumulation of sodium ions in extra- but not in intracellular space in combination with an intact endothelium. Both findings in combination are indicative of ionic extracellular edema, a subtype of cerebral edema that was only recently specified as an intermittent, yet distinct stage between cytotoxic and vasogenic edemas. In sum, here a combination of imaging techniques demonstrates the development of ionic edemas following prolonged normobaric hypoxia in agreement with cascadic models of edema formation.
Clonal hematopoiesis is associated with risk of severe Covid-19
Authors: Bolton Kelly L. , Koh Youngil , Foote Michael B. , Im Hogune , Jee Justin , Sun Choong Hyun , Safonov Anton , Ptashkin Ryan , Moon Joon Ho , Lee Ji Yeon , Jung Jongtak , Kang Chang Kyung , Song Kyoung-Ho , Choe Pyoeng Gyun , Park Wan Beom , Kim Hong Bin , Oh Myoung-don , Song Han , Kim Sugyeong , Patel Minal , Derkach Andriy , Gedvilaite Erika , Tkachuk Kaitlyn A. , Wiley Brian J. , Chan Ireaneus C. , Braunstein Lior Z. , Gao Teng , Papaemmanuil Elli , Esther Babady N. , Pessin Melissa S. , Kamboj Mini , Diaz Luis A. , Ladanyi Marc , Rauh Michael J. , Natarajan Pradeep , Machiela Mitchell J. , Awadalla Philip , Joseph Vijai , Offit Kenneth , Norton Larry , Berger Michael F. , Levine Ross L. , Kim Eu Suk , Kim Nam Joong , Zehir Ahmet
Published: October 2021

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15–2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15–3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22–3.30, p = 6×10−3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15–2.13, p = 5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.
p107 mediated mitochondrial function controls muscle stem cell proliferative fates
Authors: Bhattacharya Debasmita , Shah Vicky , Oresajo Oreoluwa , Scimè Anthony
Published: October 2021

Muscle diseases and aging are associated with impaired myogenic stem cell self-renewal and fewer proliferating progenitors (MPs). Importantly, distinct metabolic states induced by glycolysis or oxidative phosphorylation have been connected to MP proliferation and differentiation. However, how these energy-provisioning mechanisms cooperate remain obscure. Herein, we describe a mechanism by which mitochondrial-localized transcriptional co-repressor p107 regulates MP proliferation. We show p107 directly interacts with the mitochondrial DNA, repressing mitochondrial-encoded gene transcription. This reduces ATP production by limiting electron transport chain complex formation. ATP output, controlled by the mitochondrial function of p107, is directly associated with the cell cycle rate. Sirt1 activity, dependent on the cytoplasmic glycolysis product NAD+, directly interacts with p107, impeding its mitochondrial localization. The metabolic control of MP proliferation, driven by p107 mitochondrial function, establishes a cell cycle paradigm that might extend to other dividing cell types.
Humans monitor learning progress in curiosity-driven exploration
Authors: Ten Alexandr , Kaushik Pramod , Oudeyer Pierre-Yves , Gottlieb Jacqueline
Published: October 2021

Curiosity-driven learning is foundational to human cognition. By enabling humans to autonomously decide when and what to learn, curiosity has been argued to be crucial for self-organizing temporally extended learning curricula. However, the mechanisms driving people to set intrinsic goals, when they are free to explore multiple learning activities, are still poorly understood. Computational theories propose different heuristics, including competence measures (e.g., percent correct) and learning progress, that could be used as intrinsic utility functions to efficiently organize exploration. Such intrinsic utilities constitute computationally cheap but smart heuristics to prevent people from laboring in vain on unlearnable activities, while still motivating them to self-challenge on difficult learnable activities. Here, we provide empirical evidence for these ideas by means of a free-choice experimental paradigm and computational modeling. We show that while humans rely on competence information to avoid easy tasks, models that include a learning-progress component provide the best fit to task selection data. These results bridge the research in artificial and biological curiosity, reveal strategies that are used by humans but have not been considered in computational research, and introduce tools for probing how humans become intrinsically motivated to learn and acquire interests and skills on extended time scales.
Learning non-stationary Langevin dynamics from stochastic observations of latent trajectories
Authors: Genkin Mikhail , Hughes Owen , Engel Tatiana A.
Published: October 2021

Many complex systems operating far from the equilibrium exhibit stochastic dynamics that can be described by a Langevin equation. Inferring Langevin equations from data can reveal how transient dynamics of such systems give rise to their function. However, dynamics are often inaccessible directly and can be only gleaned through a stochastic observation process, which makes the inference challenging. Here we present a non-parametric framework for inferring the Langevin equation, which explicitly models the stochastic observation process and non-stationary latent dynamics. The framework accounts for the non-equilibrium initial and final states of the observed system and for the possibility that the system’s dynamics define the duration of observations. Omitting any of these non-stationary components results in incorrect inference, in which erroneous features arise in the dynamics due to non-stationary data distribution. We illustrate the framework using models of neural dynamics underlying decision making in the brain.
PGRMC1 acts as a size-selective cargo receptor to drive ER-phagic clearance of mutant prohormones
Authors: Chen Yu-Jie , Knupp Jeffrey , Arunagiri Anoop , Haataja Leena , Arvan Peter , Tsai Billy
Published: October 2021

The reticulon-3 (RTN3)-driven targeting complex promotes clearance of misfolded prohormones from the endoplasmic reticulum (ER) for lysosomal destruction by ER-phagy. Because RTN3 resides in the cytosolic leaflet of the ER bilayer, the mechanism of selecting misfolded prohormones as ER-phagy cargo on the luminal side of the ER membrane remains unknown. Here we identify the ER transmembrane protein PGRMC1 as an RTN3-binding partner. Via its luminal domain, PGRMC1 captures misfolded prohormones, targeting them for RTN3-dependent ER-phagy. PGRMC1 selects cargos that are smaller than the large size of other reported ER-phagy substrates. Cargos for PGRMC1 include mutant proinsulins that block secretion of wildtype proinsulin through dominant-negative interactions within the ER, causing insulin-deficiency. Chemical perturbation of PGRMC1 partially restores WT insulin storage by preventing ER-phagic degradation of WT and mutant proinsulin. Thus, PGRMC1 acts as a size-selective cargo receptor during RTN3-dependent ER-phagy, and is a potential therapeutic target for diabetes.
MesoNet allows automated scaling and segmentation of mouse mesoscale cortical maps using machine learning
Authors: Xiao Dongsheng , Forys Brandon J. , Vanni Matthieu P. , Murphy Timothy H.
Published: October 2021

Understanding the basis of brain function requires knowledge of cortical operations over wide spatial scales and the quantitative analysis of brain activity in well-defined brain regions. Matching an anatomical atlas to brain functional data requires substantial labor and expertise. Here, we developed an automated machine learning-based registration and segmentation approach for quantitative analysis of mouse mesoscale cortical images. A deep learning model identifies nine cortical landmarks using only a single raw fluorescent image. Another fully convolutional network was adapted to delimit brain boundaries. This anatomical alignment approach was extended by adding three functional alignment approaches that use sensory maps or spatial-temporal activity motifs. We present this methodology as MesoNet, a robust and user-friendly analysis pipeline using pre-trained models to segment brain regions as defined in the Allen Mouse Brain Atlas. This Python-based toolbox can also be combined with existing methods to facilitate high-throughput data analysis.
Breaking of Henry’s law for sulfide liquid–basaltic melt partitioning of Pt and Pd
Authors: Zhang Mingdong , Li Yuan
Published: October 2021

Platinum group elements are invaluable tracers for planetary accretion and differentiation and the formation of PGE sulfide deposits. Previous laboratory determinations of the sulfide liquid–basaltic melt partition coefficients of PGE ($${D}_{PGE}^{SL/SM}$$

D

P
G
E

S
L
/
S
M

) yielded values of 102–109, and values of >105 have been accepted by the geochemical and cosmochemical society. Here we perform measurements of $${D}_{Pt,\,Pd}^{SL/SM}$$

D

P
t
,

P
d

S
L
/
S
M

at 1 GPa and 1,400 °C, and find that $${D}_{Pt,\,Pd}^{SL/SM}$$

D

P
t
,

P
d

S
L
/
S
M

increase respectively from 3,500 to 3.5 × 105 and 1,800 to 7 × 105, as the Pt and Pd concentration in the sulfide liquid increases from 60 to 21,000 ppm and 26 to 7,000 ppm, respectively, implying non-Henrian behavior of the Pt and Pd partitioning. The use of $${D}_{Pt,\,Pd}^{SL/SM}$$

D

P
t
,

P
d

S
L
/
S
M

values of 2,000–6,000 well explains the Pt and Pd systematics of Earth’s mantle peridotites and mid-ocean ridge basalts. Our findings suggest that the behavior of PGE needs to be reevaluated when using them to trace planetary magmatic processes.
Superior robustness of anomalous non-reciprocal topological edge states
Authors: Zhang Zhe , Delplace Pierre , Fleury Romain
Published: October 2021

Robustness against disorder and defects is a pivotal advantage of topological systems1, manifested by the absence of electronic backscattering in the quantum-Hall2 and spin-Hall effects3, and by unidirectional waveguiding in their classical analogues4,5. Two-dimensional (2D) topological insulators4–13, in particular, provide unprecedented opportunities in a variety of fields owing to their compact planar geometries, which are compatible with the fabrication technologies used in modern electronics and photonics. Among all 2D topological phases, Chern insulators14–25 are currently the most reliable designs owing to the genuine backscattering immunity of their non-reciprocal edge modes, brought via time-reversal symmetry breaking. Yet such resistance to fabrication tolerances is limited to fluctuations of the same order of magnitude as their bandgap, limiting their resilience to small perturbations only. Here we investigate the robustness problem in a system where edge transmission can survive disorder levels with strengths arbitrarily larger than the bandgap—an anomalous non-reciprocal topological network. We explore the general conditions needed to obtain such an unusual effect in systems made of unitary three-port non-reciprocal scatterers connected by phase links, and establish the superior robustness of anomalous edge transmission modes over Chern ones to phase-link disorder of arbitrarily large values. We confirm experimentally the exceptional resilience of the anomalous phase, and demonstrate its operation in various arbitrarily shaped disordered multi-port prototypes. Our results pave the way to efficient, arbitrary planar energy transport on 2D substrates for wave devices with full protection against large fabrication flaws or imperfections.