bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethical risks of AI-designed products: bespoke surgical tools as a case study
Authors: Douglas David M. , Lacey Justine , Howard David
Published: September 2022

An emerging use of machine learning (ML) is creating products optimised using computational design for individual users and produced using 3D printing. One potential application is bespoke surgical tools optimised for specific patients. While optimised tool designs benefit patients and surgeons, there is the risk that computational design may also create unexpected designs that are unsuitable for use with potentially harmful consequences. We interviewed potential stakeholders to identify both established and unique technical risks associated with the use of computational design for surgical tool design and applied ethical risk analysis (eRA) to identify how stakeholders might be exposed to ethical risk within this process. The main findings of this research are twofold. First, distinguishing between unique and established risks for new medical technologies helps identify where existing methods of risk mitigation may be applicable to a surgical innovation, and where new means of mitigating risks may be needed. Second, the value of distinguishing between technical and ethical risks in such a system is that it identifies the key responsibilities for managing these risks and allows for any potential interdependencies between stakeholders in managing these risks to be made explicit. The approach demonstrated in this paper may be applied to understanding the implications of new AI and ML applications in healthcare and other high consequence domains.
Modification of the susceptibility gene TaPsIPK1 - a win-win for wheat disease resistance and yield
Authors: Macho Alberto , Wang Pengcheng , Zhu Jian-Kang
Published: September 2022

Wheat is one of the most important cereal crops, and it is essential for worldwide food security. However, wheat production is threatened by various diseases, including wheat stripe rust caused by the fungus Puccinia striiformis f. sp. tritici (Pst). The development of plant resistance against disease is usually challenged by potential reduction in crop yield due to the enhancement of plant immunity. In a recent article, Wang et al. found that TaPsIPK1 is a susceptibility gene targeted by rust effectors. Editing of TaPsIPK1 increases resistance to stripe rust without any developmental effects or yield penalty, providing an exceptional resource for developing disease resistance in wheat.
Microbial quality and antimicrobial residue of local and industrial processed fruit juice sold in Tamale, Ghana
Authors: Jimma Fidaus Iddrisu , Mohammed Amina , Adzaworlu Emmanuel Gameli , Nzeh Joseph , Quansah Lydia , Dufailu Osman Adamu
Published: September 2022

Fruits are essential part of human nutrition that provides numerous health benefits. When processed into juice, they are either packaged and stored or consumed immediately. Some reports associate foodborne illness with consumption of natural beverages contaminated with pathogenic microbes. Also, concerns of antimicrobial resistance due to antimicrobial residues in fruit juices has been raised. Thus, this study assessed the microbial quality of fruit juice by determining the incidence and load of E. coli and Salmonella spp., and the presence of antimicrobial residues in locally processed fruit juices (n = 25) and industrially (n = 3) processed fruit juices sold in Tamale, Ghana. Spread plate technique was adopted for isolation and enumeration of bacteria whilst the Premi® test kit was employed for detecting the presence of antimicrobial residue. Neither E. coli nor Salmonella spp. is recorded in all three industrially processed fruit juice samples. However, the locally processed fresh fruit juice samples recorded a prevalence rate of 88% E. coli and 40% Salmonella spp. with microbial load of 1.3 × 104 cfu/ml—9.23 × 104 cfu/ml for E. coli which is above the acceptable limits. Antimicrobial residues were absent in all 28 samples analyzed. The incidence and high E. coli load found in the local fresh fruit juice is of concern. Future studies should elucidate the pathogenicity of the isolates. Also, to avert possible foodborne illness linked with the consumption of local fresh fruit juices within Tamale and to ensure food safety, increase public health surveillance is recommended.
Migrant Health and COVID-19 Pandemic: A Cross-sectional Study of Characteristics, Clinical Features, and Health Outcome from Iran
Authors: Sohrabi Mohammad-Reza , Amin Rozhin , Maher Ali , Janbazi Shahriar , Zali Ali-Reza
Published: September 2022

Background

As the pandemic unfolds, major concerns remain with those in disadvantaged positions who may be disproportionately affected. This paper aimed to present the characteristics of COVID-19 immigrant patients and investigate whether they were disproportionately affected by COVID-19 pandemic.

Methods

A cross-sectional study was performed using data on 589,146 patients diagnosed with COVID-19 in Iran. Descriptive analyses were used to summarize the study population’s characteristics. Chi-squared test and logistic regression model were applied.

Results

After accounting for possible confounding covariates, being an immigrant was significantly associated with increased risk of death due to COVID-19 (OR 1.64, CI 1.568–1.727). When compared to Iranian-born patients, the prevalence of low blood oxygen levels on admission was higher among immigrant patients (53.9% versus 47.7%, P value < 0.001). Moreover, greater proportions of immigrants who were diagnosed with COVID-19 were admitted to an ICU (17% versus 15.8%, P value < 0.001). Patients aged 65 and above were the largest age category in both populations. However, there was a significant difference between the age profiles of patients, with children under the age of eighteen presenting 16% of immigrant patients vs 6.6% of Iranian-born patients (P value < 0.001). In both groups, more men were affected by COVID-19 than women, yet the sex bias was more prominent for migrant patients (P value < 0.001).

Conclusion

The evidence from this study revealed that immigrant patients infected with COVID-19 were more likely to suffer from severe health outcome of the disease compared to Iranian-born patients.
The management outcome of glyceryl trinitrate (GTN) compared to thrombectomy in thrombosed haemorrhoids, a prospective observational study
Authors: Hassan Mohamed , Hamza Aamir
Published: September 2022

Abstract

Background

Treatment of thrombosed haemorrhoids was mainly depending on surgery (thrombectomy) and reduction with evidence morbidity and recurrence rates.

Objectives

To evaluate efficacy of GTN compared to thrombectomy in treating thrombosed heamorrhoids, to describe the morbidity and post treatment complications of both treatment modalities.

Patients and methods

This study is descriptive observational prospective cross-sectional hospital-based study, conducted in Omdurman Teaching Hospital during period from November 2017 to December 2018. Data were collected by standardized questionnaire and analyzed by using SPSS version 20. The treatment choices was according to patient preference. Two independent samples t-test for continuous data comparing the means of the groups. The questions were answered as Yes/No and coded as 1/0 binary data so proportion test was used for comparing the two groups.

Results

Sixty patients satisfied the requirement inclusion criteria were included in the study.The majority of the patients were males (53.3%) and most frequent age group were less than 30 (48.3%) years old, ranging from 16 to 56 years with mean age 32.2 ± 9.3SD. Almost all patients presented with pain and swelling. Ninety percent had swelling less than 5 cm. Most of patient develop complications from the surgery, majority develop post operative pain (36.7%), the bleeding was dominant post surgery compared to GTN (28.33%) in day 1 P value 0.015 and 18% on first week P value 0.001.Infection was only found post surgery as patients required antibiotics and dressing P value 0.038.Few patients develop late recurrence (6.7%) post surgery mainly in second and third month follow up. In GTN usage less pain and bleeding but slightly higher numbers of patients develop dizziness (8.33%) in day 1.Overall GTN user had higher rates without complications through all the 3 months follow up period P value 0.010.

Conclusion

The GTN usage is safe, simple, effective and less morbidity than surgery.The study comes out with recommendations like increase the use of GTN instead of surgery and aware the population about the morbidity of surgery.
Hemodynamic profile effects of PM101 amiodarone formulation in patients with post-operative tachyarrhythmias
Authors: DeCoy Meredith , Page-Goertz Christopher , Nofziger Ryan , Besunder James , Raimer Patricia , Gothard David , Brown Miraides , Stewart Robert , Ruggles Cassandra , Breedlove Kristen , Clark John
Published: September 2022

Amiodarone may be considered for patients with junctional ectopic tachycardia refractory to treatment with sedation, analgesia, cooling, and electrolyte replacements. There are currently no published pediatric data regarding the hemodynamic effects of the newer amiodarone formulation, PM101, devoid of hypotensive agents used in the original amiodarone formulation. We performed a single-center, retrospective, descriptive study from January 2012 to December 2020 in a pediatric ICU. Thirty-three patients were included (22 male and 11 female) between the ages of 1.1 and 1,460 days who developed post-operative junctional ectopic tachycardia or other tachyarrhythmias requiring PM101. Data analysis was performed on hemodynamic parameters (mean arterial pressures and heart rate) and total PM101 (mg/kg) from hour 0 of amiodarone administration to hour 72. Adverse outcomes were defined as Vasoactive-Inotropic Score >20, patients requiring ECMO or CPR, or patient death. There was no statistically significant decrease in mean arterial pressures within the 6 hours of PM101 administration (p > 0.05), but there was a statistically significant therapeutic decrease in heart rate for resolution of tachyarrhythmia (p < 0.05). Patients received up to 25 mg/kg in an 8-hour time for rate control. Average rate control was achieved within 11.91 hours and average rhythm control within 62 hours. There were four adverse events around the time of PM101 administration, with three determined to not be associated with the medication. PM101 is safe and effective in the pediatric cardiac surgical population. Our study demonstrated that PM101 can be used in a more aggressive dosing regimen than previously reported in pediatric literature with the prior formulation.
BETWEEN FAIRNESS AND EFFICIENCY: TESTING WILSON’S THEORY OF PUBLIC ADMINISTRATION
Authors: Agulhon Sophie , Mueller Thomas Michael
Published: September 2022

During his first presidential term, faced with antitrust law reform, Woodrow Wilson had to deal with the reconstitution of conflicting values. These were, on the one hand, the importance of efficiency, guaranteed by the role of experts capable of effectively managing public administration; and, on the other hand, the importance of public and democratic participation, and therefore respect for traditional democratic values. Wilson faced a theoretical impasse in defining concepts such as competition and fairness when developing antitrust laws and had to put his theory of administration to the test. He opted for a pragmatic approach, based on managerial ideas and integrating the figure of the manager, expert in know-how.
THE TROLLEY META-PROBLEM
Authors: Sportiello Daniel John
Published: September 2022

For many years, philosophers have argued about the Trolley Problem – but they've also argued about whether the problem ought to interest us. According to some, the artificiality of the situations means that they involve no complicating factors – and so we ought to take our intuitions about them especially seriously. According to others, though, the artificiality of the situations means that our intuitions about them are meaningless. I hereby name the puzzle of why our intuitions about this differ the ‘Trolley Meta-Problem’. The story that follows illustrates this problem – and the Trolley Problem itself – in a humorous way.
MASK-LESS SHOPPING IS LIKE DRUNK DRIVING
Authors: Spelman Jonathan
Published: September 2022

In response to the Covid-19 pandemic, many states in the United States issued stay-at-home orders that prohibited people from leaving their homes except to access essential services. Upon reopening, a number of those states passed mask mandates requiring people to wear face coverings while in public, but as I write this, in October of 2020, there remain a substantial number of states that have not outlawed what I'll call ‘mask-less shopping’. This is a mistake. After describing the standard, public health argument for outlawing mask-less shopping and explaining why it fails, I give a better argument for outlawing mask-less shopping that depends on the claim that mask-less shopping is analogous to drunk driving. It follows that every state should outlaw it.
LETTING RIP: REBUTTING CAPRA ON THE METAPHYSICS OF FARTS
Authors: Garrett Brian , Joaquin Jeremiah Joven
Published: September 2022

Farts have not received the metaphysical attention they deserve. Bill Capra has opened the batting in his recent study of this ubiquitous rectal phenomenon. Spurred on by his sterling effort, JJ and I have added our own two bob's worth, disagreeing with much of what Bill says, and defending the buttocks-first conception of farts.
What If the Black Forest Owned Itself? A Constitutional Property Law Perspective on Rights of Nature
Authors: Hoops Björn
Published: September 2022

Ownership has been a key tool in the exploitation of nature for centuries. However, ownership could also shield natural entities from extraction and pollution if it were vested in them, rather than in humans or corporations. Through a case study of German constitutional property law, this article examines the normative content of this constitutional right. It argues that in owning themselves, natural entities would have numerous tools to fend off human interference with their self-determination. Constitutional property law would require any harmful activity affecting the natural entity to be based upon legislation and necessary to achieve a public purpose. The natural entity would enjoy broader access to justice. Courts would also often award appropriate remedies; where the natural entity would be awarded only compensation, this would be unsatisfactory because money cannot replace nature. The article finds that constitutional property law offers the potential for further protection from human interference, which has not been realized because of anthropocentric value judgments prevalent in German legal doctrine. Ecocentric approaches to ownership and invalidity as a standard remedy would play an important role in unlocking the full potential of ownership for environmental protection.
Role of Interhemispheric Heat Transport and Global Atmospheric Cooling in Multidecadal Trends of Northern Hemisphere Precipitation
Authors: Yukimoto Seiji , Oshima Naga , Kawai Hideaki , Deushi Makoto , Aizawa Takuro
Published: September 2022

Changes in the hydrological cycle in the northern hemisphere (NH) have a significant socioeconomic impact. Thus, quantifying past changes and projecting future changes in this cycle are important. We analyzed the positive and negative multidecadal trends in the NH mean precipitation since the 1950s that were accurately reproduced by a state‐of‐the‐art Earth system model. Results showed that changes in the interhemispheric heat transport play a major role in the NH atmospheric heat budget, accounting for 59% of the negative‐to‐positive trend change in NH precipitation through a north–south shift in the tropical precipitation zone, and were strongly linked to Hadley circulation anomaly. The remaining 41% corresponded to changes in atmospheric cooling with small interhemispheric differences, which were primarily related to clear‐sky longwave radiation. These findings quantitatively agreed with the results from a multimodel analysis.
Modulation of Atmospheric Rivers by the Arctic Stratospheric Polar Vortex
Authors: Lee Simon H. , Polvani Lorenzo M. , Guan Bin
Published: September 2022

Variability in atmospheric river (AR) frequency can drive hydrometeorological extremes with broad societal impacts. Mitigating the impacts of increased or decreased AR frequency requires forewarning weeks to months ahead. A key driver of Northern Hemisphere wintertime mid‐latitude subseasonal‐to‐seasonal climate variability is the stratospheric polar vortex. Here, we quantify AR frequency, landfall, genesis, and termination depending on the strength of the lower stratospheric polar vortex. We find large differences between weak and strong vortex states consistent with a latitudinal shift of the eddy‐driven jet, with the greatest differences over the British Isles, Scandinavia, and Iberia. Significant differences are also found for the Pacific Northwest of North America. Most of the seasonal‐scale stratospheric modulation of precipitation over Europe is explained by modulation of ARs. Our results provide potentially useful statistics for extended‐range prediction, and highlight the importance of ARs in bringing about the precipitation response to anomalous vortex states.
Formation of Alfvén Wave Ducts by Magnetotail Flow Bursts
Authors: Yang Ziyi , Zhang Binzheng , Lotko William , Sorathia Kareem A. , Pham Kevin , Luan Xiaoli , Dou Xiankang , Lei Jiuhou
Published: September 2022

Geomagnetic activity in Earth's outer magnetosphere stimulates intense and sometimes explosive flows of electromagnetic power propagating earthward as Alfvén waves. Observations show that among its various magnetospheric sources, Alfvénic Poynting flux from the magnetotail reaches the ionosphere with the greatest intensity. Dayside fluxes are statistically weaker though more persistent. Flankside fluxes are weakest. We show using global magnetohydrodynamic simulations that these distributions can be attributed to the formation (or not) of meridionally narrow, relatively uniform, low Alfvén conductance channels that efficiently transmit Alfvénic power to the near‐Earth space. These Alfvén ducts form naturally at the heads of flow bursts in the magnetotail but not in flankside flux tubes, where the transmission of Alfvénic power is strongly attenuated by reflections at large conductance gradients along the propagation path. The results elucidate the underlying physics that control efficient transmission of electromagnetic power from the magnetotail to low altitude to power Alfvénic aurora.
From bench to bedside: The mGluR5 system in people with and without Autism Spectrum Disorder and animal model systems
Authors: Carey Cornelia , Singh Nisha , Dunn Joel T. , Sementa Teresa , Mendez Maria Andreina , Velthuis Hester , Pereira Andreia C. , Pretzsch Charlotte Marie , Horder Jamie , Hader Stefan , Lythgoe David J. , Rotaru Diana-Georgina , Gee Anthony , Cash Diana , Veronese Mattia , Murphy Declan , McAlonan Grainne
Published: September 2022

The metabotropic glutamate receptor 5 (mGluR5) is a key regulator of excitatory (E) glutamate and inhibitory (I) γ-amino butyric acid (GABA) signalling in the brain. Despite the close functional ties between mGluR5 and E/I signalling, no-one has directly examined the relationship between mGluR5 and glutamate or GABA in vivo in the human brain of autistic individuals. We measured [18F] FPEB (18F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile) binding in 15 adults (6 with Autism Spectrum Disorder) using two regions of interest, the left dorsomedial prefrontal cortex and a region primarily composed of left striatum and thalamus. These two regions were mapped out using MEGA-PRESS voxels and then superimposed on reconstructed PET images. This allowed for direct comparison between mGluR5, GABA + and Glx. To better understand the molecular underpinnings of our results we used an autoradiography study of mGluR5 in three mouse models associated with ASD:Cntnap2knockout,Shank3knockout, and16p11.2deletion. Autistic individuals had significantly higher [18F] FPEB binding (t(13) = −2.86,p = 0.047) in the left striatum/thalamus region of interest as compared to controls. Within this region, there was a strong negative correlation between GABA + and mGluR5 density across the entire cohort (Pearson’s correlation:r(14) = −0.763,p = 0.002).Cntnap2KO mice had significantly higher mGlu5 receptor binding in the striatum (caudate-putamen) as compared to wild-type (WT) mice (n = 15,p = 0.03). There were no differences in mGluR5 binding for mice with theShank3knockout or16p11.2deletion. Given thatCntnap2is associated with a specific striatal deficit of parvalbumin positive GABA interneurons and ‘autistic’ features, our findings suggest that an increase in mGluR5 in ASD may relate to GABAergic interneuron abnormalities.
Hnrnpk maintains chondrocytes survival and function during growth plate development via regulating Hif1α-glycolysis axis
Authors: Chen Yuyu , Wu Jinna , Zhang Shun , Gao Wenjie , Liao Zhiheng , Zhou Taifeng , Li Yongyong , Su Deying , Liu Hengyu , Yang Xiaoming , Su Peiqiang , Xu Caixia
Published: September 2022

The harmonious functioning of growth plate chondrocytes is crucial for skeletogenesis. These cells rely on an appropriate intensity of glycolysis to maintain survival and function in an avascular environment, but the underlying mechanism is poorly understood. Here we show that Hnrnpk orchestrates growth plate development by maintaining the appropriate intensity of glycolysis in chondrocytes. Ablating Hnrnpk causes the occurrence of dwarfism, exhibiting damaged survival and premature differentiation of growth plate chondrocytes. Furthermore, Hnrnpk deficiency results in enhanced transdifferentiation of hypertrophic chondrocytes and increased bone mass. In terms of mechanism, Hnrnpk binds toHif1amRNA and promotes its degradation. Deleting Hnrnpk upregulates the expression of Hif1α, leading to the increased expression of downstream glycolytic enzymes and then exorbitant glycolysis. Our study establishes an essential role of Hnrnpk in orchestrating the survival and differentiation of chondrocytes, regulating the Hif1α-glycolysis axis through a post-transcriptional mechanism during growth plate development.
Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors
Authors: Blümel Lena , Qin Nan , Berlandi Johannes , Paisana Eunice , Cascão Rita , Custódia Carlos , Pauck David , Picard Daniel , Langini Maike , Stühler Kai , Meyer Frauke-Dorothee , Göbbels Sarah , Malzkorn Bastian , Liebau Max C. , Barata João T. , Jeibmann Astrid , Kerl Kornelius , Erkek Serap , Kool Marcel , Pfister Stefan M. , Johann Pascal D. , Frühwald Michael C. , Borkhardt Arndt , Reifenberger Guido , Faria Claudia C. , Fischer Ute , Hasselblatt Martin , Bartl Jasmin , Remke Marc
Published: September 2022

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor in infants that is characterized by loss of nuclear expression of SMARCB1 or SMARCA4 proteins. Recent studies show that AT/RTs comprise three molecular subgroups, namely AT/RT-TYR, AT/RT-MYC and AT/RT-SHH. The subgroups show distinct expression patterns of genes involved in ciliogenesis, however, little is known about the functional roles of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Additionally, apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. We also found significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis. Taken together, our findings indicate that primary ciliogenesis or its downstream signaling contributes to the aggressiveness of AT/RT and, therefore, may constitute a novel therapeutic target.
Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair
Authors: Audu Christopher O. , Melvin William J. , Joshi Amrita D. , Wolf Sonya J. , Moon Jadie Y. , Davis Frank M. , Barrett Emily C. , Mangum Kevin D. , Deng Hongping , Xing Xianying , Wasikowski Rachel , Tsoi Lam C. , Sharma Sriganesh B. , Bauer Tyler M. , Shadiow James , Corriere Matthew A. , Obi Andrea T. , Kunkel Steven L. , Levi Benjamin , Moore Bethany B. , Gudjonsson Johann E. , Smith Andrew M. , Gallagher Katherine A.
Published: September 2022

Macrophage plasticity is critical for normal tissue repair following injury. In pathologic states such as diabetes, macrophage plasticity is impaired, and macrophages remain in a persistent proinflammatory state; however, the reasons for this are unknown. Here, using single-cell RNA sequencing of human diabetic wounds, we identified increased JMJD3 in diabetic wound macrophages, resulting in increased inflammatory gene expression. Mechanistically, we report that in wound healing, JMJD3 directs early macrophage-mediated inflammation via JAK1,3/STAT3 signaling. However, in the diabetic state, we found that IL-6, a cytokine increased in diabetic wound tissue at later time points post-injury, regulates JMJD3 expression in diabetic wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 mechanism. Interestingly, RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells (Jmjd3f/fLyz2Cre+) identified that the STING gene (Tmem173) is regulated by JMJD3 in wound macrophages. STING limits inflammatory cytokine production by wound macrophages during healing. However, in diabetic mice, its role changes to limit wound repair and enhance inflammation. This finding is important since STING is associated with chronic inflammation, and we found STING to be elevated in human and murine diabetic wound macrophages at late time points. Finally, we demonstrate that macrophage-specific, nanoparticle inhibition of JMJD3 in diabetic wounds significantly improves diabetic wound repair by decreasing inflammatory cytokines and STING. Taken together, this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic wounds.
Black carbon and dust alter the response of mountain snow cover under climate change
Authors: Réveillet Marion , Dumont Marie , Gascoin Simon , Lafaysse Matthieu , Nabat Pierre , Ribes Aurélien , Nheili Rafife , Tuzet Francois , Ménégoz Martin , Morin Samuel , Picard Ghislain , Ginoux Paul
Published: September 2022

By darkening the snow surface, mineral dust and black carbon (BC) deposition enhances snowmelt and triggers numerous feedbacks. Assessments of their long-term impact at the regional scale are still largely missing despite the environmental and socio-economic implications of snow cover changes. Here we show, using numerical simulations, that dust and BC deposition advanced snowmelt by 17 ± 6 days on average in the French Alps and the Pyrenees over the 1979–2018 period. BC and dust also advanced by 10-15 days the peak melt water runoff, a substantial effect on the timing of water resources availability. We also demonstrate that the decrease in BC deposition since the 1980s moderates the impact of current warming on snow cover decline. Hence, accounting for changes in light-absorbing particles deposition is required to improve the accuracy of snow cover reanalyses and climate projections, that are crucial for better understanding the past and future evolution of mountain social-ecological systems.
Deciphering multi-way interactions in the human genome
Authors: Dotson Gabrielle A. , Chen Can , Lindsly Stephen , Cicalo Anthony , Dilworth Sam , Ryan Charles , Jeyarajan Sivakumar , Meixner Walter , Stansbury Cooper , Pickard Joshua , Beckloff Nicholas , Surana Amit , Wicha Max , Muir Lindsey A. , Rajapakse Indika
Published: September 2022

Chromatin architecture, a key regulator of gene expression, can be inferred using chromatin contact data from chromosome conformation capture, or Hi-C. However, classical Hi-C does not preserve multi-way contacts. Here we use long sequencing reads to map genome-wide multi-way contacts and investigate higher order chromatin organization in the human genome. We use hypergraph theory for data representation and analysis, and quantify higher order structures in neonatal fibroblasts, biopsied adult fibroblasts, and B lymphocytes. By integrating multi-way contacts with chromatin accessibility, gene expression, and transcription factor binding, we introduce a data-driven method to identify cell type-specific transcription clusters. We provide transcription factor-mediated functional building blocks for cell identity that serve as a global signature for cell types.
The AAA+ ATPase RavA and its binding partner ViaA modulate E. coli aminoglycoside sensitivity through interaction with the inner membrane
Authors: Felix Jan , Bumba Ladislav , Liesche Clarissa , Fraudeau Angélique , Rébeillé Fabrice , El Khoury Jessica Y. , Huard Karine , Gallet Benoit , Moriscot Christine , Kleman Jean-Philippe , Duhoo Yoan , Jessop Matthew , Kandiah Eaazhisai , Barras Frédéric , Jouhet Juliette , Gutsche Irina
Published: September 2022

Enteric bacteria have to adapt to environmental stresses in the human gastrointestinal tract such as acid and nutrient stress, oxygen limitation and exposure to antibiotics. Membrane lipid composition has recently emerged as a key factor for stress adaptation. The E. coli ravA-viaA operon is essential for aminoglycoside bactericidal activity under anaerobiosis but its mechanism of action is unclear. Here we characterise the VWA domain-protein ViaA and its interaction with the AAA+ ATPase RavA, and find that both proteins localise at the inner cell membrane. We demonstrate that RavA and ViaA target specific phospholipids and subsequently identify their lipid-binding sites. We further show that mutations abolishing interaction with lipids restore induced changes in cell membrane morphology and lipid composition. Finally we reveal that these mutations render E. coli gentamicin-resistant under fumarate respiration conditions. Our work thus uncovers a ravA-viaA-based pathway which is mobilised in response to aminoglycosides under anaerobiosis and engaged in cell membrane regulation.
Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast
Authors: Geldhof Vincent , de Rooij Laura P. M. H. , Sokol Liliana , Amersfoort Jacob , De Schepper Maxim , Rohlenova Katerina , Hoste Griet , Vanderstichele Adriaan , Delsupehe Anne-Marie , Isnaldi Edoardo , Dai Naima , Taverna Federico , Khan Shawez , Truong Anh-Co K. , Teuwen Laure-Anne , Richard François , Treps Lucas , Smeets Ann , Nevelsteen Ines , Weynand Birgit , Vinckier Stefan , Schoonjans Luc , Kalucka Joanna , Desmedt Christine , Neven Patrick , Mazzone Massimiliano , Floris Giuseppe , Punie Kevin , Dewerchin Mieke , Eelen Guy , Wildiers Hans , Li Xuri , Luo Yonglun , Carmeliet Peter
Published: September 2022

Since a detailed inventory of endothelial cell (EC) heterogeneity in breast cancer (BC) is lacking, here we perform single cell RNA-sequencing of 26,515 cells (including 8433 ECs) from 9 BC patients and compare them to published EC taxonomies from lung tumors. Angiogenic ECs are phenotypically similar, while other EC subtypes are different. Predictive interactome analysis reveals known but also previously unreported receptor-ligand interactions between ECs and immune cells, suggesting an involvement of breast EC subtypes in immune responses. We also identify a capillary EC subtype (LIPEC (Lipid Processing EC)), which expresses genes involved in lipid processing that are regulated by PPAR-γ and is more abundant in peri-tumoral breast tissue. Retrospective analysis of 4648 BC patients reveals that treatment with metformin (an indirect PPAR-γ signaling activator) provides long-lasting clinical benefit and is positively associated with LIPEC abundance. Our findings warrant further exploration of this LIPEC/PPAR-γ link for BC treatment.
QuasAr Odyssey: the origin of fluorescence and its voltage sensitivity in microbial rhodopsins
Authors: Silapetere Arita , Hwang Songhwan , Hontani Yusaku , Fernandez Lahore Rodrigo G. , Balke Jens , Escobar Francisco Velazquez , Tros Martijn , Konold Patrick E. , Matis Rainer , Croce Roberta , Walla Peter J. , Hildebrandt Peter , Alexiev Ulrike , Kennis John T. M. , Sun Han , Utesch Tillmann , Hegemann Peter
Published: September 2022

Rhodopsins had long been considered non-fluorescent until a peculiar voltage-sensitive fluorescence was reported for archaerhodopsin-3 (Arch3) derivatives. These proteins named QuasArs have been used for imaging membrane voltage changes in cell cultures and small animals. However due to the low fluorescence intensity, these constructs require use of much higher light intensity than other optogenetic tools. To develop the next generation of sensors, it is indispensable to first understand the molecular basis of the fluorescence and its modulation by the membrane voltage. Based on spectroscopic studies of fluorescent Arch3 derivatives, we propose a unique photo-reaction scheme with extended excited-state lifetimes and inefficient photoisomerization. Molecular dynamics simulations of Arch3, of the Arch3 fluorescent derivative Archon1, and of several its mutants have revealed different voltage-dependent changes of the hydrogen-bonding networks including the protonated retinal Schiff-base and adjacent residues. Experimental observations suggest that under negative voltage, these changes modulate retinal Schiff base deprotonation and promote a decrease in the populations of fluorescent species. Finally, we identified molecular constraints that further improve fluorescence quantum yield and voltage sensitivity.
Learning enhances encoding of time and temporal surprise in mouse primary sensory cortex
Authors: Rabinovich Rebecca J. , Kato Daniel D. , Bruno Randy M.
Published: September 2022

Primary sensory cortex has long been believed to play a straightforward role in the initial processing of sensory information. Yet, the superficial layers of cortex overall are sparsely active, even during sensory stimulation; additionally, cortical activity is influenced by other modalities, task context, reward, and behavioral state. Our study demonstrates that reinforcement learning dramatically alters representations among longitudinally imaged neurons in superficial layers of mouse primary somatosensory cortex. Learning an object detection task recruits previously unresponsive neurons, enlarging the neuronal population sensitive to touch and behavioral choice. Cortical responses decrease upon repeated stimulus presentation outside of the behavioral task. Moreover, training improves population encoding of the passage of time, and unexpected deviations in trial timing elicit even stronger responses than touches do. In conclusion, the superficial layers of sensory cortex exhibit a high degree of learning-dependent plasticity and are strongly modulated by non-sensory but behaviorally-relevant features, such as timing and surprise.
Structure of the PAPP-ABP5 complex reveals mechanism of substrate recognition
Authors: Judge Russell A. , Sridar Janani , Tunyasuvunakool Kathryn , Jain Rinku , Wang John C. K. , Ouch Christna , Xu Jun , Mafi Amirhossein , Nile Aaron H. , Remarcik Clint , Smith Corey L. , Ghosh Crystal , Xu Chen , Stoll Vincent , Jumper John , Singh Amoolya H. , Eaton Dan , Hao Qi
Published: September 2022

Insulin-like growth factor (IGF) signaling is highly conserved and tightly regulated by proteases including Pregnancy-Associated Plasma Protein A (PAPP-A). PAPP-A and its paralog PAPP-A2 are metalloproteases that mediate IGF bioavailability through cleavage of IGF binding proteins (IGFBPs). Here, we present single-particle cryo-EM structures of the catalytically inactive mutant PAPP-A (E483A) in complex with a peptide from its substrate IGFBP5 (PAPP-ABP5) and also in its substrate-free form, by leveraging the power of AlphaFold to generate a high quality predicted model as a starting template. We show that PAPP-A is a flexible trans-dimer that binds IGFBP5 via a 25-amino acid anchor peptide which extends into the metalloprotease active site. This unique IGFBP5 anchor peptide that mediates the specific PAPP-A-IGFBP5 interaction is not found in other PAPP-A substrates. Additionally, we illustrate the critical role of the PAPP-A central domain as it mediates both IGFBP5 recognition and trans-dimerization. We further demonstrate that PAPP-A trans-dimer formation and distal inter-domain interactions are both required for efficient proteolysis of IGFBP4, but dispensable for IGFBP5 cleavage. Together the structural and biochemical studies reveal the mechanism of PAPP-A substrate binding and selectivity.
Screening microbially produced Δ9-tetrahydrocannabinol using a yeast biosensor workflow
Authors: Shaw William M. , Zhang Yunfeng , Lu Xinyu , Khalil Ahmad S. , Ladds Graham , Luo Xiaozhou , Ellis Tom
Published: September 2022

Microbial production of cannabinoids promises to provide a consistent, cheaper, and more sustainable supply of these important therapeutic molecules. However, scaling production to compete with traditional plant-based sources is challenging. Our ability to make strain variants greatly exceeds our capacity to screen and identify high producers, creating a bottleneck in metabolic engineering efforts. Here, we present a yeast-based biosensor for detecting microbially produced Δ9-tetrahydrocannabinol (THC) to increase throughput and lower the cost of screening. We port five human cannabinoid G protein-coupled receptors (GPCRs) into yeast, showing the cannabinoid type 2 receptor, CB2R, can couple to the yeast pheromone response pathway and report on the concentration of a variety of cannabinoids over a wide dynamic and operational range. We demonstrate that our cannabinoid biosensor can detect THC from microbial cell culture and use this as a tool for measuring relative production yields from a library of Δ9-tetrahydrocannabinol acid synthase (THCAS) mutants.
DNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival
Authors: Wiencke J. K. , Molinaro Annette M. , Warrier Gayathri , Rice Terri , Clarke Jennifer , Taylor Jennie W. , Wrensch Margaret , Hansen Helen , McCoy Lucie , Tang Emily , Tamaki Stan J. , Tamaki Courtney M. , Nissen Emily , Bracci Paige , Salas Lucas A. , Koestler Devin C. , Christensen Brock C. , Zhang Ze , Kelsey Karl T.
Published: September 2022

Assessing individual responses to glucocorticoid drug therapies that compromise immune status and affect survival outcomes in neuro-oncology is a great challenge. Here we introduce a blood-based neutrophil dexamethasone methylation index (NDMI) that provides a measure of the epigenetic response of subjects to dexamethasone. This marker outperforms conventional approaches based on leukocyte composition as a marker of glucocorticoid response. The NDMI is associated with low CD4 T cells and the accumulation of monocytic myeloid-derived suppressor cells and also serves as prognostic factor in glioma survival. In a non-glioma population, the NDMI increases with a history of prednisone use. Therefore, it may also be informative in other conditions where glucocorticoids are employed. We conclude that DNA methylation remodeling within the peripheral immune compartment is a rich source of clinically relevant markers of glucocorticoid response.
Negative electrostatic potentials in a Hofmann-type metal-organic framework for efficient acetylene separation
Authors: Liu Yuan , Liu Junhui , Xiong Hanting , Chen Jingwen , Chen Shixia , Zeng Zheling , Deng Shuguang , Wang Jun
Published: September 2022

Efficient adsorptive separation of acetylene (C2H2) from carbon dioxide (CO2) or ethylene (C2H4) is industrially important but challenging due to the identical dynamic diameter or the trace amount. Here we show an electrostatic potential compatible strategy in a nitroprusside-based Hofmann-type metal-organic framework, Cu(bpy)NP (NP = nitroprusside, bpy = 4,4’-bipyridine), for efficient C2H2separation. The intruding cyanide and nitrosyl groups in undulating one-dimensional channels induce negative electrostatic potentials for preferential C2H2recognition instead of open metal sites in traditional Hofmann-type MOFs. As a result, Cu(bpy)NP exhibits a 50/50 C2H2/CO2selectivity of 47.2, outperforming most rigid MOFs. The dynamic breakthrough experiment demonstrates a 99.9% purity C2H4productivity of 20.57 mmol g−1from C2H2/C2H4(1/99,v/v) gas-mixture. Meanwhile, C2H2can also be captured and recognized from ternary C2H2/CO2/C2H4(25/25/50,v/v/v) gas-mixture. Furthermore, computational studies and in-situ infrared spectroscopy reveal that the selective C2H2binding arises from the compatible pore electro-environment generated by the electron-rich N and O atoms from nitroprusside anions.
Structural materials with afterglow room temperature phosphorescence activated by lignin oxidation
Authors: Wan Keliang , Tian Bing , Zhai Yingxiang , Liu Yuxuan , Wang He , Liu Shouxin , Li Shujun , Ye Wenpeng , An Zhongfu , Li Changzhi , Li Jian , James Tony D. , Chen Zhijun
Published: September 2022

Sustainable afterglow room temperature phosphorescence (RTP) materials, especially afterglow RTP structural materials, are crucial but remain difficult to achieve. Here, an oxidation strategy is developed to convert lignin to afterglow materials with a lifetime of ~ 408 ms. Specifically, lignin is oxidized to give aromatic chromophores and fatty acids using H2O2. The aromatic chromophores are locked by a fatty acid-based matrix by hydrogen bonds, triggering enhanced spin orbit coupling and long afterglow emission. More interestingly, motivated by this discovery, an auto fabrication line is built to convert wood (natural structural materials) to wood with afterglow RTP emission (RTP wood) via in situ oxidation of naturally-occurring lignin located in the wood cell walls to oxidized lignin (OL). The as-prepared RTP wood exhibits great potential for the construction of sustainable afterglow furniture. With this research we provide a new strategy to promote the sustainability of afterglow RTP materials and structural materials.
Cognitive load, fatigue and aversive simulator symptoms but not manipulated zeitgebers affect duration perception in virtual reality
Authors: Sabat Magdalena , Haładus Bartosz , Klincewicz Michał , Nalepa Grzegorz J.
Published: September 2022

The perceived duration of an interval depends on numerous aspects of the passed event both endogenous, including physiological arousal, level of wakefulness, attention, and surprise, as well as exogenous such as valence, salience, or context in the environment. There is some evidence that "time-giving" cues from the environment (zeitgebers) are coupled with time perception. The movement of the sun on the horizon was demonstrated to affect interval perception in a study conducted by Schatzschneider et al. (2016) claiming that the sun’s motion is a zeitgeber that influences time perception. In the present study, we undertake the first to our knowledge replication of this effect, extending the analysis to confounding aspects of the used paradigm. We aimed to test the effect of immersion, cognitive load, and changes in the speed of the sun on the horizon of the virtual environment on the perceived interval duration. We did not replicate the original effect, as reported by Schatzschneider et al., however, we did find that the perceived duration of an interval was affected by cognitive load, fatigue, and unpleasant symptoms caused by VR. In our analysis, we used Bayesian statistics to support our conclusion and offer its results as having some important consequences for the field.
Comparison of lamina cribrosa depth shallowing after trabeculectomy between primary open-angle glaucoma and exfoliation glaucoma
Authors: Park Do Young , Son Sunggeun , Cha Soon Cheol
Published: September 2022

The lamina cribrosa (LC) becomes shallower as intraocular pressure (IOP) decreases after trabeculectomy. The LC in eyes with exfoliation syndrome has distinctive properties in the connective tissue and extracellular matrix, but how these affect the changes in LC depth in response to IOP reduction after trabeculectomy is unknown. We analyzed pre- and postoperative spectral-domain optical coherence tomography of exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) patients who underwent trabeculectomy and investigated whether LC depth differed between XFG and POAG eyes after trabeculectomy. In total, 30 XFG eyes and 30 visual field mean deviation-matched POAG eyes were included. LC depth was determined at an average of 3.9 months after trabeculectomy. Postoperatively, the LC depth became shallower and the BMO-MRW became thicker in both XFG and POAG eyes. XFG eyes showed lesser amount of LC depth shallowing than POAG eyes. Greater preoperative LC depth, lower postoperative IOP, and absence of XFG were all associated with a greater degree of postoperative LC depth shallowing. These findings suggest that the LC of XFG eyes may inherently possess the distinctive properties of the connective tissue and extracellular matrix contained within it, which could affect the LC response to the reduction in IOP after trabeculectomy.
Extracellular vesicles derived from microgreens of Raphanus sativus L. var. caudatus Alef contain bioactive macromolecules and inhibit HCT116 cells proliferation
Authors: Kaimuangpak Karnchanok , Tamprasit Kawintra , Thumanu Kanjana , Weerapreeyakul Natthida
Published: September 2022

Extracellular vesicles (EVs) are phospholipid bilayer vesicles released from cells, containing natural cargos. Microgreens of Raphanus sativus L. var. caudatus Alef were used in this study as the source of EVs. EVs were isolated by differential centrifugation. The physical properties were determined by dynamic light scattering (DLS) and electron microscopy. The biological and chemical composition were studied by Fourier-transform infrared (FTIR) microspectroscopy and high-performance liquid chromatography analysis, respectively. EVs had a median size of 227.17 and 234.90 ± 23.30 nm determined by electron microscopy and DLS, respectively with a polydispersity index of 0.293 ± 0.019. Electron microscopy indicated the intact morphology and confirmed the size. The FTIR spectra revealed that EVs are composed of proteins as the most abundant macromolecules. Using a curve-fitting analysis, β-pleated sheets were the predominant secondary structure. Notably, the micromolecular biomarkers were not detected. EVs exerted anti-cancer activity on HCT116 colon cancer over Vero normal cells with an IC50 of 448.98 µg/ml and a selectivity index of > 2.23. To conclude, EVs could be successfully prepared with a simple and effective isolation method to contain nano-sized macromolecules possessing anti-cancer activity.