bluuebunny/crossref_metadata_2025 huggingface dataset:
Tailoring Public Health Policies
Authors: Persad Govind
Published: August 2021

In an effort to contain the spread of COVID-19, many states and countries have adopted public health restrictions on activities previously considered commonplace: crossing state borders, eating indoors, gathering together, and even leaving one’s home. These policies often focus on specific activities or groups, rather than imposing the same limits across the board. In this Article, I consider the law and ethics of these policies, which I call tailored policies.

In Part II, I identify two types of tailored policies: activity-based and group-based. Activity-based restrictions respond to differences in the risks and benefits of specific activities, such as walking outdoors and dining indoors. Group-based restrictions consider differences between groups with respect to risk and benefit. Examples are policies that treat children or senior citizens differently, policies that require travelers to quarantine when traveling to a new destination, and policies that treat individuals differently based on whether they have COVID-19 symptoms, have tested positive for COVID-19, have previous COVID-19 infection, or have been vaccinated against COVID-19.

In Part III, I consider the public health law grounding of tailored policies in the principles of “least restrictive means” and “well-targeting.” I also examine how courts have analyzed tailored policies that have been challenged on fundamental rights or equal protection grounds. I argue that fundamental rights analyses typically favor tailored policies and that equal protection does not preclude the use of tailored policies even when imperfectly crafted.

In Part IV, I consider three critiques of tailored policies, centering on the claims that they produce inequity, cause harm, or unacceptably limit liberty. I argue that we must evaluate restrictions comparatively: the question is not whether tailored policies are perfectly equitable, wholly prevent harm, or completely protect liberty, but whether they are better than untailored ones at realizing these goals in a pandemic. I also argue that evaluation must consider indirect harms and benefits as well as direct and apparent ones.
Ruthless Utilitarianism? COVID-19 State Triage Protocols May Subject Patients to Racial Discrimination and Providers to Legal Liability
Authors: Weismann Miriam F. , Holder Cheryl
Published: August 2021

As the coronavirus pandemic intensified, many communities in the United States experienced shortages of ventilators, intensive care beds, and other medical supplies and treatments. Currently, there is no single national response to provide guidance on allocation of scarce health care resources. Accordingly, states have formulated various “triage protocols” to prioritize those who will receive care and those who may not have the same access to health care services when the population demand exceeds the supply. Triage protocols address general concepts of “fairness” under accepted medical ethics rules and the consensus is that limited medical resources “should be allocated to do the greatest good for the greatest number of people.”1 The actual utility of this utilitarian ethics approach is questionable, however, leaving many questions about what is “fair” unanswered. Saving as many people as possible during a health care crisis is a laudable goal but not at the expense of ignoring patients’s legal rights, which are not suspended during the crisis. This Article examines the triage protocols from six states to determine whose rights are being recognized and whose rights are being denied, answering the pivotal question: If there is potential for disparate impact of facially neutral state triage protocols against Black Americans and other ethnic groups, is this legally actionable discrimination? This may be a case of first impression for the courts to resolve.

“[B]lack Americans are 3.5 times more likely to die of COVID-19 than [W]hite Americans … . Latinx people are almost twice as likely to die of the disease, compared with [W]hite people.”
2

“Our civil rights laws protect the equal dignity of every human life from ruthless utilitarianism … . HHS is committed to leaving no one behind during an emergency, and this guidance is designed to help health care providers meet that goal.” — Roger Severino, Office of Civil Rights Director, U.S. Department of Health and Human Services.
3
A Puzzle for Social Essences
Authors: RAVEN MICHAEL J.
Published: August 2021

The social world contains institutions (nations, clubs), groups (races, genders), objects (talismans, borders), and more. This essay explores a puzzle about the essences of social items. There is widespread consensus against social essences because of problematic presuppositions often made about them. But it is argued that essence can be freed from these presuppositions and their problems. Even so, a puzzle still arises. In a Platonic spirit, essences in general seem detached from the world. In an Aristotelian spirit, social essences in particular seem embedded in the world. The puzzle is that these inclinations are individually plausible but jointly incompatible. The essay has four aims: to clarify and refine the puzzle; to explore the puzzle's implications for essence in general and for social essences in particular; to illustrate the fruitfulness of the general distinction between detached and embedded; and to develop this distinction to sketch a novel solution to the puzzle.
Revision of two Devonian cupressocrinitids from the Schultze collection (Museum of Comparative Zoology, Harvard University) and description of a newHalocrinites(Crinoidea, Eucladida)
Authors: Bohatý Jan , Ausich William I.
Published: August 2021

Two cupressocrinitids (Crinoidea, Eucladida) from the famous crinoid collection of Dr. Ludwig J.T. Schultze deposited in the Museum of Comparative Zoology (MCZ) are revised in the present study:Cupressocrinites hybridusn. comb. andHalocrinites minorn. comb. The rareC. hybridushas a stratigraphically and regionally restricted occurrence at the Eifelian–Givetian boundary of the Hillesheim Syncline (Eifel, Rhenish Massif, Germany), but the more commonH. minoroccurs supraregionally from the Eifelian to the Frasnian (Middle to Upper Devonian). Both cupressocrinitids are redescribed on the basis of the type material stored in the MCZ. In addition, the rareHalocrinites heinorumn. sp. from the Eifelian–Givetian boundary beds and lower Givetian of the Eifel (Rhenish Massif, Germany) is described, andEncrinus townsendi(König, 1825) is questionably reassigned toRobustocrinites:R.(?)townsendin. comb. Pre- and postmortem ossicular modifications of the studied cupressocrinitid skeletons are also discussed.

UUID:http://zoobank.org/4598e1fa-8ca5-4160-8fee-6e8c6d444115
A typology of substitution: weather, armed conflict, and maritime piracy
Authors: Kikuta Kyosuke
Published: August 2021

How do rebels choose among available tactics during civil war? How do they substitute one tactic for another? Although previous studies address these questions, they narrowly focus on the presence or absence of substitution. Differentiating the varieties of substitution, however, is critical. How rebels respond to their tactical environment—including weather conditions—depends on the type of substitution. I formally derive three types of substitution and test them by exploiting weather-induced exogenous variation in rebels' tactical costs for ground and marine violent activities. The analysis of daily panel data in 31 coastal conflict countries indicates that rebels substitute violent ground activities for maritime piracy but not vice versa. This asymmetry cannot be explained without differentiating substitution types.
Trimodality approach, using modern radiation techniques, for management of locally advanced adrenocortical carcinoma – case report
Authors: Laranja André , Ferreira Carolina
Published: August 2021

Background:

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Surgery is the mainstay of treatment, still even after a R0 surgical margins, there is a high risk of recurrence.

Case Presentation:

A 26-year-old female diagnosed with a large functioning ACC treated with a trimodality approach (surgery, radiotherapy and chemotherapy). Postoperative radiotherapy was proposed regarding the high risk of recurrence. A dose of 50.4 Gy in 28 fractions was delivered to the patient using a volumetric-modulated arc therapy plan. Radiotherapy was safe and well tolerated, and no local recurrence was observed so far (13 months after radiotherapy).

Conclusions:

Due to the rarity of ACC and the lack of evidence regarding this entity, therapeutic approach can be challenging. Recent evidence suggests that radiotherapy could have an important role in the therapeutic arsenal.
Co-opting the cooperative movement? Development, decolonization, and the power of expertise at the Co-operative College, 1920s–1960s
Authors: Moulton Mo
Published: August 2021

Cooperative departments and organizations were a ubiquitous but rarely studied aspect of British colonial governance in the twentieth century. The Co-operative College in Britain provided specialized training in colonial cooperation to students from across the British Empire. The cooperative movement was a key part of the emergence of regimes of development in the decades between the 1920s and 1960s, reflecting their emphasis on modular solutions deployed by experts in an increasingly homogenizing ‘developing world’. However, the colonial and post-colonial students at the Co-operative College were also critical of colonialism and capitalism, participating in the anti-colonial internationalist effort to create a more just post-imperial world. As post-colonial governments retained cooperative structures, the former students of the Co-operative College used the movement as a counter-balance to the larger forces of nationalism and neo-colonialism.
The JewishVerfassung, the Israelinomos: the constitutional situation of the beginnings of the State of Israel in the context of Carl Schmitt's political and legal philosophy
Authors: Engelking Wojciech
Published: August 2021

The paper is an attempt to examine how Carl Schmitt's constitutional theory can be useful to analyse the Constitution of the State of Israel designed in the late 1940s – the impact of which Jacob Taubes once certified. The author analyses three projects created then by Leo Kohn through the prism of Schmitt's concept ofVerfassungandVerfassungsgesetz. He also reads in the context of Schmitt's philosophy (fromConstitutional TheoryandTheNomosof the Earth) the constitutional situation of Israel as a country where, first, the Constitution has not been passed and the basic matter of its legal system is regulated by the Basic Laws; second, citizens of Arab origin are excluded from the national community; and third, the borders of the state remain fluid and change due to the constant partition of the land.
Understanding the Reasons for Suicide Among Older Adults in Rural China Using In-Depth Interviews
Authors: Bai Xinyu , Zhou Liang , Mo Qiqing , Jia Cunxian , Ma Zhenyu
Published: August 2021

Abstract. Background: Suicide is a complex public health problem. Suicide rates are higher in rural areas than in urban areas and among older adults than any other age group in China. Aims: This study aimed to acquire a comprehensive understanding of rural older adults’ reasons for suicide through qualitative exploration and to provide additional insights for suicide prevention work. Method: In-depth interviews were conducted with people familiar with older adults who had died by suicide (“informants”). The data were analyzed using a thematic approach. Results: Data were available for 242 people who died by suicide. Informants identified two or more reasons for suicide among most people who had died. Physical illness, psychological distress, and interpersonal conflicts were the most common reasons. The rate of mental disorders as diagnosed by psychiatrists was higher than that reported by the informants. Limitations: Information bias is inevitable because of the use of proxy informants. Conclusion: The reasons for suicide are complex and diverse, and research on suicide should focus more on the mechanisms of interaction between reasons. Greater attention should be paid to physical and mental health as well as to improving interpersonal and problem-solving skills for older adults in China.
Hydrothermal Vents Are a Source of Old Refractory Organic Carbon to the Deep Ocean
Authors: Luther George W.
Published: August 2021

Based on the C‐14 data of Druffel et al. (2021, https://doi.org/10.1029/2021gl092904) along the Eastern Pacific Rise, dissolved organic carbon (DOC) in the deep ocean is old and thus refractory. Their data in combination with previous He‐3 data indicate that the source of this aged DOC is from the hot waters emanating from hydrothermal vents along the ridge axis. The isotopic and structural composition of the source DOC is unknown, which requires a concerted effort by the marine organic chemistry community to elucidate these chemical forms.
Spatial Distribution of Atmospheric Mercury Species in the Southern Ocean
Authors: Yue Fange , Xie Zhouqing , Yan Jinpei , Zhang Yanxu , Jiang Bei
Published: August 2021

Antarctica and the surrounding Southern Ocean act as an important sink in the global mercury cycle; however, corresponding studies of atmospheric mercury species in these regions are still scarce. Here, we report large‐scale observations of atmospheric gaseous elemental mercury (GEM) and gaseous oxidized mercury (GOM) in the Antarctic marine boundary layer (MBL) taken during a summer cruise. There is large variability in the spatial distribution of GOM, which is likely attributable to the diverse land surface types, including coastal Antarctica, sea‐ice region, and oceanic region, along the cruise route. In coastal Antarctica, the highest GOM level (56.23 ± 47.74 pg·m−3) might be attributed to the significant in‐situ oxidation there. Significant in‐situ oxidation of GEM could also occur in the sea‐ice region, causing the significant increase of GOM (up to 87.01 pg·m−3), while the uptake of the high content of sea‐salt aerosols in sea‐ice regions might efficiently eliminate GOM in the air, resulting in generally lower content of GOM (13.10 ± 14.48 pg·m−3) in the sea‐ice region. In the oceanic region, the lowest level of GOM (3.95 ± 4.69 pg·m−3) is due to both the uptake of sea‐salt aerosols and the seasonal melting of first‐year sea‐ice. This study provides insight to understand the mechanisms of the atmospheric mercury cycle in various land surface types in the Antarctic MBL.
Predictive Proxies of Present and Future Lightning in a Superparameterized Model
Authors: Charn Alexander B. , Parishani Hossein
Published: August 2021

A superparameterized climate model is used to assess the global performance of several previously proposed proxies for lightning. In particular, predictors incorporating hydrometeor (ice, graupel) profiles and convective vertical velocities are compared to observations, then used to estimate changes in flash rates with global warming. The choice of microphysics parameterization is also investigated, with all predictors showing higher correlations with Lightning Imaging Sensor/Optical Transient Detector observations when using a 2‐moment scheme compared to a 1‐moment representation. All proxies generally agree in their response to warming over tropical land, with notable decreases in Africa, the Middle East, and northern South America, but disagree over oceans and the midlatitudes. The product of convective available potential energy and precipitation predicts increases over these latter areas, as do the 2‐moment ice‐based proxies, while those of the 1‐moment model tend to show decreases, highlighting the importance of cloud microphysics when using climate models to simulate lightning.
Potential of Regional Ionosphere Prediction Using a Long Short‐Term Memory Deep‐Learning Algorithm Specialized for Geomagnetic Storm Period
Authors: Kim Jeong‐Heon , Kwak Young‐Sil , Kim YongHa , Moon Su‐In , Jeong Se‐Heon , Yun JongYeon
Published: August 2021

In our previous study (Moon et al., 2020, https://doi.org/10.3938/jkps.77.1265), we developed a long short‐term memory (LSTM) deep‐learning model for geomagnetic quiet days (LSTM‐quiet) to perform effective long‐term predictions for the regional ionosphere. However, their model could not predict geomagnetic storm days effectively at all. This study developed an LSTM model suitable for geomagnetic storms using the new training data set and redesigning input parameters and hyper‐parameters. We collected 131 days of geomagnetic storm cases from January 1, 2009 to December 31, 2019, provided by the Japan Meteorological Agency's Kakioka Magnetic Observatory, and obtained the interplanetary magnetic field Bz, Dst, Kp, and AE indices related to the geomagnetic storm corresponding to each storm date from the OMNI database. These indices and F2 parameters (foF2 and hmF2) of Jeju ionosonde (33.43°N, 126.30°E) were used as input parameters for the LSTM model. To test and verify the predictive performance and the usability of the LSTM model for geomagnetic storms developed in this manner, we created and diagnosed the 0.5, 1, 2, 3, 6, 12, and 24‐h predictive LSTM models. According to the results of this study, the LSTM storm model for 24‐h developed in this study achieved a predictive performance during the three geomagnetic storms about 32% (10%), 34% (17%), and 37% (5%) better in root mean square error of foF2 (hmF2) than the LSTM quiet model (Moon et al., 2020, https://doi.org/10.3938/jkps.77.1265), SAMI2, and IRI‐2016 models. We propose that the short‐term predictions of less than 3 h are sufficiently competitive than other traditional ionospheric models. Thus, this study suggests that our model can be used for short‐term prediction and monitoring of the regional mid‐latitude ionosphere.
HIF-1α promotes SARS-CoV-2 infection and aggravates inflammatory responses to COVID-19
Authors: Tian Mingfu , Liu Weiyong , Li Xiang , Zhao Peiyi , Shereen Muhammad Adnan , Zhu Chengliang , Huang Shanyu , Liu Siyu , Yu Xiao , Yue Miaomiao , Pan Pan , Wang Wenbiao , Li Yongkui , Chen Xulin , Wu Kailang , Luo Zhen , Zhang Qiwei , Wu Jianguo
Published: August 2021

Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a major pathological feature of Coronavirus Disease 2019 (COVID-19) and a crucial determinant in COVID-19 prognosis. Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control. Here, we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1α (HIF-1α) play key roles in the virus infection and pro-inflammatory responses. RNA sequencing shows that HIF-1α signaling, immune response, and metabolism pathways are dysregulated in COVID-19 patients. Clinical analyses indicate that HIF-1α production, inflammatory responses, and high mortalities occurr in elderly patients. HIF-1α and pro-inflammatory cytokines are elicited in patients and infected cells. Interestingly, SARS-CoV-2 ORF3a induces mitochondrial damage and Mito-ROS production to promote HIF-1α expression, which subsequently facilitates SARS-CoV-2 infection and cytokines production. Notably, HIF-1α also broadly promotes the infection of other viruses. Collectively, during SARS-CoV-2 infection, ORF3a induces HIF-1α, which in turn aggravates viral infection and inflammatory responses. Therefore, HIF-1α plays an important role in promoting SARS-CoV-2 infection and inducing pro-inflammatory responses to COVID-19.
Diversity, prevalence, and expression of cyanase genes (cynS) in planktonic marine microorganisms
Authors: Mao Xuewei , Chen Jianwei , van Oosterhout Cock , Zhang Huan , Liu Guangxing , Zhuang Yunyun , Mock Thomas
Published: August 2021

Cyanate is utilized by many microbes as an organic nitrogen source. The key enzyme for cyanate metabolism is cyanase, converting cyanate to ammonium and carbon dioxide. Although the cyanase gene cynS has been identified in many species, the diversity, prevalence, and expression of cynS in marine microbial communities remains poorly understood. Here, based on the full-length cDNA sequence of a dinoflagellate cynS and 260 homologs across the tree of life, we extend the conserved nature of cyanases by the identification of additional ultra-conserved residues as part of the modeled holoenzyme structure. Our phylogenetic analysis showed that horizontal gene transfer of cynS appears to be more prominent than previously reported for bacteria, archaea, chlorophytes, and metazoans. Quantitative analyses of marine planktonic metagenomes revealed that cynS is as prevalent as ureC (urease subunit alpha), suggesting that cyanate plays an important role in nitrogen metabolism of marine microbes. Highly abundant cynS transcripts from phytoplankton and nitrite-oxidizing bacteria identified in global ocean metatranscriptomes indicate that cyanases potentially occupy a key position in the marine nitrogen cycle by facilitating photosynthetic assimilation of organic N and its remineralisation to NO3 by the activity of nitrifying bacteria.
Yeast-produced RBD-based recombinant protein vaccines elicit broadly neutralizing antibodies and durable protective immunity against SARS-CoV-2 infection
Authors: Zang Jinkai , Zhu Yuanfei , Zhou Yu , Gu Chenjian , Yi Yufang , Wang Shuxia , Xu Shiqi , Hu Gaowei , Du Shujuan , Yin Yannan , Wang Yalei , Yang Yong , Zhang Xueyang , Wang Haikun , Yin Feifei , Zhang Chao , Deng Qiang , Xie Youhua , Huang Zhong
Published: August 2021

Massive production of efficacious SARS-CoV-2 vaccines is essential for controlling the ongoing COVID-19 pandemic. We report here the preclinical development of yeast-produced receptor-binding domain (RBD)-based recombinant protein SARS-CoV-2 vaccines. We found that monomeric RBD of SARS-CoV-2 could be efficiently produced as a secreted protein from transformed Pichia pastoris (P. pastoris) yeast. Yeast-derived RBD-monomer possessed functional conformation and was able to elicit protective level of neutralizing antibodies in mice. We further designed and expressed a genetically linked dimeric RBD protein in yeast. The engineered dimeric RBD was more potent than the monomeric RBD in inducing long-lasting neutralizing antibodies. Mice immunized with either monomeric RBD or dimeric RBD were effectively protected from live SARS-CoV-2 virus challenge even at 18 weeks after the last vaccine dose. Importantly, we found that the antisera raised against the RBD of a single SARS-CoV-2 prototype strain could effectively neutralize the two predominant circulating variants B.1.1.7 and B.1.351, implying broad-spectrum protective potential of the RBD-based vaccines. Our data demonstrate that yeast-derived RBD-based recombinant SARS-CoV-2 vaccines are feasible and efficacious, opening up a new avenue for rapid and cost-effective production of SARS-CoV-2 vaccines to achieve global immunization.
PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation
Authors: Sun Yilun , Chen Jiji , Huang Shar-yin N. , Su Yijun P. , Wang Wenjie , Agama Keli , Saha Sourav , Jenkins Lisa M. , Pascal John M. , Pommier Yves
Published: August 2021

Poly(ADP)-ribosylation (PARylation) regulates chromatin structure and recruits DNA repair proteins. Using single-molecule fluorescence microscopy to track topoisomerase I (TOP1) in live cells, we found that sustained PARylation blocked the repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) in a similar fashion as inhibition of the ubiquitin-proteasome system (UPS). PARylation of TOP1-DPC was readily revealed by inhibiting poly(ADP-ribose) glycohydrolase (PARG), indicating the otherwise transient and reversible PARylation of the DPCs. As the UPS is a key repair mechanism for TOP1-DPCs, we investigated the impact of TOP1-DPC PARylation on the proteasome and found that the proteasome is unable to associate with and digest PARylated TOP1-DPCs. In addition, PARylation recruits the deubiquitylating enzyme USP7 to reverse the ubiquitylation of PARylated TOP1-DPCs. Our work identifies PARG as repair factor for TOP1-DPCs by enabling the proteasomal digestion of TOP1-DPCs. It also suggests the potential regulatory role of PARylation for the repair of a broad range of DPCs.
A highly potent ruthenium(II)-sonosensitizer and sonocatalyst for in vivo sonotherapy
Authors: Liang Chao , Xie Jiaen , Luo Shuangling , Huang Can , Zhang Qianling , Huang Huaiyi , Zhang Pingyu
Published: August 2021

As a basic structure of most polypyridinal metal complexes, [Ru(bpy)3]2+, has the advantages of simple structure, facile synthesis and high yield, which has great potential for scientific research and application. However, sonodynamic therapy (SDT) performance of [Ru(bpy)3]2+ has not been investigated so far. SDT can overcome the tissue-penetration and phototoxicity problems compared to photodynamic therapy. Here, we report that [Ru(bpy)3]2+ is a highly potent sonosensitizer and sonocatalyst for sonotherapy in vitro and in vivo. [Ru(bpy)3]2+ can produce singlet oxygen (1O2) and sono-oxidize endogenous 1,4-dihydronicotinamide adenine dinucleotide (NADH) under ultrasound (US) stimulation in cancer cells. Furthermore, [Ru(bpy)3]2+ enables effective destruction of mice tumors, and the therapeutic effect can reach deep tissues over 10 cm under US irradiation. This work paves a way for polypyridinal metal complexes to be applied to the noninvasive precise sonotherapy of cancer.
Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations
Authors: Bolt Christopher Chase , Lopez-Delisle Lucille , Mascrez Bénédicte , Duboule Denis
Published: August 2021

Human families with chromosomal rearrangements at 2q31, where the human HOXD locus maps, display mesomelic dysplasia, a severe shortening and bending of the limb. In mice, the dominant Ulnaless inversion of the HoxD cluster produces a similar phenotype suggesting the same origin for these malformations in humans and mice. Here we engineer 1 Mb inversion including the HoxD gene cluster, which positioned Hoxd13 close to proximal limb enhancers. Using this model, we show that these enhancers contact and activate Hoxd13 in proximal cells, inducing the formation of mesomelic dysplasia. We show that a secondary Hoxd13 null mutation in-cis with the inversion completely rescues the alterations, demonstrating that ectopic HOXD13 is directly responsible for this bone anomaly. Single-cell expression analysis and evaluation of HOXD13 binding sites suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery
Authors: Di Franco Simone , Bianca Paola , Sardina Davide Stefano , Turdo Alice , Gaggianesi Miriam , Veschi Veronica , Nicotra Annalisa , Mangiapane Laura Rosa , Lo Iacono Melania , Pillitteri Irene , van Hooff Sander , Martorana Federica , Motta Gianmarco , Gulotta Eliana , Lentini Vincenzo Luca , Martorana Emanuele , Fiori Micol Eleonora , Vieni Salvatore , Bongiorno Maria Rita , Giannone Giorgio , Giuffrida Dario , Memeo Lorenzo , Colarossi Lorenzo , Mare Marzia , Vigneri Paolo , Todaro Matilde , De Maria Ruggero , Medema Jan Paul , Stassi Giorgio
Published: August 2021

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.

Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.
Off-the-shelf proximity biotinylation for interaction proteomics
Authors: Santos-Barriopedro Irene , van Mierlo Guido , Vermeulen Michiel
Published: August 2021

Proximity biotinylation workflows typically require CRISPR-based genetic manipulation of target cells. To overcome this bottleneck, we fused the TurboID proximity biotinylation enzyme to Protein A. Upon target cell permeabilization, the ProtA-Turbo enzyme can be targeted to proteins or post-translational modifications of interest using bait-specific antibodies. Addition of biotin then triggers bait-proximal protein biotinylation. Biotinylated proteins can subsequently be enriched from crude lysates and identified by mass spectrometry. We demonstrate this workflow by targeting Emerin, H3K9me3 and BRG1. Amongst the main findings, our experiments reveal that the essential protein FLYWCH1 interacts with a subset of H3K9me3-marked (peri)centromeres in human cells. The ProtA-Turbo enzyme represents an off-the-shelf proximity biotinylation enzyme that facilitates proximity biotinylation experiments in primary cells and can be used to understand how proteins cooperate in vivo and how this contributes to cellular homeostasis and disease.
RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage
Authors: Krais John J. , Wang Yifan , Patel Pooja , Basu Jayati , Bernhardy Andrea J. , Johnson Neil
Published: August 2021

DNA damage prompts a diverse range of alterations to the chromatin landscape. The RNF168 E3 ubiquitin ligase catalyzes the mono-ubiquitination of histone H2A at lysine (K)13/15 (mUb-H2A), forming a binding module for DNA repair proteins. BRCA1 promotes homologous recombination (HR), in part, through its interaction with PALB2, and the formation of a larger BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex. The mechanism by which BRCA1-P is recruited to chromatin surrounding DNA breaks is unclear. In this study, we reveal that an RNF168-governed signaling pathway is responsible for localizing the BRCA1-P complex to DNA damage. Using mice harboring a Brca1CC (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168− and Brca1CC alleles, which disrupted development, and reduced the efficiency of Palb2-Rad51 localization. Mechanistically, we show that RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the CC domain-mediated BRCA1-PALB2 interaction. Together, these findings establish a series of molecular interactions that connect the DNA damage signaling and HR repair machinery.
FGF2-primed 3D spheroids producing IL-8 promote therapeutic angiogenesis in murine hindlimb ischemia
Authors: Choi Jungkyun , Choi Wooshik , Joo Yunji , Chung Haeun , Kim Dokyun , Oh Seung Ja , Kim Sang-Heon
Published: August 2021

Peripheral artery disease is a progressive, devastating disease that leads to critical limb ischemia (CLI). Therapeutic angiogenesis using stem cell therapy has emerged as a promising approach for its treatment; however, adapting cell-based therapy has been limited by poor cell survival and low treatment efficiency. To overcome unmet clinical needs, we developed a fibroblast growth factor 2 (FGF2)-immobilized matrix that enabled control of cell adhesion to the surface and exerted a priming effect on the cell. Human adipose-derived stem cells (hASCs) grown in this matrix formed a functionally enhanced cells spheroid (FECS-Ad) that secreted various angiogenic factors including interleukin-8 (IL-8). We demonstrated that IL-8 was upregulated by the FGF2-mediated priming effect during FECS-Ad formation. Immobilized FGF2 substrate induced stronger IL-8 expression than soluble FGF2 ligands, presumably through the FGFR1/JNK/NF-κB signaling cascade. In IL-8-silenced FECS-Ad, vascular endothelial growth factor (VEGF) expression was decreased and angiogenic potential was reduced. Intramuscular injection of FECS-Ad promoted angiogenesis and muscle regeneration in mouse ischemic tissue, while IL-8 silencing in FECS-Ad inhibited these effects. Taken together, our data demonstrate that IL-8 contributes to therapeutic angiogenesis and suggest that FECS-Ad generated using the MBP-FGF2 matrix might provide a reliable platform for developing therapeutic agents to treat CLI.
Sex differences in antipsychotic efficacy and side effects in schizophrenia spectrum disorder: results from the BeSt InTro study
Authors: Hoekstra Sanne , Bartz-Johannessen Christoffer , Sinkeviciute Igne , Reitan Solveig K. , Kroken Rune A. , Løberg Else-Marie , Larsen Tor K. , Rettenbacher Maria , Johnsen Erik , Sommer Iris E.
Published: August 2021

Current guidelines for patients with schizophrenia spectrum disease do not take sex differences into account, which may result in inappropriate sex-specific treatment. In the BeSt InTro study, a total of 144 patients (93 men and 51 women) with a schizophrenia spectrum diagnosis and ongoing psychosis were included and randomized to amisulpride, aripiprazole, or olanzapine in flexible dose. This trial is registered with ClinicalTrials.gov (NCT01446328). Primary outcomes were sex differences in dose, dose-corrected serum levels, efficacy, and tolerability. Dosing was higher for men than for women in the aripiprazole group (p = 0.025) and, at trend level, in the olanzapine group (p = 0.056). Dose-corrected serum levels were 71.9% higher in women than in men for amisulpride (p = 0.019) and 55.8% higher in women than in men for aripiprazole (p = 0.049). In the amisulpride group, men had a faster decrease in psychotic symptoms than women (p = 0.003). Moreover, amisulpride was more effective than the other medications in men but not in women. Prolactin levels were higher in women than in men, especially for amisulpride (p < 0.001). Also, women had higher BMI increase on amisulpride compared to the two other antipsychotics (p < 0.001). We conclude that clinicians should be aware of the risks of overdosing in women, especially for amisulpride and aripiprazole. Amisulpride is highly effective in men, but in women, amisulpride showed more severe side effects and may thus not be the drug of first choice. Our study shows that sex differences should be taken into account in future studies on antipsychotics. Future research is warranted to evaluate these preliminary results.
Water budgeting in conservation agriculture-based sub-surface drip irrigation in tropical maize using HYDRUS-2D in South Asia
Authors: Patra Kiranmoy , Parihar C. M. , Nayak H. S. , Rana Biswajit , Singh V. K. , Jat S. L. , Panwar Sanjeev , Parihar M. D. , Singh L. K. , Sidhu H. S. , Gerard B. , Jat M. L.
Published: August 2021

In water scarce regions of South Asia, diversification of rice with maize is being advocated towards sustainability of cereal-based cropping systems. Adoption of innovative agronomic management practices, i.e., conservation agriculture (CA) and sub-surface drip irrigation (SSDI) are considered as key strategies for much needed interventions to address the challenges of water scarcity under projected climate change. Benefits from CA and SSDI concerning water economy are well-established, however, information about their complementarity and water budgeting in cereal-based systems are lacking. A field study was conducted with process-based model (HYDRUS-2D) to understand water transport, root water uptake and components of soil water balance in maize grown in rotation with wheat after five years of continuous adoption of conservation agriculture. In this study, altogether eight treatments comprising of 6 CA+ treatments (CA coupled with SSDI); permanent beds using sub-surface drip (PB-SSD) with (WR) and without (WOR) crop residue at different N rates, 0, 120 and 150 kg N ha−1 were compared with CA (PB using furrow irrigation-FI with crop residue-120 kg N ha−1) and conventional tillage practices (CT) (CT using FI without crop residue-120 kg N ha−1). Results showed that the model could simulate the daily changes in profile soil water content with reasonable accuracy in all the treatments. Simulated soil water balance indicated higher cumulative root water uptake (CRWU), lower cumulative evaporation (CE) and higher soil water retention in CA+ (PB-SSD+ crop residue at 150 and 120 kg N ha−1) than CA and CT plots. Hydrus-2D model efficiency > 0, RMSE between 0.009–0.026 and R2 value between 0.80–0.92 at P < 0.01 indicates that the model is performing efficiently. The mean evaporation from CA+ treatments was 10 and 36% less than CA and CT treatments, respectively. On average, CRWU under CA+ treatments were 14–48% higher than FI treatments. The mean cumulative deep drainage in CA+ plots was 80–100 mm less than CA and CT plots. In CA+ based plots significantly higher biomass production and radiation use efficiency were observed with reduced water use than CA and CT. Therefore, the study justifies the water-saving nature of CA+, while maintaining higher productivity and meeting the transpiration demand of crops and halting unnecessary evaporation and deep drainage losses.
Cx43 mediates changes in myofibroblast contraction and collagen release in human amniotic membrane defects after trauma
Authors: Costa Eleni , Okesola Babatunde O. , Thrasivoulou Christopher , Becker David L. , Deprest Jan A. , David Anna L. , Chowdhury Tina T.
Published: August 2021

The wound healing capacity of the fetal membranes after spontaneous or iatrogenic membrane rupture is unclear. We examined the healing mechanisms in amniotic membrane (AM) defects after trauma. Traumatised human AM defects were cultured for 4 days. Markers for nuclear (DAPI), cell type (vimentin, αSMA) and healing (Cx43, TGFβ1, collagen) were examined by immunofluorescence (IMF) confocal microscopy, Second Harmonic Generation (SHG) imaging and RT-qPCR. After trauma, AMCs and myofibroblasts migrated to the AM wound edge. Within four days, αSMA expressing myofibroblasts showed abundant Cx43 localized in the cytoplasmic processes. The highly contractile spindle-shaped myofibroblasts were present in the defect site and released collagen. In contrast, AMCs expressed vimentin and formed Cx43 plaques between cells found in the outer edges of the wound. Whilst AMCs were absent in the defect site, αSMA expressing myofibroblasts continued to elongate and polarize the collagen fibres. Both TGFβ1 and Cx43 gene expression were significantly increased after trauma. Cx43 has differential effects on AM cell populations that increase cellularity, contraction and potentially migration to the wound edge resulting in collagen polarisation in the AM defect site. Establishing how Cx43 regulates AM cell function could be an approach to repair defects in the membranes after trauma.
Comparative study of efficiency and characteristics of FMT and DRT installed in human cadavers for round-window stimulation
Authors: Shin Dong Ho , Kim Jong Hoon , Gottlieb Peter , Vaisbuch Yona , Puria Sunil , Cho Jin-Ho , Seong Ki Woong
Published: August 2021

Acoustic hearing aids generate amplified sound in the ear canal, and they are the standard of care for patients with mild to moderate sensorineural hearing loss. However, because of their limited frequency bandwidth, gain, and feedback, there is substantial room for improvement. Active middle ear implants, which directly vibrate the middle ear and cochlea, are an alternative approach to conventional acoustic hearing aids. They provide an opportunity to improve sound quality and speech understanding with amplification rehabilitation. For floating-mass type and direct-rod type (DRT) middle ear transducers, a differential floating-mass transducer (DFMT) and a tri-coil bellows transducer (TCBT), respectively, were fabricated to measure the output characteristics in four human temporal bones. Both were fabricated to have similar output forces per unit input and were placed in four human temporal bones to measure their output performances. The TCBT resulted in higher output than did the DFMT throughout the audible frequency range, and the output was more prominent at lower frequency ranges. In this study, we showed that DRT was a more effective method for round window stimulation. Because of its frequency characteristics and vibration efficiency, this implantation method can be utilized as a driving solution for middle ear implants.
Improvement of quality of life and symptom burden after robot-assisted radical prostatectomy in patients with moderate to severe LUTS
Authors: Leyh-Bannurah Sami-Ramzi , Wagner Christian , Schuette Andreas , Liakos Nikolaos , Karagiotis Theodoros , Mendrek Mikolaj , Rachubinski Pawel , Urbanova Katarina , Oelke Matthias , Witt Jorn H.
Published: August 2021

The aim of this study was to assess clinically meaningful differences of preoperative lower urinary tract symptoms (LUTS) and quality of life (QoL) before and after robot-assisted radical prostatectomy (RARP). Therefore we identified 5506 RARP patients from 2007 to 2018 with completed International Prostate Symptom Score (IPSS) and -QoL questionnaires before and 12 months after RARP in our institution. Marked clinically important difference (MCID) was defined by using the strictest IPSS-difference of − 8 points. Multivariable logistic regression analyses (LRM) aimed to predict ∆IPSS ≤ − 8 and were restricted to RARP patients with preoperatively moderate (IPSS 8–19) vs. severe (IPSS 20–35) LUTS burden (n = 2305). Preoperative LUTS was categorized as moderate and severe in 37% (n = 2014) and 5.3% of the complete cohort (n = 291), respectively. Here, a postoperative ∆IPSS ≤ − 8, was reported in 38% vs. 90%. In LRM, younger age (OR 0.98, 95%CI 0.97–0.99; p = 0.007), lower BMI (OR 0.94, 95%CI 0.92–0.97; p < 0.001), higher preoperative LUTS burden (severe vs. moderate [REF.] OR 15.6, 95%CI 10.4–23.4; p < 0.001), greater prostate specimen weight (per 10 g, OR 1.12, 95%CI 1.07–1.16; p < 0.001) and the event of urinary continence recovery (OR 1.66 95%CI 1.25–2.21; p < 0.001) were independent predictors of a marked LUTS improvement after RARP. Less rigorous IPSS-difference of − 5 points yielded identical predictors. To sum up, in substantial proportions of patients with preoperative moderate or severe LUTS a marked improvement of LUTS and QoL can be expected at 12 months after RARP. LRM revealed greatest benefit in those patients with preoperatively greatest LUTS burden, prostate enlargement, lower BMI, younger age and the event of urinary continence recovery.
Identification and antimicrobial susceptibility profiles of Nocardia species clinically isolated in Japan
Authors: Toyokawa Masahiro , Ohana Noboru , Ueda Akiko , Imai Minako , Tanno Daiki , Honda Mutsuko , Takano Yukiko , Ohashi Kazutaka , Saito Kyoichi , Shimura Hiroki
Published: August 2021

The aims of the present study were to profile the antimicrobial susceptibility patterns of a diverse range of Nocardia species isolated in Japan, and to determine the ability of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for species/complex identification. Identification of 153 clinical isolates was performed by full-length 16S rRNA gene sequencing as a reference method to evaluate the usefulness of MALDI-TOF MS identification. Antimicrobial susceptibility testing (AST) for 14 antibiotics was performed using the broth microdilution method against 146 of the isolates. Among the total 153 clinical isolates, Nocardia farcinica complex (25%) was the most common species, followed by Nocardia cyriacigeorgica (18%), Nocardia brasiliensis (9%), Nocardia nova (8%), and Nocardia otitidiscaviarum (7%). Among 150 isolates identified to the species/complex level by 16S rRNA gene sequencing, MALDI-TOF MS with the use of a supplemental Nocardia library (JMLD library ver.ML01) correctly identified 97.3% (n = 146) to the species/complex level and 1.3% (n = 2) to the genus level. Among the 146 Nocardia isolates that underwent AST, the susceptibilities were 100% to linezolid, 96% to amikacin, 94% to trimethoprim-sulfamethoxazole, and 76% to imipenem. None of the trimethoprim-sulfamethoxazole-resistant isolates carried either plasmid-mediated sulfonamide-resistant genes (sul1, sul2) or trimethoprim-resistant genes (dfrA).
Identification of a novel inhibitor of liver cancer cell invasion and proliferation through regulation of Akt and Twist1
Authors: Ha Jain , Lee Sewoong , Park Jiyoung , Seo Jihye , Kang Eunjeong , Yoon Haelim , Kim Ba Reum , Lee Hyeon Kyu , Ryu Seong Eon , Cho Sayeon
Published: August 2021

When primary cancer faces limited oxygen and nutrient supply, it undergoes an epithelial–mesenchymal transition, which increases cancer cell motility and invasiveness. The migratory and invasive cancer cells often exert aggressive cancer development or even cancer metastasis. In this study, we investigated a novel compound, 3-acetyl-5,8-dichloro-2-((2,4-dichlorophenyl)amino)quinolin-4(1H)-one (ADQ), that showed significant suppression of wound healing and cellular invasion. This compound also inhibited anchorage-independent cell growth, multicellular tumor spheroid survival/invasion, and metalloprotease activities. The anti-proliferative effects of ADQ were mediated by inhibition of the Akt pathway. In addition, ADQ reduced the expression of mesenchymal markers of cancer cells, which was associated with the suppressed expression of Twist1. In conclusion, ADQ successfully suppressed carcinogenic activity by inhibiting the Akt signaling pathway and Twist1, which suggests that ADQ may be an efficient candidate for cancer drug development.
Aggregation induced emission based active conjugated imidazole luminogens for visualization of latent fingerprints and multiple anticounterfeiting applications
Authors: Ravindra M. K. , Darshan G. P. , Lavanya D. R. , Mahadevan K. M. , Premkumar H. B. , Sharma S. C. , Adarsha H. , Nagabhushana H.
Published: August 2021

Aggregation-induced emission based organic heterocyclic luminogens bearing conjugated electronic structures showed much attention due to its excellent fluorescence in aggregation state. In this communication, a novel conjugated blue light emitting imidazole molecule is synthesized by one pot multicomponent reaction route is reported for the first time. The prepared molecule exhibits a strong fluorescence in aggregation state with exceptional properties, such as high purity, inexpensive, eco-friendly, large scale production, high photostability, etc. By considering these advantages, a new fluorescence based platform has been setup for in-situ visualization of latent fingerprints and its preservation by spray method followed by Poly(vinyl alcohol) masking. A clear and well defined fluorescence fingerprint images are noticed on variety of surfaces by revealing level 1–3 ridge features upon ultraviolet 365 nm light exposure. The dual nature of binding specificity as well as excellent fluorescence properties permits the visualization of latent fingerprints for longer durations (up to 365 days) with superior contrast, high sensitivity, efficiency, selectivity and minimal background hindrance. We further fabricated unclonable invisible security ink for various printing modes on valuable goods for protection against forging. The developed labels are displaying uniform distribution of ink and exceptional stability under various atmospheric environments. The development of long preservative information using aggregation-induced emission based luminogen opens up a new avenue in advanced forensic and data security applications.