bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrical polarity-dependent gating and a unique subconductance of RyR2 induced by S-adenosyl methionine via the ATP binding site
Authors: Kampfer Angela J , Balog Edward M
Published: September 2021

S-Adenosyl-L-methionine (SAM) was used to probe the functional effects exerted via the cardiac RyR isoform (RyR2) adenine nucleotide binding site. Single channel experiments revealed that SAM applied to the cytoplasmic face of RyR2 had complex voltage dependent effects on channel gating and conductance. At positive transmembrane holding potentials, SAM caused a striking reduction in channel openings and a reduced channel conductance. In contrast, at negative potentials, SAM promoted a clearly resolved subconductance state. At membrane potentials between −75 and −25 mV, the open probability of the subconductance state was independent of voltage. ATP, but not the non-adenosine-based ryanodine receptor (RyR) activator 4-chloro-m-cresol, interfered with the effects of SAM at both negative and positive potentials. This suggests that ATP and SAM interact with a common binding site. Molecular docking showed SAM bound to the adenine nucleotide binding site and formed a hydrogen bond to Glu4886 in the C-terminal end of the S6 alpha helix. In this configuration, SAM may alter the conformation of the RyR2 ion conduction pathway. This work provides novel insight into potential functional outcomes of ligand binding to the RyR adenine nucleotide binding site.
Lemur tail kinase 1 (LMTK1) regulates the endosomal localization of β-secretase BACE1
Authors: Komaki Keisuke , Takano Tetsuya , Sato Yutaka , Asada Akiko , Ikeda Shikito , Yamada Kaoru , Wei Ran , Huo Anni , Fukuchi Aoi , Saito Taro , Ando Kanae , Murayama Shigeo , Araki Wataru , Kametani Fuyuki , Hasegawa Masato , Iwatsubo Takeshi , Tomomura Mineko , Fukuda Mitsunori , Hisanaga Shin-ichi
Published: September 2021

Lemur tail kinase 1 (LMTK1), previously called apoptosis-associated tyrosine kinase (AATYK), is an endosomal Ser/Thr kinase. We recently reported that LMTK1 regulates axon outgrowth, dendrite arborization and spine formation via Rab11-mediated vesicle transport. Rab11, a small GTPase regulating recycling endosome trafficking, is shown to be associated with late-onset Alzheimer’s disease (LOAD). In fact, genome-wide association studies identified many proteins regulating vesicle transport as risk factors for LOAD. Furthermore, LMTK1 has been reported to be a risk factor for frontotemporal dementia. Then, we hypothesized that LMTK1 contributes to AD development through vesicle transport and examined the effect of LMTK1 on the cellular localization of AD-related proteins, amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1). The β-cleavage of APP by BACE1 is the initial and rate-limiting step in Aβ generation. We found that LMTK1 accumulated BACE1, but not APP, to the perinuclear endosomal compartment, whereas the kinase-negative(kn) mutant of LMTK1A did not. The β-C-terminal fragment was prone to increase under overexpression of LMTK1A kn. Moreover, the expression level of LMTK1A was reduced in AD brains. These results suggest the possibility that LMTK1 is involved in AD development through the regulation of the proper endosomal localization of BACE1.
Relative growth ofEurynolambrus australisH. Milne Edwards & Lucas, 1841 (Decapoda: Brachyura: Majidae): use of epibionts to interpret moulting patterns and maturation
Authors: McLay Colin L , Woods Chris M C
Published: September 2021

Males of the brachyuran crab Eurynolambrus australisH. Milne Edwards & Lucas, 1841 have three phases of growth recognizable by breaks in relative growth in the chelipeds in relation to carapace width. Females have two growth phases marked by increased abdomen width and pleopod length at sexual maturity. The difference between the maximum size of E. australis and the maximum size of the preceding phase in both sexes is large and may not be achieved in a single moult, suggesting that post-pubertal moulting could occur. Relative growth could involve both growth- and size-allometry. This is supported to some extent by the distribution of spirorbid tube worms. The lack of correlation between number and size of tube worms and crab carapace width suggests that epibionts do not accumulate over time. Crabs without attached tube worms (suggesting recent moulting) occur in all growth phases, but some of these may have recently moulted. Some large specimens, however, do carry a load of epibionts large enough to suggest terminal moulting. The possibility of post-pubertal moulting remains an open question.
Technical Features of Asynchronous and Synchronous Community Platforms and their Effects on Community Cohesion: A Comparative Study of Forum-based and Chat-based Online Mental Health Communities
Authors: Li Han , Kraut Robert E , Zhu Haiyi
Published: September 2021

Across online support communities, community cohesion varies by platform and can impact the self-disclosure of members and their exchanges of social support. Through a comparative study of forum and chat-based mental health communities, this research examines how technical features of both platforms influence community cohesion by affecting communication patterns among members, including evenness of communication, speed of communication, and number of participants. This study collected four weeks of data from 20 forum-based and 20 chat-based mental health communities in mainland China. Multilevel mediation analyses show that chat-based communities were more cohesive with higher member retention, network connectedness, and language conformity. Chat-based platforms facilitated faster communication and greater evenness of receiving messages among participants which in turn fostered community cohesion.
De novo RNA-Seq and Annotation of Sesquiterpenoid and Ecdysteroid Biosynthesis Genes and MicroRNAs in a Spider MiteEotetranychus kankitus
Authors: Li Gang , Zhang Jun , Liu Xun-Yan , Niu Jinzhi , Wang Jin-Jun
Published: September 2021

Eotetranychus kankitus is an important mite pest in citrus, but molecular data on the developmental processes of E. kankitus are lacking. The different development stages mix of E. kankitus was used to sequence for transcriptome and small RNAs to identify genes and predict miRNAs associated with sesquiterpenoid and ecdysteroid biosynthesis and signaling pathways. More than 36 million clean reads were assembled and 67,927 unigenes were generated. Of the unigenes, 19,300 were successfully annotated through annotation databases NR, SwissProt, COG, GO, KEGG, PFAM, and KOG. The transcripts were involved in sesquiterpenoid biosynthesis (11 genes) and ecdysteroid biosynthesis and signaling pathway (13 genes). Another, small RNA library was obtained and 31 conserved miRNAs were identified. Five most abundant miRNAs were Ek-miR-5735, Ek-miR-1, Ek-miR-263a, Ek-miR-184, and Ek-miR-8. The target genes related to sesquiterpenoid and ecdysteroid showed that 10 of the conserved miRNAs could potentially target the sesquiterpenoid and ecdysteroid pathway according to four-prediction software, sRNAT, miRanda, RNAhybrid, and Risearch2. Thus, the results of this study will provide bioinformatics information for further molecular studies of E. kankitus which may facilitate improved pest control strategies.
Comparative Capture ofTrogoderma granarium(Coleoptera: Dermestidae) andT. variabilein Floor Traps in Single Species Releases With Previously Captured Conspecific or Heterospecific Individuals
Authors: Gourgouta Marina , Baliota Georgia V , Morrison William R , Domingue Michael J , Athanassiou Christos G
Published: September 2021

In the present work, a series of tests were performed to examine the effect of previously captured adults in floor traps, on the captures of Τrogoderma granarium Everts and T. variabile Ballion, in single species releases. In a first series of tests, a single trap with kairomone oil and dead adults of single or both species was placed in a plastic container, which was used as the release arena. Subsequently, adults of both species were separately released in the arena, and the adult capture was recorded 24 h later. In a second series of trials, two traps were placed in the same arena, containing different numbers of prior seeded adults, and adult capture was similarly recorded. For T. granarium, in all cases, more adults were found inside the trap than under the trap or on the trap walls. In contrast, for T. variabile, most adults were recorded on the trap walls. In general, T. variabile had a stronger response to the traps than T. granarium. This work illustrates that previous captures of either species do not negatively affect captures of new live adults and may tend to enhance captures in some cases. This has important implications for the use of traps for the biosureveillance of these two important dermestid species.
Impacts of COVID-19 on Canadian Beekeeping: Survey Results and a Profitability Analysis
Authors: Bixby Miriam E F , Polinsky Matthew , Scarlett Rod , Higo Heather , Common Julia , Hoover Shelley E , Foster Leonard J , Zayed Amro , Cunningham Morgan , Guarna M Marta
Published: September 2021

To gauge the impact of COVID-19 on the Canadian beekeeping sector, we conducted a survey of over 200 beekeepers in the fall of 2020. Our survey results show Canadian beekeepers faced two major challenges: 1) disrupted importation of honey bees (Hymenoptera: Apidae) (queen and bulk bees) that maintain populations; and 2) disrupted arrival of temporary foreign workers (TFWs). Disruptions in the arrival of bees and labor resulted in fewer colonies and less colony management, culminating in higher costs and lower productivity. Using the survey data, we develop a profitability analysis to estimate the impact of these disruptions on colony profit. Our results suggest that a disruption in either foreign worker or bee arrival allows beekeepers to compensate and while colony profits are lower, they remain positive. When both honey bee and foreign workers arrivals are disrupted for a beekeeper, even when the beekeeper experiences less significant colony health and cost impacts, a colony with a single pollination contract is no longer profitable, and a colony with two pollination contracts has significantly reduced profitability. As COVID-19 disruptions from 2020 and into 2021 become more significant to long-term colony health and more costly to a beekeeping operation, economic losses could threaten the industry’s viability as well as the sustainability of pollination-dependent crop sectors across the country. The economic and agricultural impacts from the COVID-19 pandemic have exposed a vulnerability within Canada’s beekeeping industry stemming from its dependency on imported labor and bees. Travel disruptions and border closures pose an ongoing threat to Canadian agriculture and apiculture in 2021 and highlight the need for Canada’s beekeeping industry to strengthen domestic supply chains to minimize future risks.
Recent Youth-Led and Rights-Based Climate Change Litigation in Canada: Reconciling Justiciability, Charter Claims and Procedural Choices
Authors: Cameron Camille , Weyman Riley
Published: September 2021

This analysis examines three recent and ongoing Canadian climate change litigation cases: ENvironnement JEUnesse c Procureur général du Canada, La Rose v Canada and Mathur v Ontario. Consistent with international climate change litigation trends, these cases are youth-led and rights-based and they advance claims for present and future generations. They present apparently conflicting judicial views on the justiciability of climate change claims and on the use of the Canadian Charter of Rights and Freedoms to advance such claims. We examine these issues. We also analyse the insights the cases offer into the connections between litigants’ procedural choices and early success, either in withstanding a motion to strike, or in obtaining court authorisation to proceed by way of class action.
A Path Toward Sustainable Development Along the Belt and Road
Authors: Lorenzo Johanna Aleria P
Published: September 2021

The article scrutinizes the purported synergies between the Belt and Road Initiative (BRI) and the United Nations (UN) 2030 Agenda for Sustainable Development by evaluating the transnational legal order regulating environmental and social impacts of BRI economic activities. From the perspective of international law and sustainable development, three problematic features are identified. First, the bilateral character of agreements between China and BRI-participating States produces fragmented and variable sustainability standards. Second, the informality of State-to-State arrangements often hinder parliamentary and public deliberation in host States. Lastly, BRI decision-making processes restrict non-State actor participation and thereby disregard the very communities harmed by infrastructure projects.

To clear its path to sustainability and bring it closer to the UN agenda, BRI’s legal and regulatory framework must become multilateral, transparent, and inclusive. The proposal entails bringing to fore the relevant background international legal norms, especially on environmental, labor, and human rights protection, and consolidating them in a framework agreement that sets minimum sustainability safeguards for transboundary economic activities like foreign-funded infrastructure projects. Reforms are imperative because the subject matter of the Initiative requires international cooperation and involves not only the economic, environmental, and social concerns of two States but also implicates the goals and interests of the international community.
Special and Differential Treatment Under the World Trade Organization: A Legal Typology
Authors: Hegde Vineet , Wouters Jan
Published: September 2021

The World Trade Organization (WTO) Secretariat has developed a typology to categorize various Special and Differential Treatment (SDT) provisions in WTO agreements. This typology is based on the aims and intended effects of such provisions. However, it fails to highlight their legal effects. A legal typology is particularly important because the developed Members note that the developing Members have taken advantage of the system through this treatment and intend to abolish SDT for certain advanced developing Members, whereas developing Members have called SDT a non-negotiable and treaty-embedded ‘right’. Moreover, developing Members have called for an effective operation of SDT provisions. These claims give rise to two questions: (i) do SDT provisions provide legal rights to developing Members? (ii) if so, what provisions confer differential treatment rights? In this article we devise a legal typology for SDT by distinguishing the provisions that confer rights and duties from provisions that constitute merely political commitments. We also consider the types, and the scope, of rights and duties that result in a special or differential treatment. Our results, inter alia, highlight that only 21% of SDT provisions oblige developed Members to provide differential treatment to developing Members. The rest are mere best-effort endeavors and political commitments. We provide our observations for this design feature and explain the underlying rationale of developing Members’ position on SDT. Lastly, we provide a blueprint to resolve the North–South deadlock.
Influence of European Beech (Fagales: Fagaceae) Rot Hole Habitat Characteristics on Invertebrate Community Structure and Diversity
Authors: Cuff Jordan P , Windsor Fredric M , Gilmartin Emma C , Boddy Lynne , Jones T Hefin
Published: September 2021

Hollows of veteran trees (i.e., rot holes) provide habitat for many rare and threatened saproxylic invertebrates. Rot holes are highly heterogeneous, particularly in terms of substrate and microclimate conditions. There is, however, a dearth of information regarding the differences in biological communities inhabiting rot holes with different environmental conditions. Invertebrates were sampled from European beech (Fagus sylvatica) rot holes in Windsor, Savernake, and Epping Forests (United Kingdom). For each rot hole, physical and environmental conditions were measured, including tree diameter, rot hole dimensions, rot hole height, substrate density, water content, and water potential. These parameters were used to assess the influence of environmental conditions and habitat characteristics on invertebrate communities. Rot hole invertebrate communities were extremely diverse, containing both woodland generalist and saproxylic specialist taxa. Large variation in community structure was observed between rot holes and across woodlands; all sites supported threatened and endangered taxa. Environmental conditions in rot holes were highly variable within and between woodland sites, and communities were predominantly structured by these environmental conditions. In particular, turnover between invertebrate communities was linked to high β-diversity. The linked heterogeneity of environmental conditions and invertebrate communities in rot holes suggests that management of deadwood habitats in woodlands should strive to generate environmental heterogeneity to promote invertebrate diversity. Additional research is required to define how management and conservation activities can further promote enhanced biodiversity across rot holes.
Seasonal variation in home range size of evening bats (Nycticeius humeralis) in an urban environment
Authors: Hall Ellen M , Bennett Victoria J
Published: September 2021

Despite the negative impacts of urbanization on bats, green spaces in urban environments, such as parks, cemeteries, and golf courses, have the potential to provide resources necessary for these animals. Water resources in these areas include natural or semi-natural ponds, streams, and drainage ditches. Such water resources, however, are frequently ephemeral when subject to prolonged periods of high temperatures and low precipitation. We hypothesized that home ranges of evening bats (Nycticeius humeralis) would increase in size or shift from urban green spaces into surrounding neighborhoods to access alternative resources, such as residential swimming pools, when water resources in green spaces are scarce. To explore whether seasonal variations in bat home ranges occurred, we radio-tracked resident evening bats in a local park system during their summer activity period 2017–2019 in Fort Worth, Texas, USA. We used Local Convex Hulls created by associating point locations with their nearest neighbor to estimate home range size, location, and the percentage area that fell within the surrounding neighborhood. We compared these variables to temperature and precipitation using various regression models. We successfully tracked 30 bats over the 3-year period and found a positive correlation between home range size and temperature. Home range sizes increased 6-fold when temperatures exceeded 30°C. Our study indicates the importance of urban neighborhoods surrounding green spaces in providing alternative resources, such as water, for bats. If managed appropriately, these urban areas have the potential to act as oases for bat populations.
Climatic dissimilarity associated with phylogenetic breaks
Authors: Cab-Sulub Leticia , Álvarez-Castañeda Sergio Ticul
Published: September 2021

Shared phylogenetic breaks often are associated with clear geographic barriers but some common phylogeographic breaks may lack obvious underlying mechanisms. A phylogenetic break involving multiple taxa was found in the Baja California Peninsula that was associated with a past sea barrier. However, geological evidence is lacking for this barrier’s past existence, and despite its current absence, the genetic breaks have persisted. This work explores the relationships between the current climatic niches for matrilineages of 11 vertebrate species as a possible explanation for the current geographic partitioning of matrilineages. We evaluated the climatic occupancy of each matrilineage through ecological niche models, background similarity, niche overlap, niche divergence, and Mantel tests. We found disparities in the climatic occupancy between north and south matrilineage of each taxon. Northern matrilineages are associated with lower temperatures and winter rains, while southern matrilineages reside in areas with higher temperatures and summer rains.
Factors predicting habitat use by leopards in human-altered landscapes
Authors: McManus Jeannine , Marshal Jason P , Keith Mark , Tshabalala Thulani , Smuts Bool , Treves Adrian
Published: September 2021

Transformed landscapes caused by human activity leave remnant patches of natural habitat for wildlife. The persistence of species in the face of such transformation depends on individuals’ ability to adapt to novel habitat, and to secure resources and reproductive opportunities despite habitat alterations. The leopard, Panthera pardus, is the last free-roaming top carnivore in South Africa whose high trophic status and wide-ranging movements make them an effective focal species in conservation planning. Using location data from leopards, we investigated key correlates of habitat selection in human-altered landscapes at two spatial scales. We compared sex-related differences and predicted how conspecific home range locations influenced habitat selection. Leopards avoided human-altered landscapes more strongly at the large spatial scale, where both sexes selected core areas near formally protected areas. Conspecific home range locations had a strong positive effect at both spatial scales for males, while for females, conspecifics explained fine-scale habitat selection by selecting areas near neighboring females. Spatial scale, sex-related differences, and conspecific location play roles in habitat selection for solitary felids and have implications for conservation planning and management. Excluding these factors may result in inappropriate species management policies.
How Should the Precautionary Principle Apply to Pregnant Women in Clinical Research?
Authors: van der Zande Indira S E , van der Graaf Rieke , Oudijk Martijin A , van Delden Johannes J M
Published: September 2021

The precautionary principle is often invoked in relation to pregnant women and may be one of the underlying reasons for their continuous underrepresentation in clinical research. The principle is appealing, because potential fetal harm as a result of research participation is considered to be serious and irreversible. In our paper, we explore through conceptual analysis whether and if so how the precautionary principle should apply to pregnant women. We argue that the principle is a decision-making strategy underlying risk-benefit decisions in clinical research, which can be applied to pregnant women. However, the current application is a strong one, leading to the promotion of absolute exclusion or, less often, absolute inclusion of pregnant women. In order to change this paralyzing situation, a shift toward weak precautionary thinking is necessary. Instead of automatic extreme precaution, a balance will be found between harms and potential benefits of including pregnant women in clinical research.
Theory Without Theories: Well-Being, Ethics, and Medicine
Authors: Hawkins Jennifer
Published: September 2021

Medical ethics would be better if people were taught to think more clearly about well-being or (what I take to be the same thing) the concept of what is good for a person. Yet for a variety of reasons, bioethicists have generally paid little attention to this concept. Here, I argue, first, that focusing on general theories of welfare is not useful for practical medical ethics. I argue, second, for what I call the “theory-without-theories approach” to welfare in practical contexts. The first element of this approach is a focus on examining important and relatively uncontroversial constituents of welfare as opposed to general theories. The second key element is a framework for thinking about choice in relation to welfare, a framework I refer to as “the mild objectivity framework.” I conclude with illustrations of the way in which the “theory without theories approach” can improve thinking in medicine.
Cancer Incidence in World Trade Center Rescue and Recovery Workers: 14 Years of Follow-Up
Authors: Li Jiehui , Yung Janette , Qiao Baozhen , Takemoto Erin , Goldfarb David G , Zeig-Owens Rachel , Cone James E , Brackbill Robert M , Farfel Mark R , Kahn Amy R , Schymura Maria J , Shapiro Moshe Z , Dasaro Christopher R , Todd Andrew C , Kristjansson Dana , Prezant David J , Boffetta Paolo , Hall Charles B
Published: September 2021

Background

Statistically significantly increased cancer incidence has been reported from 3 cohorts of World Trade Center (WTC) disaster rescue and recovery workers. We pooled data across these cohorts to address ongoing public concerns regarding cancer risk 14 years after WTC exposure.

Methods

From a combined deduplicated cohort of 69 102 WTC rescue and recovery workers, a sample of 57 402 workers enrolled before 2009 and followed through 2015 was studied. Invasive cancers diagnosed in 2002-2015 were identified from 13 state cancer registries. Standardized incidence ratios (SIRs) were used to assess cancer incidence. Adjusted hazard ratios (aHRs) were estimated from Cox regression to examine associations between WTC exposures and cancer risk.

Results

Of the 3611 incident cancers identified, 3236 were reported as first-time primary (FP) cancers, with an accumulated 649 724 and 624 620 person-years of follow-up, respectively. Incidence for combined FP cancers was below expectation (SIR = 0.96, 95% confidence interval [CI] = 0.93 to 0.99). Statistically significantly elevated SIRs were observed for melanoma-skin (SIR = 1.43, 95% CI = 1.24 to 1.64), prostate (SIR = 1.19, 95% CI = 1.11 to 1.26), thyroid (SIR = 1.81, 95% CI = 1.57 to 2.09), and tonsil (SIR = 1.40, 95% CI = 1.00 to 1.91) cancer. Those arriving on September 11 had statistically significantly higher aHRs than those arriving after September 17, 2001, for prostate (aHR = 1.61, 95% CI = 1.33 to 1.95) and thyroid (aHR = 1.77, 95% CI = 1.11 to 2.81) cancers, with a statistically significant exposure-response trend for both.

Conclusions

In the largest cohort of 9/11 rescue and recovery workers ever studied, overall cancer incidence was lower than expected, and intensity of WTC exposure was associated with increased risk for specific cancer sites, demonstrating the value of long-term follow-up studies after environmental disasters.
Impact of Blinding on Patient-Reported Outcome Differences Between Treatment Arms in Cancer Randomized Controlled Trials
Authors: Efficace Fabio , Cella David , Aaronson Neil K , Calvert Melanie , Cottone Francesco , Di Maio Massimo , Perrone Francesco , Sparano Francesco , Gamper Eva-Maria , Vignetti Marco , Giesinger Johannes M
Published: September 2021

Some concerns have been raised about potential bias in patient-reported outcome (PRO) results from open-label cancer randomized controlled trials (RCTs). We investigated if open-label trials favor the experimental treatment over the standard treatment more frequently than blinded trials. We also examined if the effect of blinding differs for distal vs more proximal PROs. We assessed 538 RCTs with a PRO endpoint conducted in the most prevalent cancers, of which 366 (68.0%) were open-label, 148 (27.5%) were blinded, and 24 (4.5%) were categorized as unclear. In our multivariable logistic regression model, we did not observe a statistically significant association of the independent variable treatment concealment (blinded vs open-label) on the dependent variable measuring the proportion of trials favoring the experimental treatment (adjusted odds ratio = 1.19, 95% confidence interval = 0.79 to 1.79; 2-sided P = .40). This was also the case when comparing distal and proximal PROs. Our findings provide novel evidence-based data that support the validity of PRO results from open-label cancer RCTs.
SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1–Negative Lung Adenocarcinomas
Authors: Tanaka Ichidai , Dayde Delphine , Tai Mei Chee , Mori Haruki , Solis Luisa M , Tripathi Satyendra C , Fahrmann Johannes F , Unver Nese , Parhy Gargy , Jain Rekha , Parra Edwin R , Murakami Yoshiko , Aguilar-Bonavides Clemente , Mino Barbara , Celiktas Muge , Dhillon Dilsher , Casabar Julian Phillip , Nakatochi Masahiro , Stingo Francesco , Baladandayuthapani Veera , Wang Hong , Katayama Hiroyuki , Dennison Jennifer B , Lorenzi Philip L , Do Kim-Anh , Fujimoto Junya , Behrens Carmen , Ostrin Edwin J , Rodriguez-Canales Jaime , Hase Tetsunari , Fukui Takayuki , Kajino Taisuke , Kato Seiichi , Yatabe Yasushi , Hosoda Waki , Kawaguchi Koji , Yokoi Kohei , Chen-Yoshikawa Toyofumi F , Hasegawa Yoshinori , Gazdar Adi F , Wistuba Ignacio I , Hanash Samir , Taguchi Ayumu
Published: September 2021

Background

Approximately 20% of lung adenocarcinoma (LUAD) is negative for the lineage-specific oncogene Thyroid transcription factor 1 (TTF-1) and exhibits worse clinical outcome with a low frequency of actionable genomic alterations. To identify molecular features associated with TTF-1–negative LUAD, we compared the transcriptomic and proteomic profiles of LUAD cell lines. SRGN , a chondroitin sulfate proteoglycan Serglycin, was identified as a markedly overexpressed gene in TTF-1–negative LUAD. We therefore investigated the roles and regulation of SRGN in TTF-1–negative LUAD.

Methods

Proteomic and metabolomic analyses of 41 LUAD cell lines were done using mass spectrometry. The function of SRGN was investigated in 3 TTF-1–negative and 4 TTF-1–positive LUAD cell lines and in a syngeneic mouse model (n = 5 to 8 mice per group). Expression of SRGN was evaluated in 94 and 105 surgically resected LUAD tumor specimens using immunohistochemistry. All statistical tests were 2-sided.

Results

SRGN was markedly overexpressed at mRNA and protein levels in TTF-1–negative LUAD cell lines (P < .001 for both mRNA and protein levels). Expression of SRGN in LUAD tumor tissue was associated with poor outcome (hazard ratio = 4.22, 95% confidence interval = 1.12 to 15.86, likelihood ratio test, P = .03), and with higher expression of Programmed cell death 1 ligand 1 (PD-L1) in tumor cells and higher infiltration of Programmed cell death protein 1–positive lymphocytes. SRGN regulated expression of PD-L1 as well as proinflammatory cytokines, including Interleukin-6, Interleukin-8, and C-X-C motif chemokine 1 in LUAD cell lines; increased migratory and invasive properties of LUAD cells and fibroblasts; and enhanced angiogenesis. SRGN was induced by DNA demethylation resulting from Nicotinamide N-methyltransferase–mediated impairment of methionine metabolism.

Conclusions

Our findings suggest that SRGN plays a pivotal role in tumor–stromal interaction and reprogramming into an aggressive and immunosuppressive tumor microenvironment in TTF-1–negative LUAD.
Challenges for Clinical Cannabis and Cannabinoid Research in the United States
Authors: Cooper Ziva D , Abrams Donald I , Gust Steven , Salicrup Alejandro , Throckmorton Douglas C
Published: September 2021

Significant changes have occurred in the policy landscape surrounding cannabis legalization, production, and use around the globe and across the United States. With widespread availability of novel cannabis and cannabis-based products, there is an urgent need to understand their safety and effectiveness for medical indications. Three primary barriers contribute to the difficulty in initiating research geared toward answering the most pressing public health questions: the US regulatory status of cannabis and cannabinoids, sources for cannabis and cannabinoid study medications, and limited funding and resources to support studies. Despite these hurdles, research is rapidly increasing, and recent changes in the United States have paved the way for exciting new work. Here, challenges and barriers to cannabis and cannabinoid research are described from the perspectives of the National Institute on Drug Abuse, National Institutes of Health; the US Food and Drug Administration; and 2 clinical researchers. Barriers specifically to studying cannabis, cannabinoids, and cancer are emphasized.
On the Risks of Using the Sequential Product-Level SSNIP Approach to Identify Relevant Antitrust Markets‡
Authors: Padilla Jorge , Piccolo Salvatore , Sääskilahti Pekka
Published: September 2021

In a recent influential paper Coate et al. (2021) have criticized the sequential product-level approach to market definition in merger review. They argue that a simultaneous market-level approach to critical loss is more appropriate than a product-level critical loss analysis, because under certain plausible demand scenarios (nonlinear demand functions) the latter could yield the wrong answer on market definition—i.e., excessively broad or narrow markets. We extend their analysis by showing that a sequential product-level approach actually leads to an excessively narrow market definition when the typical nonlinear demand functions used in merger analysis are employed.
Compromising Aid to Protect International Staff: The Politics of Humanitarian Threat Perception after the Arab Uprisings
Authors: Scott Emily K M
Published: September 2021

Scholars expect operational compromises by humanitarian organizations to follow attacks on aid workers. However, in response to the War in Syria, organizations compromised aid and adopted clandestine, cross-border, remote management, and conflict-actor aligned approaches, which best protected international aid workers. This was despite declining rates of attack against them, relative to their national staff counterparts. This article asks why international aid workers were withdrawn and aid was compromised in the wake of the Arab Uprisings by traditional risk-taking organizations: Médecins Sans Frontières (MSF) and the International Committee of the Red Cross (ICRC). Drawing on political ethnography and interviews with aid workers, I show that shocking violent events, everyday insecurity, and changes in the nature of threat have significant effect on threat perception and explain compromises where rates of attack do not. This paper offers a picture of the micro- and field-level foundations of organizational threat perception and decisions about whose security matters.
Potential therapeutic efficacy of pachymic acid in chronic kidney disease induced in rats: role of Wnt/β-catenin/renin–angiotensin axis
Authors: Younis Nahla N , Mohamed Hoda E , Shaheen Mohamed A , Abdelghafour Asmaa M , Hammad Sally K
Published: September 2021

Objectives

Chronic kidney disease (CKD) is a major public health problem associated with high mortality. The therapeutic effects of pachymic in CKD management and its underlying mechanisms have not been studied. Therefore, we aimed to investigate the possible inhibitory effect of PA on renal Wnt/β-catenin signalling in CKD.

Methods

CKD was induced in rats by doxorubicin (DOX; 3.5 mg/kg i.p., twice weekly for 3 weeks). Rats were treated orally with PA (10 mg/kg/day), LOS (10 mg/kg/day) or their combination (PA + LOS) for 4 weeks starting after the last dose of DOX.

Key findings

DOX-induced renal injury was characterized by high serum cystatin-C, and urine albumin/creatinine ratio, renal content of podocin and klotho were decreased. Tumour necrosis factor-α, interleukin-6, interleukin-1β, Wnt1, active β-catenin/total β-catenin ratio and fibronectin along with mRNA expression of RENIN, ACE and AT1 were increased in renal tissues. Treatment with either PA or LOS ameliorated all DOX-induced changes. The combined treatment was more effective in improving all changes than monotherapy.

Conclusions

These results suggest a new therapeutic benefit of PA in ameliorating CKD in rats through its up-regulatory effect on renal klotho thereby preventing Wnt/β-catenin reactivation and RAS gene expression. PA/LOS combination provided an additional inhibition of Wnt/β-catenin signalling and its downstream targets.
Angiotensin II upregulates endothelin receptors through the adenosine monophosphate-activated protein kinase/sirtuin 1 pathway in vascular smooth muscle cells
Authors: Zhang Xin , Zhang Hongmei , Yang Xinpu , Qin Qiaohong , Sun Xia , Hou Ying , Chen Di , Jia Min , Su Xingli , Chen Yulong
Published: September 2021

Objectives

This study was designed to test our hypothesis that angiotensin II (Ang II) upregulates endothelin (ET) receptors in vascular smooth muscle cells (VSMCs).

Methods

Rat superior mesenteric artery (SMA) without endothelium was cultured in serum-free medium for 24 h in the presence of Ang II with or without metformin or nicotinamide. In vivo, rats were implanted subcutaneously with a mini-osmotic pump infusing AngII (500 ng/kg/min) for 4 weeks. The level of protein expression was determined using Western blotting. The contractile response to ET receptor agonists was studied using sensitive myography. Caudal artery blood pressure (BP) was measured using non-invasive tail-cuff plethysmography.

Key findings

The results showed that Ang II significantly increased ET receptors and decreased phosphorylated-adenosine monophosphate-activated protein kinase α (p-AMPKα) in SMA. Furthermore, metformin significantly inhibited Ang II-upregulated ET receptors and upregulated Ang II-decreased sirtuin 1 (Sirt1). However, this effect was reversed by nicotinamide. Moreover, the in-vivo results showed that metformin not only inhibited Ang II-induced upregulation of ET receptors but also recovered Ang II-decreased p-AMPKα and Sirt1. In addition, metformin significantly inhibited Ang II-elevated BP. However, the effect was reversed by nicotinamide, except for p-AMPKα.

Conclusions

Ang II upregulated ET receptors in VSMCs to elevate BP by inhibiting AMPK, thereby inhibiting Sirt1.
Three-dimensional printed dosage forms based on disease-focussed perspectives
Authors: Gültekin Hazal Ezgi , Tuğcu Demiröz Fatmanur , Tort Serdar , Acartürk Füsun
Published: September 2021

Objectives

Three-dimensional printing (3DP) has gained importance worldwide recently as a novel drug manufacturing technology. 3DP technologies are suitable in the pharmaceutical field because of having the potential in personalized medicine. The aim of this review is to present an overview of the use of 3DP technologies in pharmaceutical area, their working principles and critical process parameters. In addition, this review presents an innovative approach that evaluates the use of 3DP technologies on disease to disease.

Key findings

This review covers the potential use of 3DP technologies in different diseases by evaluating them on a research basis. These diseases can be summarized as cardiovascular, neurological, respiratory, oncological, inflammatory, vaginal, dermatological and other diseases. It has been focussed on manuscripts that published after 2015. Studies on the use of 3DP in each disease group have been systematically reviewed by considering the methods, types of printers used and the prepared dosage forms. Oral formulations (tablets and films), implants, topical systems and vaccines are some of the examples of the mentioned dosage forms.

This review presented a systematic and novel overview of the use of 3DP in the treatment of different clinical disorders.
Fructus arctii: an overview on its traditional uses, pharmacology and phytochemistry
Authors: Li Ying , Wang Qi , Wei Hao-Cheng , Liang Yi-Yu , Niu Feng-Jv , Li Kun-Wei , Zhou Sheng-Jun , Zhou Chang-Zheng
Published: September 2021

Objectives

Fructus arctii (F. arctii) is the dried ripe fruit of Arctium lappa Willd (Asteraceae). It is being used as a traditional medicine in China, Japan, Iran, Europe, Afghanistan, India, etc. for cough, inflammation, clearing the heat, detoxification, cancer and diabetes. This review summarized the botanical description, distribution, ethnopharmacology, bioactive constituents and pharmacological actions of F. arctii including methods to assess its quality. In addition, this review also provides insights into future research directions on F. arctii to further explore its bioactive constituents, mechanism involved in pharmacological activity, and clinical use including the development of new analytical methods for assessing the quality.

Key findings

The comprehensive analysis of the literature revealed that F. arctii contains lignans, volatile oil, flavonoids, sesquiterpenoids, triterpenes, phenolic acids, etc. Experimental studies on various extracts and drug formulations showed that it has antioxidant, antimicrobial, hypoglycaemic, lipid-lowering, anti-inflammatory, analgesic, antiviral, anti-tumour activity, etc.

The pharmacological activity of a few major constituents in F. arctii have been identified. However, there are still need more studies and more new technologies to prove the pharmacological activity and the effective mechanism of the other constituents that undergoing uncertain. Except for the animal experiments, clinical studies should be carried out to provide the evidence for clinical application.
Characteristics of microSilicon diode detector for electron beam dosimetry
Authors: Akino Yuichi , Das Indra J , Fujiwara Masateru , Kaneko Akari , Masutani Takashi , Mizuno Hirokazu , Isohashi Fumiaki , Suzuki Osamu , Seo Yuji , Tamari Keisuke , Ogawa Kazuhiko
Published: September 2021

A microSilicon™ (PTW type 60023), a new unshielded diode detector succeeding Diode E (model 60017, PTW), was characterized for electron beam dosimetry and compared with other detectors. Electron beams generated from a TrueBeam linear accelerator were measured using the microSilicon, Diode E, and microDiamond synthetic single-crystal diamond detector. Positional accuracy of microSilicon was measured by data collected in air and water. The percent depth dose (PDD), off-center ratio (OCR), dose–response linearity, dose rate dependence, and cone factors were evaluated. The PDDs were compared with data measured using a PPC40 plane-parallel ionization chamber. The maximum variations of depth of 50% and 90% of the maximum dose, and practical depth among all detectors and energies were 0.9 mm. The maximum variations of the bremsstrahlung dose among all detectors and energies were within 0.3%. OCR showed good agreement within 1% for the flat and tail regions. The microSilicon detector showed a penumbra width similar to microDiamond, whereas Diode E showed the steepest penumbra shape. All detectors showed good dose–response linearity and stability against the dose rate; only Diode E demonstrated logarithmic dose rate dependency. The cone factor measured with microSilicon was within ±1% for all energies and cone sizes. We demonstrated that the characteristics of microSilicon is suitable for electron beam dosimetry. The microSilicon detector can be a good alternative for electron beam dosimetry in terms of providing an appropriate PDD curve without corrections, high spatial resolution for OCR measurements and cone factors.
Impact of respiratory motion in dosimetric and clinical advantages for adjuvant left-sided breast radiotherapy
Authors: Kuo Chia-Chuan , Chang Chin-Chieh , Cheng Hao-Wen , Lin Jang-Chun , Tsai Jo-Ting
Published: September 2021

We investigated the organ-sparing effect of the deep inspiration breath hold (DIBH) technique among different levels of lung expansion for left-side breast radiotherapy. This retrospective study enrolled 30 patients who received adjuvant left breast radiotherapy after breast-conserving surgery (BCS). Simulation scans of both DIBH and deep breathing four-dimensional computed tomography (4DCT) were acquired, and three treatment plans were generated for each patient. One plan was based on the DIBH images, and the other two plans were based on the mid-lung expansion (ME) and initial lung expansion (IE) phases retrieved from 4DCT data sets. Dosimetric comparisons and normal tissue complication probability (NTCP) models were conducted. We used image registration for displacement analysis and sought potential factors related to the dose benefit of DIBH. The DIBH plans resulted significantly lower doses to the heart, left ventricle (LV) and left anterior descending coronary artery (LAD), including the high- to low-dose areas, followed by the ME plans and IE plans (p < 0.05). DIBH reduced the risk of long-term cardiac mortality by 40% and radiation pneumonitis of the left lung by 37.96% compared with the IE plans (p < 0.001). The reduction in the mean dose to the heart and LV significantly correlated with anterior displacement of the left lung. The DIBH technique is a feasible tool to provide dosimetric and clinical advantages for adjuvant left-sided breast radiotherapy. Breathing pattern and the level of lung expansion seem to play an important role.
Colonic actinomycosis presenting as a palpable colonic mass with normal colonic mucosa
Authors: Charernsuk Mai , Tunruttanakul Suppadech , Tunruttanakul Ratchanee , Chareonsil Borirak
Published: September 2021

Colonic actinomycosis is rare and can present as an ill-defined intra-abdominal mass that can be difficult to differentiate from colon cancer. This case report aims to share the details of this case and provide diagnostic clues. A 63-year-old female presented with a palpable right-sided abdominal mass. Computed tomography (CT) revealed irregular thickening of the colonic hepatic flexure, and colonoscopy detected no abnormalities. Five months later, the patient returned with an increase in the mass size. Repeat CT revealed lesion expansion, with suspected abdominal wall invasion. Extended right-hemicolectomy with abdominal wall wedge resection was performed, and the histological results were compatible with actinomycosis infection. Colonic actinomycosis is a rare chronic inflammatory disease. Normal colonic mucosa during colonoscopy, with clinical and imaging findings, may help physicians diagnose the condition preoperatively.
Aspergillus fumigatus cerebral abscess and sphenoid sinus osteomyelitis in an immunocompetent patient following previous nasopharyngeal carcinoma and radiotherapy
Authors: Kim Bernard J H , Garcia Redmond Joseph , Donaldson Annabelle D , Aspoas A Robert
Published: September 2021

Cerebral mycosis is extremely rare in immunocompetent patients. A 61-year-old male presented with a 3-month history of worsening left-sided headaches and 3-week history of left-sided upper lip paraesthesia. Magnetic resonance imaging revealed an enhancing lesion in the left temporal lobe. Histopathology of this lesion revealed what initially resembled a zygomycete but additional cultures obtained on further surgical debridement revealed the infection to be Aspergillus fumigatus with associated sphenoid sinus osteomyelitis. We postulate that the presentation was related to the patient’s previous radiotherapy for nasopharyngeal carcinoma. To the best of our knowledge, this is the only report of such a case.
Aortic valve insufficiency after Impella device insertion that required aortic valve replacement after Heart Mate III left ventricular assist device implantation: a case report.
Authors: Ueda Kohei , Yoshitani Kenji , Hosotani Shunsuke , Hayashi Hisanori , Fukushima Satsuki , Ohnishi Yoshihiko
Published: September 2021

The Impella (Abiomed, Danvers, MA, USA) is a minimally invasive axial-flow catheter used in severe heart failure. We describe a case in which aortic insufficiency occurred after Impella insertion, required extra surgical intervention twice. A 33-year-old man with familial dilated cardiomyopathy was admitted to our hospital due to acute decompensation of heart failure. Despite intensive medical treatment, his hemodynamic status did not improve. Firstly, Impella was emergently implanted, and HeartMate III (Abbott, Plymouth, MN, USA) implantation was performed 2 weeks after. In the HeartMate III implantation, new aortic insufficiency had revealed and central aortic valve closure was performed concomitantly. However, on postoperative Day1, the coaptation stitch had untied, causing severe aortic insufficiency which led to another emergent operation of aortic valve replacement. We suggest that indications for Impella implantation need to be carefully discussed beforehand, especially with patients who may undergo implantation of left ventricular assist device.