bluuebunny/crossref_metadata_2025 huggingface dataset:
The first families of highly symmetric Kirkman Triple Systems whose orders fill a congruence class
Authors: Bonvicini Simona , Buratti Marco , Garonzi Martino , Rinaldi Gloria , Traetta Tommaso
Published: October 2021

Kirkman triple systems (KTSs) are among the most popular combinatorial designs and their existence has been settled a long time ago. Yet, in comparison with Steiner triple systems, little is known about their automorphism groups. In particular, there is no known congruence class representing the orders of a KTS with a number of automorphisms at least close to the number of points. We partially fill this gap by proving that whenever$$v \equiv 39$$v≡39(mod 72), or$$v \equiv 4^e48 + 3$$v≡4e48+3(mod$$4^e96$$4e96) and$$e \ge 0$$e≥0, there exists a KTS onvpoints having at least$$v-3$$v-3automorphisms. This is only one of the consequences of an investigation on the KTSs with an automorphism groupGacting sharply transitively on all but three points. Our methods are all constructive and yield KTSs which in many cases inherit some of the automorphisms ofG, thus increasing the total number of symmetries. To obtain these results it was necessary to introduce new types of difference families (the doubly disjoint ones) and difference matrices (the splittable ones) which we believe are interesting by themselves.
Creatine deficiency and heart failure
Authors: Del Franco Annamaria , Ambrosio Giuseppe , Baroncelli Laura , Pizzorusso Tommaso , Barison Andrea , Olivotto Iacopo , Recchia Fabio A. , Lombardi Carlo M. , Metra Marco , Ferrari Chen Yu F. , Passino Claudio , Emdin Michele , Vergaro Giuseppe
Published: October 2021

Impaired cardiac energy metabolism has been proposed as a mechanism common to different heart failure aetiologies. The energy-depletion hypothesis was pursued by several researchers, and is still a topic of considerable interest. Unlike most organs, in the heart, the creatine kinase system represents a major component of the metabolic machinery, as it functions as an energy shuttle between mitochondria and cytosol. In heart failure, the decrease in creatine level anticipates the reduction in adenosine triphosphate, and the degree of myocardial phosphocreatine/adenosine triphosphate ratio reduction correlates with disease severity, contractile dysfunction, and myocardial structural remodelling. However, it remains to be elucidated whether an impairment of phosphocreatine buffer activity contributes to the pathophysiology of heart failure and whether correcting this energy deficit might prove beneficial. The effects of creatine deficiency and the potential utility of creatine supplementation have been investigated in experimental and clinical models, showing controversial findings. The goal of this article is to provide a comprehensive overview on the role of creatine in cardiac energy metabolism, the assessment and clinical value of creatine deficiency in heart failure, and the possible options for the specific metabolic therapy.
Completeness for the Classical Antecedent Fragment of Inquisitive First-Order Logic
Authors: Grilletti Gianluca
Published: October 2021

Inquisitive first order logic "Equation missing" is an extension of first order classical logic, introducing questions and studying the logical relations between questions and quantifiers. It is not known whether "Equation missing" is recursively axiomatizable, even though an axiomatization has been found for fragments of the logic (Ciardelli, 2016). In this paper we define the $$\mathsf {ClAnt}$$
ClAnt
—classical antecedent—fragment, together with an axiomatization and a proof of its strong completeness. This result extends the ones presented in the literature and introduces a new approach to study the axiomatization problem for fragments of the logic.
Radiocarbon Dated Trends and Central Mediterranean Prehistory
Authors: Parkinson Eóin W. , McLaughlin T. Rowan , Esposito Carmen , Stoddart Simon , Malone Caroline
Published: October 2021

This paper reviews the evidence for long term trends in anthropogenic activity and population dynamics across the Holocene in the central Mediterranean and the chronology of cultural events. The evidence for this has been constituted in a database of 4608 radiocarbon dates (of which 4515 were retained for analysis following initial screening) from 1195 archaeological sites in southern France, Italy and Malta, spanning the Mesolithic to Early Iron Age periods, c. 8000 to 500 BC. We provide an overview of the settlement record for central Mediterranean prehistory and add to this an assessment of the available archaeological radiocarbon evidence in order to review the traditional narratives on the prehistory of the region. This new chronology has enabled us to identify the most significant points in time where activity levels, population dynamics and cultural change have together caused strong temporal patterning in the archaeological record. Some of these episodes were localized to one region, whereas others were part of pan-regional trends and cultural trajectories that took many centuries to play out fully, revealing prehistoric societies subject to collapse, recovery, and continuing instability over the long-term. Using the radiocarbon evidence, we model growth rates in the various regions so that the tempo of change at certain points in space and time can be identified, compared, and discussed in the context of demographic change. Using other published databases of radiocarbon data, we have drawn comparisons across the central Mediterranean to wider prehistoric Europe, and northern Africa. Finally, we include a brief response to the synchronously published but independently developed paper (Palmisano et al. in J World Prehist 34(3), 2021). While there are differences in our respective approaches, we share the general conclusions that large-scale trends can been identified through meta-analyses of the archaeological record, and these offer new perspectives on how society functioned.
Big data theory based spectrum sensing algorithm for the satellite cognitive radio network
Authors: Yang Mingchuan , Shao Xinye , Xue Guanchang , Xie Bingyu
Published: October 2021

In order to deal with the difficulty of spectrum sensing in cognitive satellite wireless networks, a large-scale cognitive network spectrum sensing algorithm based on big data analysis theory is studied, and a new algorithm using mean exponential eigenvalue is proposed. This new approach fully uses all the eigenvalues in sample covariance matrix of the sensing results to make the decision, which can effectively improve the detection performance without obtaining the prior information from licensed users. Through simulation, the performance of various large scale cognitive radio spectrum sensing algorithms based on big data analysis theory is compared, and the influence of satellite to ground channel conditions and the number of sensing nodes on the performance of the algorithm is discussed.
Social Participation as a Moderator for Caregivers’ Psychological Distress: a Dynamic Panel Data Model Analysis in Japan
Authors: Oshio Takashi , Sugiyama Kemmyo
Published: October 2021

The adverse impact of caregiving on caregivers’ mental health and the positive impact of social participation (SP) on health are both well understood. This study examined the moderating effect of SP on the association between family caregiving and caregivers’ psychological distress (PD). We used longitudinal data from 27,869 individuals born between 1946 and 1955 collected from a 14-wave nationwide survey, which was conducted from 2005 to 2018. We estimated dynamic panel data models, which could control for an individual’s time-invariant attributes in a dynamic framework, to examine how SP moderated the association between informal caregiving and a caregiver’s PD (defined by a Kessler score of 13 or higher). We observed that the onset of caregiving increased the probability of PD by 2.1% (95% confidence interval [CI]: 1.5%–2.6%) and 1.0% (95% CI: 0.5%–1.6%) for women and men, respectively, compared to 3.4% and 2.8% as the prevalence of PD for women and men, respectively. SP moderated the association between caregiving and a caregiver’s PD by 55.8% (95% CI: 31.9%–79.8%) and 73.5% (95% CI: 36.1%–110.9%) for women and men, respectively. In addition, the moderating effect of SP on a caregiver’s PD increased as the caregiver’s age advanced especially in women. These results suggest the need to keep family caregivers from being socially isolated, especially as they get older.
Some results on isometric composition operators on Lipschitz spaces
Authors: Rueda Zoca Abraham
Published: October 2021

Given two metric spaces M and N we study, motivated by a question of N. Weaver, conditions under which a composition operator $$C_\phi :{\mathrm {Lip}}_0(M)\longrightarrow {\mathrm {Lip}}_0(N)$$

C
ϕ

:

Lip
0

(
M
)

⟶

Lip
0

(
N
)

is an isometry depending on the properties of $$\phi $$
ϕ
. We obtain a complete characterisation of those operators $$C_\phi $$

C
ϕ

in terms of a property of the function $$\phi $$
ϕ
in the case that $$B_{{\mathcal {F}}(M)}$$

B

F
(
M
)

is the closed convex hull of its preserved extreme points. Also, we obtain necessary condition for $$C_\phi $$

C
ϕ

being an isometry in the case that M is geodesic.
Personalization of medical treatments in oncology: time for rethinking the disease concept to improve individual outcomes
Authors: Bizzarri Mariano , Fedeli Valeria , Monti Noemi , Cucina Alessandra , Jalouli Maroua , Alwasel Saleh H. , Harrath Abdel Halim
Published: October 2021

The agenda of pharmacology discovery in the field of personalized oncology was dictated by the search of molecular targets assumed to deterministically drive tumor development. In this perspective, genes play a fundamental “causal” role while cells simply act as causal proxies, i.e., an intermediate between the molecular input and the organismal output. However, the ceaseless genomic change occurring across time within the same primary and metastatic tumor has broken the hope of a personalized treatment based only upon genomic fingerprint. Indeed, current models are unable in capturing the unfathomable complexity behind the outbreak of a disease, as they discard the contribution of non-genetic factors, environment constraints, and the interplay among different tiers of organization. Herein, we posit that a comprehensive personalized model should view at the disease as a “historical” process, in which different spatially and timely distributed factors interact with each other across multiple levels of organization, which collectively interact with a dynamic gene-expression pattern. Given that a disease is a dynamic, non-linear process — and not a static-stable condition — treatments should be tailored according to the “timing-frame” of each condition. This approach can help in detecting those critical transitions through which the system can access different attractors leading ultimately to diverse outcomes — from a pre-disease state to an overt illness or, alternatively, to recovery. Identification of such tipping points can substantiate the predictive and the preventive ambition of the Predictive, Preventive and Personalized Medicine (PPPM/3PM). However, an unusual effort is required to conjugate multi-omics approaches, data collection, and network analysis reconstruction (eventually involving innovative Artificial Intelligent tools) to recognize the critical phases and the relevant targets, which could help in patient stratification and therapy personalization.
Season- and Trend-aware Symbolic Approximation for Accurate and Efficient Time Series Matching
Authors: Kegel Lars , Hartmann Claudio , Thiele Maik , Lehner Wolfgang
Published: October 2021

Processing and analyzing time series datasets have become a central issue in many domains requiring data management systems to support time series as a native data type. A core access primitive of time series is matching, which requires efficient algorithms on-top of appropriate representations like the symbolic aggregate approximation (SAX) representing the current state of the art. This technique reduces a time series to a low-dimensional space by segmenting it and discretizing each segment into a small symbolic alphabet. Unfortunately, SAX ignores the deterministic behavior of time series such as cyclical repeating patterns or a trend component affecting all segments, which may lead to a sub-optimal representation accuracy. We therefore introduce a novel season- and a trend-aware symbolic approximation and demonstrate an improved representation accuracy without increasing the memory footprint. Most importantly, our techniques also enable a more efficient time series matching by providing a match up to three orders of magnitude faster than SAX.
Parametric whirl flutter study using different modelling approaches
Authors: Koch Christopher
Published: October 2021

This paper demonstrates the importance of assessing the whirl flutter stability of propeller configurations with a detailed aeroelastic model instead of local pylon models. Especially with the growing use of electric motors for propulsion in air taxis and commuter aircraft whirl flutter becomes an important mode of instability. These configurations often include propeller which are powered by lightweight electric motors and located at remote locations, e.g. the wing tip. This gives rise to an aeroelastic instability called whirl flutter, involving the gyroscopic whirl modes of the engine. The driving parameters for this instability are the dynamics of the mounting structure. Using a generic whirl flutter model of a propeller at the tip of a lifting surface, parameter studies on the flutter stability are carried out. The aeroelastic model consists of a dynamic MSC.Nastran beam model coupled with the unsteady ZAERO ZONA6 aerodynamic model and strip theory for the propeller aerodynamics. The parameter studies focus on the influence of different substructures (ranging from local engine mount stiffness to global aircraft dynamics) on the aeroelastic stability of the propeller. The results show a strong influence of the level of detail of the aeroelastic model on the flutter behaviour. The coupling with the lifting surface is of major importance, as it can stabilise the whirl flutter mode. Including wing unsteady aerodynamics into the analysis can also change the whirl flutter behaviour. This stresses the importance of including whirl flutter in the aeroelastic stability analysis on aircraft level.
The Overlap Between Problematic Smartphone Use and Problematic Social Media Use: a Systematic Review
Authors: Marino Claudia , Canale Natale , Melodia Fiordalisa , Spada Marcantonio M. , Vieno Alessio
Published: October 2021

Purpose of Review

Over the last decade, problematic smartphone use (PSU) and problematic social media use (PSMU) have emerged as new potential problematic behaviours. Several studies have suggested that smartphones are predominantly used for social purposes (i.e., using messaging apps and social networking sites). The aim of the current article is to provide a systematic review of the extant literature that has explicitly analysed the association between PSU and PSMU in order to examine study characteristics in terms of samples analysed and effect sizes of the associations reported. This systematic review is based on the ongoing debate about whether the smartphone can be considered as the medium of one or more problematic activities, including PSMU.

Recent Findings

Existing evidence suggests that the effect sizes of the associations between PSU and PSMU are medium to large and large across the 13 studies included, with the largest correlations observed between PSU and problematic WhatsApp use or general PSMU. Overall, reviewed results suggest a partial overlap between the two problematic behaviours.

PSU and PSMU are overlapped mostly because the smartphone is a common medium to use social media, especially concerning instant messaging apps like WhatsApp. Moreover, PSU should be preferentially studied with a focus on specific types of apps used rather than a more holistic phenomenon.
Discordant Crown Rump Length (CRL) in Twins: Is it a Matter of Concern?—The Indian Perspective
Authors: Sabu Brinda , Suresh Sudarshan , Seshadri Suresh
Published: October 2021

To evaluate the impact of discordant Crown Rump Length (CRL) noted in the first trimester on the outcome of monochorionic (MC) and dichorionic (DC) twin gestations and to establish it's role as a predictor of adverse outcomes. This was a retrospective case control study carried out at a tertiary fetal medicine centre in South India between June 2013 and May 2018. Cases were obtained from the database of the centre. All viable monochorionic diamniotic (MCDA) and dichorionic diamniotic (DCDA) twin pregnancies scanned between 11 and 14 weeks gestational age after excluding fetuses with structural abnormalities were included in the study. The impact of discordant CRL ≥ 10% on the outcomes of twins was evaluated. Among 2627 twin pregnancies 2298 (87.5%) were dichorionic and 329 (12.5%) were monochorionic. Among the DC twin pregnancies CRL discordance ≥ 10% was found in 124 (5.4%) while 2174 (94.6%) were concordant. Among the MC twin pregnancies CRL discordance ≥ 10% was found in 20 (6.1%) while 309 (93.9%) were concordant. In DC twin pregnancies we found a significant association between CRL discordance of ≥ 10% and fetal loss (p = 0.001), mean GA at delivery (p = 0.002) and mean birth weight (p = 0.04). However in MC twin pregnancies we did not find any association between discordant CRL and adverse outcomes. When the CRL discordance cutoff was increased to ≥ 16% (95th centile), there was a significant increase in the aforementioned adverse outcomes in DC twin pregnancies while in MC twin pregnancies there was a significant increase in fetal loss (p = 0.027). To evaluate CRL discordance as a predictor of adverse outcomes, receiver operating curves were created for each outcome studied. But they failed to show the predictive accuracy in both CRL ≥ 10% and CRL ≥ 16% groups. CRL discordance in DC twin pregnancies are more commonly associated with adverse outcomes than MC twin pregnancies and it significantly increases when CRL C 16% (95th centile) was used as cutoff. Hence CRL discordance of ≥ 16% should be set as the cutoff to identify pregnancies at risk. However we reiterate that discordant CRL, irrespective of the cutoff used, is not a robust predictor of adverse outcomes.
Mechanical properties, crystallographic texture, and in vitro bio-corrosion of low-alloyed Zn–Mg, produced by hot and cold drawing for biodegradable surgical wires
Authors: Milenin Andrij , Wróbel Mirosław , Kustra Piotr , Packo Marek , Byrska-Wójcik Dorota , Sulej-Chojnacka Joanna , Płonka Bartłomiej
Published: October 2021

The paper is devoted to the study of the mechanical, microstructural, and bio-corrosive behavior of low-alloyed Zn–Mg biodegradable surgical wires for bone reconstructions. Three biodegradable alloys with different magnesium content have been studied, their production technology has been developed and the product properties have been determined. The technology includes casting, extrusion, hot and cold drawing of the wire, and the product surface finishing. The paper shows the most important stages of the process (i.e., extrusion and drawing) in detail. The technological parameters have been selected based on the results of the computer modeling. The flow stress–strain curves of extruded materials have been obtained at various strain rates and temperatures. Two drawing technologies have been compared. The first one is the room temperature conventional wire drawing. In the second one, the first few passes have been made at an elevated temperature and the rest at room temperature. This allowed avoiding the breaking of the wire during the first passes (a typical issue of the conventional technology for these alloys) and increasing the ductility of the final product. Mechanical properties, bio-corrosion, and crystallographic texture of the material were determined at different stages of the processing. A simultaneous increase in the wire strength, the number of repeated bending until the rupture of the wire, and in the bio-corrosion rate due to drawing has been registered. This phenomenon coincided with a change in the crystallographic texture. It has been shown that the product tensile strength of about 250–300 MPa can be reduced by about 30% due to surgical knots tied on it.
Defending Iran
Authors: Bahgat Gawdat , Ehteshami Anoushiravan
Published: October 2021

Since the 1979 revolution, the ruling establishment of Iran has developed and articulated a defense strategy reflective of the country's Iran-Iraq war experience and its international isolation. Its asymmetrical warfare doctrine, use of irregular forces in military campaigns, deployment of ballistic missiles, use of fast naval vessels to harass and confuse adversaries, and finally development of a sophisticated cyber warfare capability, are all features of this unique defense strategy. Based on a wide range of primary sources in Persian, Arabic and English, Gawdat Bahgat and Anoushiravan Ehteshami offer a detailed and authoritative analysis of Iran's defense strategy. Additionally, this book provides a comparative analysis of the Islamic Republic's capabilities in relation to Israel and Saudi Arabia, its main regional adversaries. Framing Tehran's threat perceptions following the revolution within a wider historical context, this book will facilitate further analytical reflections on the country's changing role in the region, and its relations further afield, with the United States, Europe, Russia and China.
The Financial Crisis of 2008
Authors: Wigmore Barrie A.
Published: October 2021

Supported by ten years of research, Wigmore has gathered extensive data covering the 2008 financial crisis and subsequent recovery to provide the first comprehensive history of the period. Financial crises cannot occur unless institutional investors finance the bubbles that created them. Wigmore follows the trail of data putting pressure on institutional investors to achieve higher levels of returns that led to over-leverage throughout the financial system and placed such a burden on recovery. Here is a 'very good picture - and painful reminder - of the crisis' evolution across multiple asset classes, structures, participants, and geographies.' This work serves as a critical analysis of modern portfolio management and an important reference work for financial professionals, academics, investors, and students.
The Mind of the Censor and the Eye of the Beholder
Authors: Corn-Revere Robert
Published: October 2021

Beginning in the nineteenth century with Anthony Comstock, America's 'censor in chief,' The Mind of the Censor and the Eye of the Beholder explores how censors operate and why they wore out their welcome in society at large. This book explains how the same tactics were tried and eventually failed in the twentieth century, with efforts to censor music, comic books, television, and other forms of popular entertainment. The historic examples illustrate not just the mindset and tactics of censors, but why they are the ultimate counterculture warriors and why, in free societies, censors never occupy the moral high ground. This book is for anyone who wants to know more about why freedom of speech is important and how protections for free expression became part of the American identity.
A Dramaturgy of Death: Performing (And Spectating) Filial Piety in Early China
Authors: Radice Thomas
Published: October 2021

This essay analyzes the early Chinese elite discourse on filial death rituals, arguing that early Chinese texts depict these rituals as performance events. Building on spectacle of xiao sacrifices in the Western Zhou Dynasty, Eastern Zhou authors conceived of filial death rituals as dramaturgical phenomena that underscored not only what needed to be performed, but also how it should be performed, and led to an important distinction between personal dispositions and inherited ritual protocol. This distinction, then, led to concerns about artifice in human behavior, both inside and outside the Ruist (Confucian) tradition. By end of the Warring States Period and in the early Western Han Dynasty, with the embracement of artifice in self-cultivation, the dramatic role of the filial son in death rituals became even more developed and complex, requiring the role of cultivated spectators to be engaged critics who recognized the nuances of cultivated performances.
The Bretons in French Politics: Regional Mobilization within and beyond the Central State
Authors: Cole Alistair , Pasquier Romain
Published: October 2021

This article revisits the French region of Brittany on the basis of sustained empirical research over a 25-year period. It identifies the twin use of influence and identity as forming a key part of an accepted and largely diffused territorial repertoire, based on affirming distinctiveness for reasons of vertical linkage, as well as horizontal capacity building. This article explores the different facets of this model of territorial influence. The two twin dimensions concern: first, a well-versed mechanism of lobbying central institutions and actors to defend the Breton interest; second, the use of territorial identity markers to forward the regional cause, relying on social movements and a broad capacity for regional mobilization. Within this overarching context, the Breton case demonstrates an intelligent instrumental use of identity and identity markers, but mainstream Breton forces recognize that this only makes sense in the light of the national level of regulation and structure of opportunities. The logic of this position is to integrate the Brittany region into a national model of territorial integration, while playing up identity markers to secure the maximum benefit for the region.
Field surveys can improve predictions of habitat suitability for reintroductions: a swift fox case study
Authors: Paraskevopoulou Zoe , Shamon Hila , Songer Melissa , Ruxton Graeme , McShea William J.
Published: October 2021

Reintroductions are challenging, and success rates are low despite extensive planning and considerable investment of resources. Improving predictive models for reintroduction planning is critical for achieving successful outcomes. The IUCN Guidelines for Reintroductions and Other Conservation Translocations recommend that habitat suitability assessments account for abiotic and biotic factors specific to the species to be reintroduced and, where needed, include habitat quality variables. However, habitat assessments are often based on remotely-sensed or existing geographical data that do not always reliably represent habitat quality variables. We tested the contribution of ground-based habitat quality metrics to habitat suitability models using a case study of the swift fox Vulpes velox, a mesocarnivore species for which a reintroduction is planned. Field surveys for habitat quality included collection of data on the main threat to the swift fox (the coyote Canis latrans), and for swift fox prey species. Our findings demonstrated that the inclusion of habitat quality variables derived from field surveys yielded better fitted models and a 16% increase in estimates of suitable habitat. Models including field survey data and models based only on interpolated geographical and remotely-sensed data had little overlap (38%), demonstrating the significant impact that different models can have in determining appropriate locations for a reintroduction. We advocate that ground-based habitat metrics be included in habitat suitability assessments for reintroductions of mesocarnivores.
The conscious state of the dying patient: An integrative review
Authors: O'Connor Tricia , Paterson Catherine , Gibson Jo , Strickland Karen
Published: October 2021

Objectives

The cognitive state of the dying in the last days of life may deteriorate, resulting in a reduced ability to communicate their care needs. Distressing symptoms, physical and existential, may go unrecognized and untreated. The objectives of this integrative review were to systematically interrogate the literature to determine the changing conscious state of dying adults and to identify changes in their care needs.

Methods

An integrative review protocol was registered with PROSPERO (CRD42020160475). The World Health Organization definition of palliative care informed the review. CINAHL, MEDLINE (OVID), Scopus, PsycINFO, Cochrane Library, and PubMed were searched from inception to October 2019 using search strategies for each database. Inclusion and exclusion criteria were applied. Methodological quality was appraised using the Joanna Briggs Institute Checklist for the Case Series appraisal tool. Extracted data were synthesized using a narrative approach.

Results

Of 5,136 papers identified, 11 quantitative case series studies were included. Six themes were identified: conscious state and change over time, awareness, pain, absence of holistic care, the voiceless patient, and signs and symptoms of dying.

Significance of results

In the last days of life, the physical and conscious state of the dying patient declines, resulting in an inability to express their care needs. Dignity in dying and freedom from pain and suffering are both an imperative and a human right; and unvoiced care needs can result in unnecessary suffering and distress. This review revealed that little is known about how healthcare professionals assess holistic care needs at this vulnerable time. Although much has been written about palliative and end-of-life care, the assessment of care needs when patients are no longer able to voice their own needs has largely been ignored, with little attention from clinical, educational, or research perspectives. This gap in evidence has important implications for the dying and their families.
Roles of circadian clocks in cancer pathogenesis and treatment
Authors: Lee Yool
Published: October 2021

Circadian clocks are ubiquitous timing mechanisms that generate approximately 24-h rhythms in cellular and bodily functions across nearly all living species. These internal clock systems enable living organisms to anticipate and respond to daily changes in their environment in a timely manner, optimizing temporal physiology and behaviors. Dysregulation of circadian rhythms by genetic and environmental risk factors increases susceptibility to multiple diseases, particularly cancers. A growing number of studies have revealed dynamic crosstalk between circadian clocks and cancer pathways, providing mechanistic insights into the therapeutic utility of circadian rhythms in cancer treatment. This review will discuss the roles of circadian rhythms in cancer pathogenesis, highlighting the recent advances in chronotherapeutic approaches for improved cancer treatment.
HUGO Gene Nomenclature Committee (HGNC) recommendations for the designation of gene fusions
Authors: Bruford Elspeth A. , Antonescu Cristina R. , Carroll Andrew J. , Chinnaiyan Arul , Cree Ian A. , Cross Nicholas C. P. , Dalgleish Raymond , Gale Robert Peter , Harrison Christine J. , Hastings Rosalind J. , Huret Jean-Loup , Johansson Bertil , Le Beau Michelle , Mecucci Cristina , Mertens Fredrik , Verhaak Roel , Mitelman Felix
Published: October 2021

Gene fusions have been discussed in the scientific literature since they were first detected in cancer cells in the early 1980s. There is currently no standardized way to denote the genes involved in fusions, but in the majority of publications the gene symbols in question are listed either separated by a hyphen (-) or by a forward slash (/). Both types of designation suffer from important shortcomings. HGNC has worked with the scientific community to determine a new, instantly recognizable and unique separator—a double colon (::)—to be used in the description of fusion genes, and advocates its usage in all databases and articles describing gene fusions.
Association between polygenic risk for Alzheimer’s disease, brain structure and cognitive abilities in UK Biobank
Authors: Tank Rachana , Ward Joey , Flegal Kristin E. , Smith Daniel J. , Bailey Mark E. S. , Cavanagh Jonathan , Lyall Donald M.
Published: October 2021

Previous studies testing associations between polygenic risk for late-onset Alzheimer’s disease (LOAD-PGR) and brain magnetic resonance imaging (MRI) measures have been limited by small samples and inconsistent consideration of potential confounders. This study investigates whether higher LOAD-PGR is associated with differences in structural brain imaging and cognitive values in a relatively large sample of non-demented, generally healthy adults (UK Biobank). Summary statistics were used to create PGR scores for n = 32,790 participants using LDpred. Outcomes included 12 structural MRI volumes and 6 concurrent cognitive measures. Models were adjusted for age, sex, body mass index, genotyping chip, 8 genetic principal components, lifetime smoking, apolipoprotein (APOE) e4 genotype and socioeconomic deprivation. We tested for statistical interactions between APOE e4 allele dose and LOAD-PGR vs. all outcomes. In fully adjusted models, LOAD-PGR was associated with worse fluid intelligence (standardised beta [β] = −0.080 per LOAD-PGR standard deviation, p = 0.002), matrix completion (β = −0.102, p = 0.003), smaller left hippocampal total (β = −0.118, p = 0.002) and body (β = −0.069, p = 0.002) volumes, but not other hippocampal subdivisions. There were no significant APOE x LOAD-PGR score interactions for any outcomes in fully adjusted models. This is the largest study to date investigating LOAD-PGR and non-demented structural brain MRI and cognition phenotypes. LOAD-PGR was associated with smaller hippocampal volumes and aspects of cognitive ability in healthy adults and could supplement APOE status in risk stratification of cognitive impairment/LOAD.
CRISPR screens identify cholesterol biosynthesis as a therapeutic target on stemness and drug resistance of colon cancer
Authors: Gao Shanshan , Soares Fraser , Wang Shiyan , Wong Chi Chun , Chen Huarong , Yang Zhenjie , Liu Weixin , Go Minnie Y. Y. , Ahmed Musaddeque , Zeng Yong , O’Brien Catherine Adell , Sung Joseph J. Y. , He Housheng Hansen , Yu Jun
Published: October 2021

Cancer stem cells (CSCs) are responsible for tumor progression, recurrence, and drug resistance. To identify genetic vulnerabilities of colon cancer, we performed targeted CRISPR dropout screens comprising 657 Drugbank targets and 317 epigenetic regulators on two patient-derived colon CSC-enriched spheroids. Next-generation sequencing of pooled genomic DNAs isolated from surviving cells yielded therapeutic candidates. We unraveled 44 essential genes for colon CSC-enriched spheroids propagation, including key cholesterol biosynthetic genes (HMGCR, FDPS, and GGPS1). Cholesterol biosynthesis was induced in colon cancer tissues, especially CSC-enriched spheroids. The genetic and pharmacological inhibition of HMGCR/FDPS impaired self-renewal capacity and tumorigenic potential of the spheroid models in vitro and in vivo. Mechanistically, HMGCR or FDPS depletion impaired cancer stemness characteristics by activating TGF-β signaling, which in turn downregulated expression of inhibitors of differentiation (ID) proteins, key regulators of cancer stemness. Cholesterol and geranylgeranyl diphosphate (GGPP) rescued the growth inhibitory and signaling effect of HMGCR/FDPS blockade, implying a direct role of these metabolites in modulating stemness. Finally, cholesterol biosynthesis inhibitors and 5-FU demonstrated antitumor synergy in colon CSC-enriched spheroids, tumor organoids, and xenografts. Taken together, our study unravels novel genetic vulnerabilities of colon CSC-enriched spheroids and suggests cholesterol biosynthesis as a potential target in conjunction with traditional chemotherapy for colon cancer treatment.
Enzalutamide versus bicalutamide in patients with nonmetastatic castration-resistant prostate cancer: a prespecified subgroup analysis of the STRIVE trial
Authors: Penson David F. , Armstrong Andrew J. , Concepcion Raoul S. , Agarwal Neeraj , Olsson Carl A. , Karsh Lawrence I. , Dunshee Curtis J. , Duggan William , Shen Qi , Sugg Jennifer , Haas Gabriel P. , Higano Celestia S.
Published: October 2021

Background

In the phase 2, randomized, double-blind STRIVE trial, enzalutamide significantly reduced the risk of prostate cancer progression or death versus bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic CRPC (nmCRPC). The objective of this protocol-specified subgroup analysis of STRIVE was to investigate the benefit of enzalutamide versus bicalutamide specifically in patients with nmCRPC.

Methods

Patients (N = 139) were stratified by disease stage and randomized to enzalutamide 160 mg/day plus androgen deprivation therapy (ADT; n = 70) or bicalutamide 50 mg/day plus ADT (n = 69).

Results

Baseline characteristics of patients with nmCRPC were comparable between groups. At a median of 17 months follow-up, enzalutamide reduced the risk of progression or death by 76% versus bicalutamide in patients with nmCRPC (hazard ratio [HR], 0.24; 95% CI 0.14–0.42). Enzalutamide reduced risk of prostate-specific antigen progression by 82% versus bicalutamide in patients with nmCRPC (HR, 0.18; 95% CI 0.10–0.34). The most frequently reported adverse events by patients receiving enzalutamide were fatigue (36.2%), hot flush (20.3%), decreased appetite (17.4%), dizziness (17.4%), and nausea (17.4%).

Conclusions

This STRIVE subgroup analysis of patients with nmCRPC illustrates the benefit of enzalutamide in reducing the risk of progression or death versus bicalutamide in patients with nmCRPC.

Trial registration

ClinicalTrials.gov identifier NCT01664923.
Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer
Authors: Li Kai , Shi Houhui , Zhang Benxia , Ou Xuejin , Ma Qizhi , Chen Yue , Shu Pei , Li Dan , Wang Yongsheng
Published: October 2021

Myeloid-derived suppressor cells (MDSCs) are a heterogenic population of immature myeloid cells with immunosuppressive effects, which undergo massive expansion during tumor progression. These cells not only support immune escape directly but also promote tumor invasion via various non-immunological activities. Besides, this group of cells are proved to impair the efficiency of current antitumor strategies such as chemotherapy, radiotherapy, and immunotherapy. Therefore, MDSCs are considered as potential therapeutic targets for cancer therapy. Treatment strategies targeting MDSCs have shown promising outcomes in both preclinical studies and clinical trials when administrated alone, or in combination with other anticancer therapies. In this review, we shed new light on recent advances in the biological characteristics and immunosuppressive functions of MDSCs. We also hope to propose an overview of current MDSCs-targeting therapies so as to provide new ideas for cancer treatment.
Coordination of root auxin with the fungus Piriformospora indica and bacterium Bacillus cereus enhances rice rhizosheath formation under soil drying
Authors: Xu Feiyun , Liao Hanpeng , Zhang Yingjiao , Yao Minjie , Liu Jianping , Sun Leyun , Zhang Xue , Yang Jinyong , Wang Ke , Wang Xiaoyun , Ding Yexin , Liu Chen , Rensing Christopher , Zhang Jianhua , Yeh Kaiwun , Xu Weifeng
Published: October 2021

Moderate soil drying (MSD) is a promising agricultural technique that can reduce water consumption and enhance rhizosheath formation promoting drought resistance in plants. The endophytic fungus Piriformospora indica (P. indica) with high auxin production may be beneficial for rhizosheath formation. However, the integrated role of P. indica with native soil microbiome in rhizosheath formation is unclear. Here, we investigated the roles of P. indica and native bacteria on rice rhizosheath formation under MSD using high-throughput sequencing and rice mutants. Under MSD, rice rhizosheath formation was significantly increased by around 30% with P. indica inoculation. Auxins in rice roots and P. indica were responsible for the rhizosheath formation under MSD. Next, the abundance of the genus Bacillus, known as plant growth-promoting rhizobacteria, was enriched in the rice rhizosheath and root endosphere with P. indica inoculation under MSD. Moreover, the abundance of Bacillus cereus (B. cereus) with high auxin production was further increased by P. indica inoculation. After inoculation with both P. indica and B. cereus, rhizosheath formation in wild-type or auxin efflux carrier OsPIN2 complemented line rice was higher than that of the ospin2 mutant. Together, our results suggest that the interaction of the endophytic fungus P. indica with the native soil bacterium B. cereus favors rice rhizosheath formation by auxins modulation in rice and microbes under MSD. This finding reveals a cooperative contribution of P. indica and native microbiota in rice rhizosheath formation under moderate soil drying, which is important for improving water use in agriculture.
Barriers to clinical adoption of pharmacogenomic testing in psychiatry: a critical analysis
Authors: Virelli Catherine R. , Mohiuddin Ayeshah G. , Kennedy James L.
Published: October 2021

Pharmacogenomics (PGx) is the study of genetic influences on an individual’s response to medications. Improvements in the quality and quantity of PGx research over the past two decades have enabled the establishment of commercial markets for PGx tests. Nevertheless, PGx testing has yet to be adopted as a routine practice in clinical care. Accordingly, policy regulating the commercialization and reimbursement of PGx testing is in its infancy. Several papers have been published on the topic of challenges, or ‘barriers’ to clinical adoption of this healthcare innovation. However, many do not include recent evidence from randomized controlled trials, economic utility studies, and qualitative assessments of stakeholder opinions. The present paper revisits the most cited barriers to adoption of PGx testing: evidence for clinical utility, evidence for economic effectiveness, and stakeholder awareness. We consider these barriers in the context of reviewing PGx literature published over the past two decades and emphasize data from commercial PGx testing companies, since they have published the largest datasets. We conclude with a discussion of existing limitations to PGx testing and recommendations for progress.
Efficacy and safety of cabozantinib for patients with advanced hepatocellular carcinoma based on albumin-bilirubin grade
Authors: Kelley Robin Kate , Miksad Rebecca , Cicin Irfan , Chen YenHsun , Klümpen Heinz-Josef , Kim Stefano , Lin Zhong-Zhe , Youkstetter Jillian , Hazra Saswati , Sen Suvajit , Cheng Ann-Lii , El-Khoueiry Anthony B. , Meyer Tim , Abou-Alfa Ghassan K.
Published: October 2021

Background

Albumin-bilirubin (ALBI) grade is an objective measure of liver function for patients with hepatocellular carcinoma (HCC). The tyrosine kinase inhibitor cabozantinib is approved for patients with advanced HCC who have received prior sorafenib based on the phase 3 CELESTIAL trial (NCT01908426). Cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated HCC.

Methods

Patients were randomised 2:1 to receive cabozantinib 60 mg or placebo orally every day. Clinical outcomes in patients with ALBI grade 1 or 2 at baseline were evaluated in CELESTIAL. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin, with an ALBI grade of 1 defined as  ≤ −2.60 score and a grade of 2 as a score of > −2.60 to  ≤ −1.39.

Results

Cabozantinib improved OS and PFS versus placebo in both ALBI grade 1 (hazard ratio [HR] [95% CI]: 0.63 [0.46–0.86] and 0.42 [0.32–0.56]) and ALBI grade 2 (HR [95% CI]: 0.84 [0.66–1.06] and 0.46 [0.37–0.58]) subgroups. Adverse events were consistent with those in the overall population. Rates of grade 3/4 adverse events associated with hepatic decompensation were generally low and were more common among patients in the ALBI grade 2 subgroup.

Discussion

These results provide initial support of cabozantinib in patients with advanced HCC irrespective of ALBI grade 1 or 2.

Trial registration number

ClinicalTrials.gov number, NCT01908426.
Graded heterogeneity of metabotropic signaling underlies a continuum of cell-intrinsic temporal responses in unipolar brush cells
Authors: Guo Chong , Huson Vincent , Macosko Evan Z. , Regehr Wade G.
Published: October 2021

Many neuron types consist of populations with continuously varying molecular properties. Here, we show a continuum of postsynaptic molecular properties in three types of neurons and assess the functional correlates in cerebellar unipolar brush cells (UBCs). While UBCs are generally thought to form discrete functional subtypes, with mossy fiber (MF) activation increasing firing in ON-UBCs and suppressing firing in OFF-UBCs, recent work also points to a heterogeneity of response profiles. Indeed, we find a continuum of response profiles that reflect the graded and inversely correlated expression of excitatory mGluR1 and inhibitory mGluR2/3 pathways. MFs coactivate mGluR2/3 and mGluR1 in many UBCs, leading to sequential inhibition-excitation because mGluR2/3-currents are faster. Additionally, we show that DAG-kinase controls mGluR1 response duration, and that graded DAG kinase levels correlate with systematic variation of response duration over two orders of magnitude. These results demonstrate that continuous variations in metabotropic signaling can generate a stable cell-autonomous basis for temporal integration and learning over multiple time scales.
Efficient and precise single-cell reference atlas mapping with Symphony
Authors: Kang Joyce B. , Nathan Aparna , Weinand Kathryn , Zhang Fan , Millard Nghia , Rumker Laurie , Moody D. Branch , Korsunsky Ilya , Raychaudhuri Soumya
Published: October 2021

Recent advances in single-cell technologies and integration algorithms make it possible to construct comprehensive reference atlases encompassing many donors, studies, disease states, and sequencing platforms. Much like mapping sequencing reads to a reference genome, it is essential to be able to map query cells onto complex, multimillion-cell reference atlases to rapidly identify relevant cell states and phenotypes. We present Symphony (https://github.com/immunogenomics/symphony), an algorithm for building large-scale, integrated reference atlases in a convenient, portable format that enables efficient query mapping within seconds. Symphony localizes query cells within a stable low-dimensional reference embedding, facilitating reproducible downstream transfer of reference-defined annotations to the query. We demonstrate the power of Symphony in multiple real-world datasets, including (1) mapping a multi-donor, multi-species query to predict pancreatic cell types, (2) localizing query cells along a developmental trajectory of fetal liver hematopoiesis, and (3) inferring surface protein expression with a multimodal CITE-seq atlas of memory T cells.
High-resolution positron emission microscopy of patient-derived tumor organoids
Authors: Khan Syamantak , Shin June Ho , Ferri Valentina , Cheng Ning , Noel Julia E. , Kuo Calvin , Sunwoo John B. , Pratx Guillem
Published: October 2021

Tumor organoids offer new opportunities for translational cancer research, but unlike animal models, their broader use is hindered by the lack of clinically relevant imaging endpoints. Here, we present a positron-emission microscopy method for imaging clinical radiotracers in patient-derived tumor organoids with spatial resolution 100-fold better than clinical positron emission tomography (PET). Using this method, we quantify 18F-fluorodeoxyglucose influx to show that patient-derived tumor organoids recapitulate the glycolytic activity of the tumor of origin, and thus, could be used to predict therapeutic response in vitro. Similarly, we measure sodium-iodine symporter activity using 99mTc- pertechnetate and find that the iodine uptake pathway is functionally conserved in organoids derived from thyroid carcinomas. In conclusion, organoids can be imaged using clinical radiotracers, which opens new possibilities for identifying promising drug candidates and radiotracers, personalizing treatment regimens, and incorporating clinical imaging biomarkers in organoid-based co-clinical trials.