bluuebunny/crossref_metadata_2025 huggingface dataset:
Thorn in Your Side or Thorn in Your Head? Anxiety and Stress as Correlates of Exercise-Related Transient Abdominal Pain
Authors: Wynne Jaison L. , Wilson Patrick B.
Published: December 2021

Objectives:

The etiology of exercise-related transient abdominal pain (ETAP) is not congruent among researchers notwithstanding numerous studies on the matter. No pursuit has sought to correlate ETAP with factors such as anxiety, stress, sleep dysfunction, and pain sensitivity that are linked to other gastrointestinal (GI) disturbances in athletes.

Design:

Cross-sectional observational study involving an anonymous survey.

Setting:

Online.

Participants:

One hundred sixty-eight male and female adults running at least 10 miles/wk.

Assessments of risk factors:

Age, body mass index, years of running experience, GI symptoms, the State-Trait Inventory for Cognitive and Somatic Anxiety (STICSA), Perceived Stress Scale (PSS)-14, Sleep Problems Index-I, and Pain Sensitivity Questionnaire.

Main outcomes:

Exercise-related transient abdominal pain prevalence over the past month as well as ETAP severity and frequency.

Results:

Exercise-related transient abdominal pain occurred in 39.9% of participants at least once in the past month. Exercise-related transient abdominal pain–positive runners were significantly younger and less experienced than ETAP-negative runners. Exercise-related transient abdominal pain–positive runners demonstrated higher resting and running-related GI symptoms, PSS-14, and STICSA scores compared with ETAP-negative runners. After accounting for age and experience, the ETAP-positive group had STICSA and PSS-14 scores that were 3.4 [95% confidence interval (CI), 1.0-5.8] and 4.1 (95% CI, 1.2-6.0) points higher, respectively, than the ETAP-negative group. State-Trait Inventory for Cognitive and Somatic Anxiety scores were significantly, modestly correlated (ρ = 0.27, P = 0.03) with ETAP frequency but not severity in runners who were ETAP-positive.

Conclusions:

In runners, this is the first investigation to reveal that anxiety and stress are associated with the presence of ETAP.
Soy consumption, cognitive function, and dementia
Authors: Szczerba Edyta , Koch Manja , Schlesinger Sabrina
Published: December 2021

Purpose of review

With the rising number of people living with dementia, the interest in modifiable risk factors including dietary intake for dementia is increasing. Although there is a growing body of evidence investigating soy's health effects, the direction and strength of the association between soy consumption and risk of dementia and cognitive decline are still uncertain. Thus, we aimed to review the evidence linking soy consumption to dementia and cognitive function.

Recent findings

Some studies showed that higher intake of total soy products was associated with a lower risk or prevalence of cognitive impairment. Some studies pointed to an inverse association between higher tofu consumption and cognitive function, whereas a higher intake of soybean was associated with better cognitive function.

Previous studies are scarce and have provided contradictory results. Soy is a high-protein alternative to red meat and processed meat. Further studies are needed to clarify the safety and potential preventive effects particularly in healthy populations before clinical disease manifestation and irreversible injury have occurred.
Inequality and child health: dynamic population health interventions
Authors: Halfon Neal , Russ Shirley A. , Kahn Robert S.
Published: December 2021

Purpose of review

Established social gradients across a wide range of child health issues including obesity, anxiety, infectious diseases, injuries, prematurity and low birth weight suggest that much illness is avoidable and there is an imperative to intervene in this whole of society issue. This review examines recent advances in understanding of the pathways to health and health inequalities and their application to interventions to improve health equity.

Recent findings

Children's health develops over the life course in ways that are profoundly influenced by their entire developmental ecosystem including individual, family, community and system-level factors. Interventions to address child health inequalities must include action on the structural determinants of health, a greater focus on family and community health development, and attention to the acquisition of developmental capabilities. Nascent dynamic population health initiatives that address whole developmental ecosystems such as All Children Thrive, Better Start Bradford and Generation V, hold real promise for achieving child health equity.

Pathways to health inequalities are driven by social and structural determinants of health. Interventions to address inequalities need to be driven less by older biomedical models, and more by prevailing ecological and complex systems models incorporating a life course health development approach.
Brief Report: Nicotine Metabolism Ratio Increases in HIV-Positive Smokers on Effective Antiretroviral Therapy: A Cohort Study
Authors: Bien-Gund Cedric H. , Bilker Warren , Schnoll Robert A. , Tyndale Rachel F. , Ho Joshua I. , Bremner Remy , Ashare Rebecca L. , Gross Robert
Published: December 2021

Background:

People with HIV (PWH) smoke tobacco at much higher rates than the general population. Previous research has shown that PWH have faster nicotine metabolism than HIV-uninfected individuals, which may underlie this disparity, but the cause is unknown. We investigated whether higher nicotine metabolite ratio (NMR; 3-hydroxycotinine:cotinine), a validated biomarker of nicotine metabolism through CYP2A6, was associated with antiretroviral use among HIV-infected smokers.

Methods:

We conducted a retrospective cohort study of HIV-positive smokers in the University of Pennsylvania Center for AIDS Research cohort. We compared the NMR before viral suppression (>10,000 copies/mL) and after viral suppression on antiretroviral therapy (<200 copies/mL). We used mixed-effects linear regression to analyze the change in NMR after viral suppression and assessed for effect modification by efavirenz use.

Results:

Eighty-nine individuals were included in the study. We observed effect modification by efavirenz use (interaction term for efavirenz use, P < 0.001). Among those on nonefavirenz regimens, the mean NMR increased by 0.14 (95% confidence interval: 0.05 to 0.23, P = 0.002). Among those on efavirenz-containing regimens, the mean NMR increased by 0.53 (95% confidence interval: 0.39–0.66, P < 0.001).

Conclusions:

We observed a clinically and statistically significant increase in NMR after viral suppression among smokers with HIV, which more than doubled among those on efavirenz-based regimens. Higher NMR among HIV-positive smokers on antiretroviral therapy may help explain the higher rates of tobacco use and lower quit rates among PWH in care. These findings suggest that regimen choice and other modifiable factors may be targets for future attempts to increase success rates for tobacco cessation among PWH.
Evidence-based Surgical Competency Outcomes from the Clinical Readiness Program
Authors: Andreatta Pamela , Bowyer Mark W. , Ritter E. Matthew , Remick Kyle , Knudson Mary Margaret , Elster Eric A.
Published: December 2021

Objectives:

1) Evaluate the value and strength of a competency framework for identifying and measuring performance requirements for expeditionary surgeons; 2) Verify psychometric integrity of assessment instrumentation for measuring domain knowledge and skills; 3) Identify gaps in knowledge and skills capabilities using assessment strategies; 4) Examine shared variance between knowledge and skills outcomes, and the volume and diversity of routine surgical practice.

Background:

Expeditionary military surgeons provide care for patients with injuries that extend beyond the care requirements of their routine surgical practice. The readiness of these surgeons to independently provide accurate care in expeditionary contexts is important for casualty care in military and civilian situations. Identifying and closing performance gap areas are essential for assuring readiness.

Methods:

We implemented evidence-based processes for identifying and measuring the essential performance competencies for expeditionary surgeons. All assessment instrumentation was rigorously examined for psychometric integrity. Performance outcomes were directly measured for expeditionary surgical knowledge and skills and gap areas were identified. Knowledge and skills assessment outcomes were compared, and also compared to the volume and diversity of routine surgical practice to determine shared variance.

Results:

Outcomes confirmed the integrity of assessment instrumentation and identified significant performance gaps for knowledge and skills in the domain.

Conclusions:

Identification of domain competencies and performance benchmarks, combined with best-practices in assessment instrumentation, provided a rigorous and defensible framework for quantifying domain competencies. By identifying and implementing strategies for closing performance gap areas, we provide a positive process for assuring surgical competency and clinical readiness.
Graham Wood. 6 February 1934—4 November 2016
Authors: Lyon Stuart
Published: December 2021

Graham Wood was a world-leading corrosion scientist who bridged both the aqueous (electrochemical) corrosion and high-temperature oxidation branches of the subject. His analytical predictions of depletion and enrichment profiles in substrate and scale during preferential oxidation have long been confirmed in practice. He also demonstrated that transient oxides can be vital solid lubricants in oxidative friction and wear processes. He elucidated ionic transport in amorphous anodic films, leading to precise models of pore initiation, development and closure, thus allowing the strict design of anodic films for practical application. He set up, and headed, the Corrosion and Protection Centre at the University of Manchester Institute of Science and Technology (UMIST) and was instrumental in initiating the Corrosion and Protection Centre Industrial Service, which, respectively, became the world's largest academic centre on the study of materials degradation and the world's largest corrosion consulting organization. While keeping active in research, he held increasingly senior administrative roles, where he established a specialist graduate school and helped prepare UMIST to full independence from the Victoria University of Manchester.
Amyand David Buckingham. 28 January 1930—4 February 2021
Authors: Clary David C. , Orr Brian J.
Published: December 2021

David Buckingham was a chemical physicist and theoretical chemist who made fundamental contributions to the understanding of optical, electric and magnetic properties of molecules. Born in Australia, he was an undergraduate at the University of Sydney and the first PhD research student of John Pople (FRS 1961) at Cambridge, and there he made significant advances in the theory of intermolecular forces and nonlinear optics. He then moved to Oxford, where he and his group performed the first direct measurement of a molecular electric quadrupole moment. He was elected to the first chair of theoretical chemistry at the University of Bristol, where he wrote a particularly influential article on molecular moments, higher-order polarizabilities and intermolecular forces. His next appointment was at the University of Cambridge as the first holder of the 1968 Chair of Chemistry, and he was head of a distinguished department of theoretical chemistry for 28 years. With colleagues he pioneered experiment and theory on vibrational optical activity and developed a powerful model to predict the structures of weakly-bound molecules. A man of broad interests and achievements, he played first class cricket in the 1950s.
Alan Herbert Cowley. 29 January 1934—2 August 2020
Authors: Jones Richard A. , Kemp Richard A. , Lasch Jonathan G. , Lattman Michael , Norman Nicholas C.
Published: December 2021

Alan Cowley was one of the most creative main group chemists of his generation, and had a central role in what was often described as the renaissance of main group chemistry. Throughout his career Alan always had an eye for what was new. In his early years as an independent researcher, Alan made many fundamental contributions to the chemistry of phosphorus, not only in terms of the synthesis of new compounds but also in their study by employing novel analytical and computational methods. Starting in the 1980s he was at the forefront of emerging research into low-coordinate phosphorus chemistry and made seminal contributions in the areas of multiply bonded species, such as phosphenium ions and diphosphenes, as well as in the transition metal coordination chemistry of phosphinidenes. In the second half of his career, Alan also turned his attention to the study of single source precursors for important solid-state electronic materials, many of which were far superior to known examples. In all of the many areas in which Alan worked, he was a great collaborator with colleagues and researchers across the world, both in chemistry and in other disciplines. This was made all the easier by Alan's charm and easy-going nature, which was also manifest in the interactions he had with his many group members over a period of almost half a century. Alan was a gentleman in every sense and is much missed by friends, colleagues, collaborators and family.
Wind-driven and buoyancy-driven circulation in the subtropical North Atlantic Ocean
Authors: Bryden Harry L.
Published: December 2021

Continuous observations of ocean circulation at 26°N in the subtropical Atlantic Ocean have been made since April 2004 to quantify the strength and variability in the Atlantic Meridional overturning circulation (AMOC), in which warm, upper waters flow northward and colder deep waters below 1100 m depth return southward. The principal components of the AMOC are northward western boundary current transport in the Gulf Stream and Antilles Current, northward surface Ekman transport and southward thermocline recirculation, all of which are generally considered to be part of the wind-driven circulation. Southward flowing deep waters below 1100 m depth are usually considered to represent the buoyancy-driven circulation. We argue that the Gulf Stream is partially wind-driven but also partially buoyancy-driven as it returns upper waters upwelled in the global ocean back to water mass formation regions in the northern Atlantic. Seasonal to interannual variations in the circulation at 26°N are principally wind-driven. Variability in the buoyancy-driven circulation occurred in a sharp reduction in 2009 in the southward flow of Lower North Atlantic Deep Water when its transport decreased by 30% from pre-2009 values. Over the 14-year observational period from 2004 to 2018, the AMOC declined by 2.4 Sv from 18.3 to 15.9 Sv.
Selection for biparental inheritance of mitochondria under hybridization and mitonuclear fitness interactions
Authors: Allison Tom M. , Radzvilavicius Arunas L. , Dowling Damian K.
Published: December 2021

Uniparental inheritance (UPI) of mitochondria predominates over biparental inheritance (BPI) in most eukaryotes. However, examples of BPI of mitochondria, or paternal leakage, are becoming increasingly prevalent. Most reported cases of BPI occur in hybrids of distantly related sub-populations. It is thought that BPI in these cases is maladaptive; caused by a failure of female or zygotic autophagy machinery to recognize divergent male-mitochondrial DNA ‘tags’. Yet recent theory has put forward examples in which BPI can evolve under adaptive selection, and empirical studies across numerous metazoan taxa have demonstrated outbreeding depression in hybrids attributable to disruption of population-specific mitochondrial and nuclear genotypes (mitonuclear mismatch). Based on these developments, we hypothesize that BPI may be favoured by selection in hybridizing populations when fitness is shaped by mitonuclear interactions. We test this idea using a deterministic, simulation-based population genetic model and demonstrate that BPI is favoured over strict UPI under moderate levels of gene flow typical of hybridizing populations. Our model suggests that BPI may be stable, rather than a transient phenomenon, in hybridizing populations.
Prenatal acoustic programming of mitochondrial function for high temperatures in an arid-adapted bird
Authors: Udino Eve , George Julia M. , McKenzie Matthew , Pessato Anaïs , Crino Ondi L. , Buchanan Katherine L. , Mariette Mylene M.
Published: December 2021

Sound is an essential source of information in many taxa and can notably be used by embryos to programme their phenotypes for postnatal environments. While underlying mechanisms are mostly unknown, there is growing evidence for the involvement of mitochondria—main source of cellular energy (i.e. ATP)—in developmental programming processes. Here, we tested whether prenatal sound programmes mitochondrial metabolism. In the arid-adapted zebra finch, prenatal exposure to ‘heat-calls’—produced by parents incubating at high temperatures—adaptively alters nestling growth in the heat. We measured red blood cell mitochondrial function, in nestlings exposed prenatally to heat- or control-calls, and reared in contrasting thermal environments. Exposure to high temperatures always reduced mitochondrial ATP production efficiency. However, as expected to reduce heat production, prenatal exposure to heat-calls improved mitochondrial efficiency under mild heat conditions. In addition, when exposed to an acute heat-challenge,LEAKrespiration was higher in heat-call nestlings, and mitochondrial efficiency low across temperatures. Consistent with its role in reducing oxidative damage,LEAKunder extreme heat was also higher in fast growing nestlings. Our study therefore provides the first demonstration of mitochondrial acoustic sensitivity, and brings us closer to understanding the underpinning of acoustic developmental programming and avian strategies for heat adaptation.
Molecular basis of parental contributions to the behavioural tolerance of elevated pCO2in a coral reef fish
Authors: Monroe Alison A. , Schunter Celia , Welch Megan J. , Munday Philip L. , Ravasi Timothy
Published: December 2021

Knowledge of adaptive potential is crucial to predicting the impacts of ocean acidification (OA) on marine organisms. In the spiny damselfish,Acanthochromis polyacanthus, individual variation in behavioural tolerance to elevated pCO2has been observed and is associated with offspring gene expression patterns in the brain. However, the maternal and paternal contributions of this variation are unknown. To investigate parental influence of behavioural pCO2tolerance, we crossed pCO2-tolerant fathers with pCO2-sensitive mothers and vice versa, reared their offspring at control and elevated pCO2levels, and compared the juveniles' brain transcriptional programme. We identified a large influence of parental phenotype on expression patterns of offspring, irrespective of environmental conditions. Circadian rhythm genes, associated with a tolerant parental phenotype, were uniquely expressed in tolerant mother offspring, while tolerant fathers had a greater role in expression of genes associated with histone binding. Expression changes in genes associated with neural plasticity were identified in both offspring types: the maternal line had a greater effect on genes related to neuron growth while paternal influence impacted the expression of synaptic development genes. Our results confirm cellular mechanisms involved in responses to varying lengths of OA exposure, while highlighting the parental phenotype's influence on offspring molecular phenotype.
Use of orthogonal serine integrases to multiplex plasmid conjugation and integration from E. coli into Streptomyces
Authors: Gao Hong , Smith Margaret C. M.
Published: December 2021

Some major producers of useful bioactive natural products belong to the genus

Streptomyces

or related actinobacteria. Genetic engineering of these bacteria and the pathways that synthesize their valuable products often relies on serine integrases. To further improve the flexibility and efficiency of genome engineering via serine integrases, we explored whether multiple integrating vectors encoding orthogonally active serine integrases can be introduced simultaneously into

Streptomyces

recipients via conjugal transfer and integration. Pairwise combinations of

Escherichia coli

donors containing vectors encoding orthogonal serine integrases were used in each conjugation. Using donors containing plasmids (of various sizes) encoding either the φBT1 or the φC31 integration systems, we observed reproducible simultaneous plasmid integration into

Streptomyces coelicolor

and Streptomyces lividans at moderate frequencies after conjugation. This work demonstrated how site-specific recombination based on orthogonal serine integrases can save researchers time in genome engineering experiments in

Streptomyces

.
Chryseobacterium lecithinasegens sp. nov., a siderophore-producing bacterium isolated from soil at the bottom of a pond
Authors: Kutsuna Ryo , Mashima Izumi , Miyoshi-Akiyama Tohru , Muramatsu Yuki , Tomida Junko , Kawamura Yoshiaki
Published: December 2021

Bacterial strain PAGU 2197T, which was isolated from soil collected from the bottom of a pond in Japan, is characterized in this study. Cells of strain PAGU 2197T were aerobic, Gram-negative, short rod-shaped, non-motile, flexirubin-producing, oxidase-positive, catalase-positive and lecithinase-negative. A phylogenetic study based on 16S rRNA gene sequences and multilocus sequence analysis (gyrB, rpoB and rpoD) indicated that strain PAGU 2197T belongs to the genus

Chryseobacterium

and is a member of an independent lineage including

Chryseobacterium tructae

CCUG 60111T (sequence similarity, 95.9 %),

Chryseobacterium lactis

CCUG 60566T (93.4 %) and

Chryseobacterium viscerum

CCUG 60103T (91.6 %). The average nucleotide identity values were 80.83–85.04 %. Because average nucleotide identity values of 95–96 % exceed the 70 % DNA–DNA hybridization cutoff value for species discrimination, strain PAGU 2197T represents a novel species in the genus

Chryseobacterium

. The genome of strain PAGU 2197T was 4 967 738 bp with a G+C content of 35.5 mol%. The sole respiratory quinone of strain PAGU 2197T was MK-6; the major cellular fatty acids were iso-C15 : 0, iso-C17 : 0 3OH, summed feature 3 (C16 : 1
 ω7c and/or C16 : 1
 ω6c) and summed feature 9 (iso-C17 : 1
 ω9c and/or C16 : 0 10-methyl); and the major polar lipids were phosphoglycolipids and phosphatidylethanolamine. These results indicate that strain PAGU 2197T should be classified as representing a novel species in the genus

Chryseobacterium

, for which the name Chryseobacterium lecithinasegens sp. nov. is proposed, with strain PAGU 2197T (=NBRC 114264T=CCUG 75150T) as the type strain.
Effect of Romosozumab on Trabecular Bone Score Compared to Anti-Resorptive Agents in Postmenopausal Women with Osteoporosis
Authors: Jeong Chaiho , Kim Jinyoung , Lim Yejee , Ha Jeonghoon , Kang Moo Il , Baek Ki-Hyun
Published: December 2021

Background: Romosozumab has shown significant improvement in bone mineral density (BMD) in previously reported trials. However, BMD reflects only bone strength and does not offer insight into the bone microarchitecture. The trabecular bone score (TBS) is a non-invasive tool used to assess bone microarchitecture. Several previous studies have evaluated the efficacy of anti-osteoporotic agents using the TBS. However, data regarding the potency of romosozumab based on the TBS is lacking. This retrospective observational cohort study demonstrated the impact of romosozumab use on the TBS.Methods: The primary outcome was the percentage change in the TBS from baseline to post-treatment. Postmenopausal osteoporosis patients were followed up for 6 and 12 months after romosozumab (210 mg monthly, N =10) and denosumab (60 mg every 6 months, N=21) or ibandronate (150 mg monthly, N=24) treatments, respectively. Patients who had previously used osteoporosis medications were included, if any the washout period was sufficient.Results: The percentage change in TBS from baseline to post-treatment was 2.53±2.98% (6 months, N=10; P=0.04), 0.59%±3.26% (12 months, N=21; P=0.48), and -0.45±3.66% (12 months, N=24; P=0.51) in the romosozumab, denosumab, and ibandronate groups, respectively. Romosozumab demonstrated a noticeable increase in TBS, although it did not reach the least significant change (5.8%) in TBS.Conclusions: Romosozumab improved the TBS in postmenopausal women with osteoporosis. TBS may be potentially useful for monitoring romosozumab treatment.
Stroke prevalence among isolated systolic hypertension subjects in Indonesia
Authors: Pamelasari Defi , Azam Mahalul , Fibriana Arulita Ika , Rahadian Arief , Saefurrohim Muhamad Zakki , Aljunid Syed Mohamed
Published: December 2021

Introduction

Hypertension has been known to be a decisive factor for stroke in the elderly; however, limited studies reported stroke risk factors in subjects with isolated systolic hypertension (ISH).

Methods

This cross-sectional survey was conducted using Riskesdas 2018 secondary data. Subjects aged 55 years who had a systolic blood pressure ≥140 mmHg and diastolic < 90 mmHg were included as the study sample. According to the National Institute of Health Research and Development, the Ministry of Health, Republic of Indonesia, all study variables were measured using household and individual questionnaires. The data were analyzed using the chi-square test and Fisher’s test.

Results

Of 3159 subjects with ISH 8.3% had a stroke, the risk factors that had a significant relationship with the prevalence of stroke (p<0.005) were gender (1,790; 1,420-2,256), smoking habits (1,645; 1,291-2,096), physical and mental stress (2,080; 1,618-2,673), area of residence (1,720; 1,331-2222), and education level (0.656; 0.515-0.835).

Conclusion

Prevalence of stroke among ISH in Indonesia was 8.3%. Female with smoking habits, had mental and physical stress, liviing in urban area, and had low level eduatcion were associated with the status of stroke in ISH subjects in Indonesia.
The interkingdom horizontal gene transfer in 44 early diverging fungi boosted their metabolic, adaptive and immune capabilities
Authors: Ciach Michał Aleksander , Pawłowska Julia , Górecki Paweł , Muszewska Anna
Published: December 2021

Numerous studies have been devoted to individual cases of horizontally acquired genes in fungi. It has been shown that such genes expand the hosts’ metabolic capabilities and contribute to their adaptations as parasites or symbionts. Some studies have provided an extensive characterization of the horizontal gene transfer (HGT) in Dikarya. However, in the early diverging fungi (EDF), a similar characterization is still missing. In order to fill this gap, we have designed a computational pipeline to obtain a statistical sample of reliable HGT events with a possibly minimal number of false detections. We have analyzed 44 EDF proteomes and identified 829 xenologs in fungi ranging fromChytridiomycotaandBlastocladiomycotatoMucoromycota. We have identified several patterns and statistical properties of EDF HGT. Ancestrally aquatic fungi are generally more likely to acquire foreign genetic material than terrestrial ones. Endosymbiotic bacteria can be a source of useful xenologs, as exemplified by NOD-like receptors transferred toMortierellomycota. Closely related fungi have similar rates of intronization of xenologs. The number of post-transfer paralogs of a protein can be described by a heavy-tailed Yule-Simons distribution. Post-transfer gene fusions complicate the landscape of HGT. We have designed a methodology to obtain a reliable, statistical sample of inter-kingdom xenologs across the tree of life of EDF to give a preliminary characterization of their general properties and patterns. We show that HGT is driven by bursts of gene exchange and duplication, resulting in highly divergent numbers and molecular properties of xenologs between fungal lineages. A close ecological relationship with another organism seems to be a predisposing condition for HGT, but does not always result in an extensive gene exchange. We argue that there is no universal approach for HGT identification and inter- and intra kingdom transfers require tailored identification methods. Our results help to better understand how and to what extent HGT has shaped the metabolic, adaptive, and immune capabilities of fungi.
Structure of the RZZ complex and molecular basis of Spindly-driven corona assembly at human kinetochores
Authors: Raisch Tobias , Ciossani Giuseppe , d’Amico Ennio , Cmentowski Verena , Carmignani Sara , Maffini Stefano , Merino Felipe , Wohlgemuth Sabine , Vetter Ingrid R. , Raunser Stefan , Musacchio Andrea
Published: December 2021

In metazoans, a ≍1 megadalton (MDa) super-complex comprising the Dynein-Dynactin adaptor Spindly and the ROD-Zwilch-ZW10 (RZZ) complex is the building block of a fibrous biopolymer, the kinetochore fibrous corona. The corona assembles on mitotic kinetochores to promote microtubule capture and spindle assembly checkpoint (SAC) signaling. We report here a high-resolution cryo-EM structure that captures the essential features of the RZZ complex, including a farnesyl binding site required for Spindly binding. Using a highly predictivein vitroassay, we demonstrate that the SAC kinase MPS1 is necessary and sufficient for corona assembly at supercritical concentrations of the RZZ-Spindly (RZZS) complex, and describe the molecular mechanism of phosphorylation-dependent filament nucleation. We identify several structural requirements for RZZS polymerization in rings and sheets. Finally, we identify determinants of kinetochore localization and corona assembly of Spindly. Our results describe a framework for the long-sought-for molecular basis of corona assembly on metazoan kinetochores.
A point mutation in the nucleotide exchange factor eIF2B constitutively activates the integrated stress response by allosteric modulation
Authors: Wang Lan , Boone Morgane , Lawrence Rosalie E , Frost Adam , Walter Peter , Schoof Michael
Published: December 2021

In eukaryotic cells, stressors reprogram the cellular proteome by activating the integrated stress response (ISR). In its canonical form, stress-sensing kinases phosphorylate the eukaryotic translation initiation factor eIF2 (eIF2-P), which ultimately leads to reduced levels of ternary complex required for initiation of mRNA translation. Translational control is primarily exerted through a conformational switch in eIF2’s nucleotide exchange factor, eIF2B, which shifts from its active A-State conformation to its inhibited I-State conformation upon eIF2-P binding, resulting in reduced nucleotide exchange on eIF2. Here, we show functionally and structurally how a single histidine to aspartate point mutation in eIF2B’s β subunit (H160D) mimics the effects of eIF2-P binding by promoting an I-State like conformation, resulting in eIF2-P independent activation of the ISR. These findings corroborate our previously proposed (Schoof et al. 2021) A/I-State model of allosteric ISR regulation.
The Direct Subjective Refraction: Unsupervised measurements of the subjective refraction using defocus waves
Authors: -Lopez Victor Rodriguez , Hernandez-Poyatos Alfonso , Dorronsoro Carlos
Published: December 2021

We present the Direct Subjective Refraction (DSR), a new subjective refraction method, and validate it vs the Traditional Subjective Refraction (TSR) and an unsupervised version of it (UTSR). We project an optotunable lens onto the eye to create Temporal Defocus Waves produces flicker and chromatic distortions, minimum when the mean optical power of the wave matches the spherical equivalent of the eye. 25 subjects performed the DSR visual and UTSR tasks without supervision. DSR is more repeatable than TSR and UTSR (standard deviations ±0.17D, ±0.28, and ±0.47D). The time per repetition of DSR is only 39s (almost 6 min for TSR). Cyclopegia severely affects UTSR, but not DSR, confirming that the DSR task de-activates the accommodative system. DSR is a new method to obtain the spherical equivalent that does not requires supervision and overpasses existing subjective methods in terms of accuracy, precision, and measurement time.
Engineering RNA viruses with unnatural amino acid to evoke adjustable immune response in mice
Authors: Zheng Zhetao , Wang Yu , Wu Xuesheng , Zhang Haoran , Chen Hongmin , Lin Haishuang , Shen Yuxuan , Xia Qing
Published: December 2021

Ribonucleic acid (RNA) viruses pose heavy burdens on public-health systems. Synthetic biology holds great potential for artificially controlling their replication, a strategy that could be used to attenuate infectious viruses but is still in the exploratory stage. Herein, we used the genetic-code expansion technique to convert Enterovirus 71 (EV71), a model of RNA virus, into a controllable EV71 strain carrying the unnatural amino acid (UAA) Nε-2-azidoethyloxycarbonyl-L-lysine (NAEK), which we termed an EV71-NAEK virus. EV71-NAEK could recapitulate an authentic NAEK time- and dose-dependent infection in vitro and in vivo, which could serve as a novel method to manipulate virulent viruses in conventional laboratories. We further validated the prophylactic effect of EV71-NAEK in two mouse models. In susceptible parent mice, vaccination with EV71-NAEK elicited a strong immune response and potentially protected their neonatal offspring from lethal challenge similar to that of commercial vaccines. Meanwhile, in transgenic mice harboring a PylRS-tRNAPyl pair, substantial elements of genetic-code expansion technology, EV71-NAEK evoked an adjustable neutralizing-antibody response in a strictly external NAEK dose-dependent manner. These findings suggested that EV71-NAEK could be the basis of a feasible immunization program for populations with different levels of immunity. Moreover, we expanded the strategy to generate controllable coxsackieviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for conceptual verification. In combination, these results could underlie a competent strategy for attenuating viruses and priming the immune system via artificial control, which might be a promising direction for the development of amenable vaccine candidates and be broadly applied to other RNA viruses.
Machine Learning Model for Predicting Outcomes of Biologic Therapy in Psoriasis
Authors: Du Amy X. , Ali Zarqa , Ajgeiy Kawa K. , Dalager Maiken G. , Dam Tomas N. , Egebjerg Alexander , Nissen Christoffer V. S. , Skov Lone , Thomsen Simon Francis , Emam Sepideh , Gniadecki Robert
Published: December 2021

Background

Biological agents used for the therapy of psoriasis lose efficacy over time, which leads to discontinuation of the drug. Optimization of long-term biologic treatment is an area of medical need but there are currently no prediction tools for biologic drug discontinuation.

Objective

To compare the accuracy of the risk factor-based frequentist statistical model to machine learning to predict the 5-year probability of biologic drug discontinuation.

Methods

The national Danish psoriasis biologic therapy registry, Dermbio, comprising 6,172 treatment series with anti-TNF (Etanercept, Infliximab, Adalimumab), Ustekinumab, Guselkumab and anti-IL17 (Secukinumab and Ixekizumab) in 3,388 unique patients was used as data source. Hazard ratios (HR) were computed for all available predictive factors using Cox regression analysis. Different machine learning (ML) models for the prediction of 5-year risk of drug discontinuation were trained using the 5-fold cross validation technique and using 10 clinical features routinely assessed in psoriasis patients as input variables. Model performance was assessed using the area under the receiver operating characteristic curve (AUC).

Results

The lowest 5-year risk of discontinuation was associated with therapy with ustekinumab or ixekizumab, male sex and no previous exposure to biologic therapy. The predictive model based on those risk factors had an AUC of 0.61. The best ML model (gradient boosted tree) had an AUC of 0.85.

Conclusions

A machine learning-based approach, more than a statistical model, accurately predicts the risk of discontinuation of biologic therapy based on simple patient variables available in clinical practice. ML might be incorporated into clinical decision making.
Mitochondria-targeted antioxidant supplementation augments acute exercise-induced increases in muscle PGC1α mRNA and improves training-induced increases in peak power independent of mitochondrial content and function in untrained middle-aged men
Authors: Broome S. C. , Pham T. , Braakhuis A. J. , Narang R. , Wang H. W. , Hickey A. J. R. , Mitchell C. J. , Merry T. L.
Published: December 2021

The role of mitochondrial ROS production and signalling in muscle adaptations to exercise training has not been explored in detail. Here we investigated the effect of supplementation with the mitochondria-targeted antioxidant MitoQ on a) the skeletal muscle mitochondrial and antioxidant gene transcriptional response to acute high-intensity exercise and b) skeletal muscle mitochondrial content and function following exercise training. In a randomised, double-blind, placebo-controlled, parallel design study, 23 untrained men (age: 44 ± 7 years, VO2peak: 39.6 ± 7.9 ml/kg/min) were randomised to receive either MitoQ (20 mg/d) or a placebo for 10 days before completing a bout of high-intensity interval exercise (cycle ergometer, 10 × 60 s at VO2peakworkload with 75 s rest). Blood samples and vastus lateralis muscle biopsies were collected before exercise and immediately and 3 hours after exercise. Participants then completed high-intensity interval training (HIIT; 3 sessions per week for 3 weeks) and another blood sample and muscle biopsy were collected. MitoQ supplementation augmented acute exercise-induced increases in skeletal muscle mRNA expression of the major regulator of proteins involved in mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α). Despite this, training-induced increases in skeletal muscle mitochondrial content were unaffected by MitoQ supplementation. HIIT-induced increases in VO2peakand 20 km time trial performance were also unaffected by MitoQ while MitoQ augmented training-induced increases in peak power achieved during the VO2peaktest. These data suggest that MitoQ supplementation enhances the effect of training on peak power, which may be related to the augmentation of skeletal muscle PGC1α expression following acute exercise. However, this effect does not appear to be related to an effect of MitoQ supplementation on HIIT-induced mitochondrial biogenesis in skeletal muscle and may therefore be the result of other adaptations mediated by PGC1α.
Genetic factors affecting immune phenotypes in type 1 diabetes
Authors: Chu Xiaojing , Janssen Anna W.M. , Koenen Hans , Chang Linzhung , He Xuehui , Joosten Irma , Stienstra Rinke , Kuijpers Yunus , Wijmenga Cisca , Xu Cheng-Jian , Netea Mihai , Tack Cees J. , Li Yang
Published: December 2021

Large inter-individual variability in immunological cell composition and function determines immune responses in general and susceptibility to immune-mediated diseases in particular. While much has been learned about the genetic variants relevant for type 1 diabetes, the pathophysiological mechanisms through which these variations exert their effects are unknown. In this study, we characterize the genetic factors influencing immune responses in patients with type 1 diabetes. Genetic variants that determine susceptibility to T1D significantly affect T cell composition. Specifically, the CCR5+ regulatory T cells associate with T1D through the CCR region, suggesting a shared genetic regulation. Genome-wide quantitative trait loci (QTL) mapping analysis of immune traits revealed 15 genetic loci that influence immune responses in T1D. Among them, 12 have never been reported in healthy population studies, implying a disease-specific genetic regulation. Altogether this study provides new insights into the genetic factors that affect immunological responses in T1D.
Parental perspectives on the grief and support needs of children and young people bereaved during the Covid-19 pandemic: Qualitative findings from a national survey
Authors: Harrop Emily , Goss Silvia , Longo Mirella , Seddon Kathy , Torrens-Burton Anna , Sutton Eileen , Farnell Damian JJ , Penny Alison , Nelson Annmarie , Byrne Anthony , Selman Lucy E.
Published: December 2021

Background

During the Covid-19 pandemic, many children and young people have experienced the death of close family members, whilst also facing unprecedented disruption to their lives. This study aimed to investigate the experiences and support needs of bereaved children and young people from the perspective of their parents and guardians.

Methods

We analysed cross-sectional qualitative free-text data from a survey of adults bereaved in the UK during the pandemic. Participants were recruited via media, social media, national associations and community/charitable organisations. Thematic analysis was conducted on free text data collected from parent/guardian participants in response to a survey question on the bereavement experiences and support needs of their children.

Results

Free-text data from 104 parent and grandparent participants was included. Three main themes were identified: the pandemic-related challenges and struggles experienced by children and young people; family support and coping; and support from schools and services. Pandemic-related challenges include the impacts of being separated from the relative prior to their death, isolation from peers and other family members, and disruption to daily routines and wider support networks. Examples were given of effective family coping and communication, but also of difficulties relating to parental grief and children’s existing mental health problems. Schools and bereavement organisations’ provision of specialist support was valued, but there was evidence of unmet need, with some participants reporting a lack of access to specialist grief or mental health support.

Conclusion

Children and young people have faced additional strains and challenges associated with pandemic bereavement. We recommend resources and initiatives that facilitate supportive communication within family and school settings, adequate resourcing of school and community-based specialist bereavement/mental health services, and increased information and signposting to the support that is available.
Pharmacokinetics of ß-d-N4-hydroxycytidine, the parent nucleoside of prodrug molnupiravir, in non-plasma compartments of patients with SARS-CoV-2 infection
Authors: FitzGerald Richard , Dickinson Laura , Else Laura , Fletcher Thomas , Hale Colin , Amara Alieu , Walker Lauren , Penchala Sujan Dilly , Lyon Rebecca , Shaw Victoria , Greenhalf William , Bullock Katie , Lavelle-Langham Lara , Reynolds Helen , Painter Wendy , Holman Wayne , Ewings Sean , Griffiths Gareth , Khoo Saye
Published: December 2021

ß-d-N4-hydroxycytidine (NHC), the parent nucleoside of molnupiravir, a COVID-19 antiviral, was quantified at sites of SARS-CoV-2 transmission in twelve patients enrolled in AGILE CST-2 (NCT04746183). Saliva, nasal and tear concentrations were 3, 21 and 22% that of plasma. Saliva and nasal NHC concentrations were significantly correlated with plasma (p<0.0001).
Deeply-Dyed Nanobead System Based Lateral Flow Assay for Rapid Point-of-Care Drug Testing
Authors: Fan Lingzhi , Wu Jianbing , Yang Jing , Li Fugang , Yan Wannian , Tan Fei , Zhang Madeline , Draz Mohamed S. , Han Huanxing , Zhang Pengfei
Published: December 2021

Point-of-care test (POCT), which allows for rapid and sensitive screening of drugs abuse, is essential and can significantly reduce the clinical, economic and social impact of the opioid crisis worldwide. However, the traditional gold nanoparticle-based lateral flow immunoassay strip is not sensitive enough for detection of trace drugs in hair sample. Herein, we aimed to develop a more specific system using a composite polymer-based nanobead that is deeply dyed with phthalocyanine or similar oil soluble dyes, and termed as deeply dyed nanobead (DDNB). The prepared composite nanobeads displayed a clear core-shell structure and the core/shell ratios were readily controlled by polymer/dye feeding ratios. The absorbance stable nanobeads capped with carboxyl groups were covalently conjugated with antibodies, and were employed for preparation of lateral flow immunoassay strips for sensitive detection of drugs in hair with naked eye. The developed platform allows the detection of drugs such as morphine and methamphetamine in hair samples within 13 min (including hair sample processing ∼5 min). The cut-off value of DDNB strip for methamphetamine detection with naked eye is down to concentration of 8.0 ng/mL, which is about 3.1 times more sensitive than the traditional gold nanoparticles based lateral flow immunoassay. Moreover, the colorful DDNB system has the potential for multiplexing detection of analytes at point-of-care settings and with low cost.
Likely community transmission of COVID-19 infections between neighboring, persistent hotspots in Ontario, Canada
Authors: Mucaki Eliseos J. , Shirley Ben C. , Rogan Peter K.
Published: December 2021

Introduction

This study aimed to produce community-level geo-spatial mapping of confirmed COVID-19 cases in Ontario, Canada in near real-time to support decision-making. This was accomplished by area-to-area geostatistical analysis, space-time integration, and spatial interpolation of COVID-19 positive individuals.

Methods

COVID-19 cases and locations were curated for geostatistical analyses from March 2020 through June 2021, corresponding to the first, second, and third waves of infections. Daily cases were aggregated according to designated forward sortation area [FSA], and postal codes [PC] in municipal regions covering Hamilton, Kitchener/Waterloo, London, Ottawa, Toronto, and Windsor/Essex county. Hotspots were identified with area-to-area tests including Getis-Ord Gi*, Global Moran’s I spatial autocorrelation, and Local Moran’s I asymmetric clustering and outlier analyses. Case counts were also interpolated across geographic regions by Empirical Bayesian Kriging, which localizes high concentrations of COVID-19 positive tests, independent of FSA or PC boundaries. TheGeostatistical Disease Epidemiology Toolbox, which is freely-available software, automates the identification of these regions and produces digital maps for public health professionals to assist in pandemic management of contact tracing and distribution of other resources.

Results/Discussion

This study provided indicators in real-time of likely, community-level disease transmission through innovative geospatial analyses of COVID-19 incidence data. Municipal and provincial results were validated by comparisons with known outbreaks at long-term care and other high density residences and on farms. PC-level analyses revealed hotspots at higher geospatial resolution than public reports of FSAs, and often sooner. Results of different tests and kriging were compared to determine consistency among hotspot assignments. Concurrent or consecutive hotspots in close proximity suggested potential community transmission of COVID-19 from cluster and outlier analysis of neighboring PCs and by kriging. Results were also stratified by population based-categories (sex, age, and presence/absence of comorbidities). Earlier recognition of hotspots could reduce public health burdens of COVID-19 and expedite contact tracing.