bluuebunny/crossref_metadata_2025 huggingface dataset:
Glial TGFβ activity promotes axon survival in peripheral nerves
Authors: Lassetter Alexandria P. , Corty Megan M. , Barria Romina , Sheehan Amy E. , Hill Jo , Aicher Sue A. , Fox A. Nicole , Freeman Marc R.
Published: September 2021

Axons can represent the majority of the volume of a neuron and are energetically very demanding. Specialized glia ensheathe axons and are believed to support axon function and maintenance throughout life, but molecular details of glia-neuron support mechanisms remain poorly defined. Here we identify a collection of secreted and transmembrane genes that are required in glia for long-term axon survival in vivo. We show that key components of the TGFβ superfamily are required cell-autonomously in glia for peripheral nerve maintenance, although their loss does not disrupt glial morphology. We observe age-dependent neurodegeneration in the absence of glial TGFβ signaling that can be rescued by genetic blockade of Wallerian degeneration. Our data argue that glial TGFβ signaling normally acts to promote axon survival and suppress neurodegeneration.

Significance Statement

Axon maintenance is critical to preserving the functional integrity of the nervous system across animal lifespan. Glia contribute to axon maintenance, but their precise roles remain to be fully characterized. We identify glial genes that regulate axon support and provide new molecular insight into the means by which glia promote axon survival, which may help explain why neurodegeneration occurs when glia are lost in disease. We show that TGFβ signaling in mature glia is essential for long-term maintenance of axons, and that loss of TGFβ signaling activates an axon death signaling pathway.
Extensive germline-somatic interplay drives prostate cancer through HNF1B co-option of TMPRSS2-ERG
Authors: Giannareas Nikolaos , Zhang Qin , Yang Xiayun , Tian Yijun , Zhang Peng , Yang Yuehong , Manninen Aki , Wang Liang , Wei Gong-Hong
Published: September 2021

Genome-wide association studies have identified 270 loci conferring risk for prostate cancer (PCa), yet the underlying biology and clinical impact remain to be investigated. Here we observe an enrichment of transcription factor genes including HNF1B within PCa risk-associated regions. While focused on the 17q12/HNF1B locus, we find a strong eQTL for HNF1B and multiple potential causal variants involved in the regulation of HNF1B expression in PCa. An unbiased genome-wide co-expression analysis reveals PCa-specific somatic TMPRSS2-ERG fusion as a transcriptional mediator of this locus and the HNF1B eQTL signal is ERG fusion status dependent. We investigate the role of HNF1B and find its involvement in several pathways related to cell cycle progression and PCa severity. Furthermore, HNF1B interacts with TMPRSS2-ERG to co-occupy large proportion of genomic regions with a remarkable enrichment of additional PCa risk alleles. We finally show that HNF1B co-opts ERG fusion to mediate mechanistic and biological effects of the PCa risk-associated locus 17p13.3/VPS53/FAM57A/GEMIN4. Taken together, we report an extensive germline-somatic interaction between TMPRSS2-ERG fusion and genetic variations underpinning PCa risk association and progression.
In vitro antimicrobial and cytotoxic activity of Lippia origanoides essential oil against bacteria of potential health concern
Authors: Quiguanás-Guarín Edwin Stiven , Agudelo Juan Pablo Bedoya , López-Carvajal Jhon Esteban , Tabares Yuly Andrea Ramírez , Sanabria Leonardo Padilla , Castaño-Osorio Jhon Carlos
Published: September 2021

Due to the growing resistance they develop of bacteria to drugs, the search for alternatives in natural products is considered important such as Lippia origanoides essential oil. Here, the antibacterial activity of the oil and two of its major chemical components were tested against bacteria of potential health concern. The cytotoxicity of these compounds was evaluated in human erythrocytes and Vero cells. 51 compounds were identified in the LOEO, being terpinen-4-ol, γ-Terpinene, citronellal and thymol the main. LOEO and thymol showed antibacterial activity from 904 μg/mL and 200 μg/mL, respectively. γ-Terpinene did not show activity any concentration tested. LOEO showed hemolysis at concentration of 3000 μg/mL and thymol at 100 μg/mL. LOEO and thymol showed cytotoxicity in the evaluated cell lines at 250 μg/mL and 100 μg/mL, respectively. These compounds have a moderate cytotoxicity so it’s considered necessary to study alternatives to reduce the in vitro cytotoxicity of these compounds.

Abstract Figure
Structural and Biochemical Rationale for Enhanced Spike Protein Fitness in Delta and Kappa SARS-CoV-2 Variants
Authors: Saville James W. , Mannar Dhiraj , Zhu Xing , Srivastava Shanti S. , Berezuk Alison M. , Demers Jean-Philippe , Zhou Steven , Tuttle Katharine S. , Sekirov Inna , Kim Andrew , Li Wei , Dimitrov Dimiter S. , Subramaniam Sriram
Published: September 2021

The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In this study, we assess structural and biochemical aspects of viral fitness for these two variants using cryo-electron microscopy (cryo-EM), ACE2-binding and antibody neutralization analyses. Both variants demonstrate escape of antibodies targeting the N-terminal domain, an important immune hotspot for neutralizing epitopes. Compared to wild-type and Kappa lineages, Delta variant spike proteins show modest increase in ACE2 affinity, likely due to enhanced electrostatic complementarity at the RBD-ACE2 interface, which we characterize by cryo-EM. Unexpectedly, Kappa variant spike trimers form a novel head-to-head dimer-of-trimers assembly, which we demonstrate is a result of the E484Q mutation. The combination of increased antibody escape and enhanced ACE2 binding provides an explanation, in part, for the rapid global dominance of the Delta variant.
Changes to the mtDNA copy number during yeast culture growth
Authors: Galeota-Sprung Ben , Fernandez Amy , Sniegowski Paul
Published: September 2021

We show that the mtDNA copy number in growing cultures of the yeast Saccharomyces cerevisiae increases by a factor of up to 4, being lowest (∼10 per haploid genome) and stable during rapid fermentative growth, and highest at the end of the respiratory phase. When yeast are grown on glucose, the onset of the mtDNA copy number increase coincides with the early stages of the diauxic shift, and the increase continues through respiration. A lesser yet still substantial copy number increase occurs when yeast are grown on a nonfermentable carbon source, i.e. when there is no diauxic shift. The mtDNA copy number increase during and for some time after the diauxic shift is not driven by an increase in cell size. The copy number increase occurs in both haploid and diploid strains, but is markedly attenuated in a diploid wild isolate that is a ready sporulator. Strain-to-strain differences in mtDNA copy number are least apparent in fermentation and most apparent in late respiration or stationary phase. While changes in mitochondrial morphology and function were previously known to accompany changes in physiological state, it had not been previously shown that the mtDNA copy number changes substantially over time in a clonal growing culture. The mtDNA copy number in yeast is therefore a highly dynamic phenotype.
Signatures of plant defense response specificity mediated by herbivore-associated molecular patterns in legumes
Authors: Steinbrenner Adam D. , Saldivar Evan , Hodges Nile , Chaparro Antonio F. , Schmelz Eric A.
Published: September 2021

I.

Chewing herbivores activate plant defense responses through a combination of mechanical wounding and elicitation by herbivore associated molecular patterns (HAMPs). HAMPs are wound response amplifiers; however, specific defense outputs may also exist that strictly require HAMP-mediated defense signaling. To investigate HAMP-mediated signaling and defense responses, we characterized cowpea transcriptome changes following elicitation by inceptin, a peptide HAMP common in Lepidoptera larvae oral secretions. Following inceptin treatment, we observed large-scale reprogramming of the transcriptome consistent with 3 different response categories: 1) amplification of mechanical wound responses, 2) temporal extension through accelerated or prolonged responses, and 3) examples of inceptin-specific elicitation and suppression. At both early and late timepoints, namely 1 and 6 hours, large sets of transcripts specifically accumulated following inceptin elicitation but not wounding alone. Further inceptin-regulated transcripts were classified as reversing changes induced by wounding alone. Within key signaling and defense related gene families, inceptin-elicited responses commonly targeted select subsets of wound-induced transcripts. Transcripts displaying the largest inceptin-elicited fold-changes included terpene synthases (TPS) and peroxidases (POX) that correspond with induced volatile production and increased peroxidase activity in cowpea. Characterization of inceptin-elicited cowpea defenses via heterologous expression in Nicotiana benthamiana demonstrated that specific cowpea TPS and POX were able to confer terpene emission and the reduced growth of beet armyworm (Spodoptera exigua) herbivores, respectively. Collectively, our present findings in cowpea support a model where HAMP-elicitation both amplifies concurrent wound responses and specifically contributes to the activation of selective outputs associated with direct and indirect anti-herbivore defenses.

II.

Significance Statement

Plants recognize herbivore-associated molecular patterns (HAMPs) to induce defenses, but interactions with the more general wound response are not well-understood. We leveraged a known HAMP-receptor interaction to characterize transcriptomic modulation of the wound response by the peptide HAMP, inceptin. Inceptin not only amplifies wound responses, but can specifically induce or suppress transcripts with demonstrated functions in direct and indirect defense against herbivores. The plant immune system thus recognizes HAMPs to fine-tune wound responses against herbivory.
Biosynthesis of linear protein nanoarrays using the flagellar axoneme
Authors: Ishikawa Hiroaki , Tian Jie L. , Yu Jefer E. , Marshall Wallace F. , Qin Hongmin
Published: September 2021

Applications in biotechnology and synthetic biology often make use of soluble proteins, but there are many potential advantages to anchoring enzymes to a stable substrate, including stability and the possibility for substrate channeling. To avoid the necessity of protein purification and chemical immobilization, there has been growing interest in bio-assembly of protein-containing nanoparticles, exploiting the self-assembly of viral capsid proteins or other proteins that form polyhedral structures. But these nanoparticle are limited in size which constrains the packaging and the accessibility of the proteins. The axoneme, the insoluble protein core of the eukaryotic flagellum or cilium, is a highly ordered protein structure that can be several microns in length, orders of magnitude larger than other types of nanoparticles. We show that when proteins of interest are fused to specific axonemal proteins and expressed in living cells, they become incorporated into linear arrays which have the advantages of high protein loading capacity, high stability, and single-step purification with retention of biomass. The arrays can be isolated as membrane enclosed vesicle or as exposed protein arrays. The approach is demonstrated for both fluorescent proteins and enzymes, and in the latter case it is found that incorporation into axoneme arrays provides increased stability for the enzyme.
Mpe1 senses the polyadenylation signal in pre-mRNA to control cleavage and polyadenylation
Authors: Rodríguez-Molina Juan B. , O’Reilly Francis J. , Sheekey Eleanor , Maslen Sarah , Skehel J. Mark , Rappsilber Juri , Passmore Lori A.
Published: September 2021

Most eukaryotic messenger RNAs (mRNAs) are processed at their 3’-end by the cleavage and polyadenylation factor (CPF/CPSF). CPF mediates endonucleolytic cleavage of the pre-mRNA and addition of a polyadenosine (poly(A)) tail, which together define the 3’-end of the mature transcript. Activation of CPF is highly regulated to maintain fidelity of RNA processing. Here, using cryoEM of yeast CPF, we show that the Mpe1 subunit directly contacts the polyadenylation signal sequence in nascent pre- mRNA. This RNA-mediated link between the nuclease and polymerase modules promotes activation of the CPF endonuclease and controls polyadenylation. Mpe1 rearrangement is antagonized by another subunit, Cft2.In vivo, depletion of Mpe1 leads to widespread defects in transcription termination by RNA Polymerase II, resulting in transcription interference on neighboring genes. Together, our data suggest that Mpe1 plays a major role in selecting the cleavage site, activating CPF and ensuring timely transcription termination.
A new mathematical model of phyllotaxis to solve the genuine puzzle spiromonostichy
Authors: Yonekura Takaaki , Sugiyama Munetaka
Published: September 2021

The view is widely accepted that the inhibitory effect of existing leaf primordia on new primordium formation determines phyllotactic patterning. Previous studies have shown that mathematical models based on such inhibitory effect can generate most of phyllotactic patterns. However, a few types of phyllotaxis still remain unaddressed. A notable example is costoid phyllotaxis showing spiromonostichy, which is characterized by a steep spiral with a small divergence angle and is unique to Costaceae plants. Costoid phyllotaxis has been called a “genuine puzzle” because it seems to disagree with the inhibitory effect-based mechanism. In an attempt to produce a steep spiral pattern, we developed a new mathematical model assuming that each leaf primordium emits not only the inhibitory effect but also some inductive effect. Computer simulations with the new model successfully generated a steep spiral pattern when these two effects met a certain relationship. The obtained steep spiral matched the real costoid phyllotaxis observed with Costus megalobractea. We also found by the mathematical model analysis that the early phyllotactic transition in the seedlings of this plant can be explained by the SAM enlargement.
Chronic exposure to odors at naturally occurring concentrations triggers limited plasticity in early stages ofDrosophilaolfactory processing
Authors: Gugel Zhannetta V. , Maurais Elizabeth , Hong Elizabeth J.
Published: September 2021

In insects and mammals, olfactory experience in early life alters olfactory behavior and function in later life. In the vinegar flyDrosophila, flies chronically exposed to a high concentration of a monomolecular odor exhibit reduced behavioral aversion to the familiar odor when it is re- encountered. This change in olfactory behavior has been attributed to selective decreases in the sensitivity of second-order olfactory projection neurons (PNs) in the antennal lobe that respond to the overrepresented odor. However, since odorant compounds do not occur at similarly high concentrations in natural sources, the role of odor experience-dependent plasticity in natural environments is unclear. Here, we investigated olfactory plasticity in the antennal lobe of flies chronically exposed to odors at concentrations that are typically encountered in natural odor sources. These stimuli were chosen to each strongly and selectively excite a single PN type to saturating firing rates, facilitating a rigorous assessment of the selectivity of olfactory plasticity for PNs directly excited by overrepresented stimuli. Unexpectedly, we found that chronic exposure to three such odors did not result in decreased PN sensitivity, but rather mildly increased responses to weak stimuli in most PN types. Odor-evoked PN activity in response to stronger stimuli was mostly unaffected by odor experience. When present, plasticity was observed broadly in multiple PN types and thus was not selective for PNs receiving direct input from the chronically active ORNs. We further investigated the DL5 olfactory coding channel and found that chronic odor-mediated excitation of its input ORNs did not affect PN intrinsic properties, local inhibitory innervation, ORN responses, or ORN-PN synaptic strength; however, broad-acting lateral excitation evoked by some odors was increased. These results show that PN odor coding is only mildly affected by strong persistent activation of a single olfactory input, highlighting the stability of early stages of insect olfactory processing to significant perturbations in the sensory environment.
Dissecting the subtropical adaptation traits and cuticle synthesis pathways via the genome of the subtropical blueberryVaccinium darrowii
Authors: Cui Fuqiang , Ye Xiaoxue , Li Xiaoxiao , Yang Yifan , Hu Zhubing , Overmyer Kirk , Brosché Mikael , Yu Hong , Salojärvi Jarkko
Published: September 2021

Vaccinium darrowiiis a subtropical wild blueberry species, which was used to breed economically important southern highbush cultivars. The adaptation traits ofV. darrowiito subtropical climate would provide valuable information for breeding blueberry and perhaps other plants, especially against the background of global warming. Here, we assembled theV. darrowiigenome into 12 pseudochoromosomes using Oxford Nanopore long reads complemented with Hi-C scaffolding technologies, and predicted 41 815 genes using RNAseq evidence. Syntenic analysis across threeVacciniumspecies revealed a highly conserved genome structure, with the highest collinearity betweenV. darrowiiandV. corymbosum. This conserved genome structure may explain the high fertilization during crossbreeding betweenV. darrowiiand other blueberry cultivars. Gene expansion and tandem duplication analysis indicated possible roles of defense and flowering associated genes in adaptation ofV. darrowiito the subtropics. The possibleSOC1genes inV. darrowiiwere identified with phylogeny and expression analysis. Blueberries are covered in a thick cuticle layer and contain anthocyanins, which confer their powdery blue color. Using RNA-sequencing, the cuticle biosynthesis pathways ofVacciniumspecies were delineated here inV. darrowii. This result could serve as a reference for breeding berries with customer-desired colors. TheV. darrowiireference genome, together with the unique traits of this species, including diploid genome, short vegetative phase, and high compatibility in hybridization with other blueberries, makeV. darrowiia potential research model for blueberry species.
Central hormone-sensitive lipase is located at synapses and is necessary for normal memory performance in mice
Authors: Skoug Cecilia , Holm Cecilia , Duarte João M.N.
Published: September 2021

Hormone-sensitive lipase (HSL) is mainly present in the adipose tissue where it hydrolyses diacylglycerol. Although brain expression of HSL has been reported, its presence in different cellular compartments is uncertain, and its role in regulating brain lipid metabolism remains hitherto unexplored. We propose that HSL has a role in regulating the availability of bioactive lipids necessary for adequate neuronal function. Therefore, we tested the hypothesis that dampening HSL activity leads to brain dysfunction. We found HSL protein and activity throughout all the mouse brain, localised in neurons and especially enriched in synapses. HSL null mice were then analysed using a battery of behavioural tests. Relative to wild-type littermates, HSL null mice showed impaired short- and long-term memory, but preserved exploratory behaviours. Molecular analysis of the cortex and hippocampus showed increased expression of genes involved in glucose utilization in the hippocampus but not cortex of HSL null mice compared to controls. Lipidomics analyses indicated an impact of HSL deletion on the profile of bioactive lipids, including endocannabinoids and eicosanoids that are known to modulate neuronal activity, cerebral blood blow and inflammation processes. Accordingly, mild increases in expression of pro-inflammatory cytokines suggest low grade inflammation in HSL null mice compared to littermates. We conclude that HSL has a homeostatic role in maintaining pools of lipids that are needed for brain function. It remains to be tested, however, whether the recruitment of HSL for the synthesis of these lipids occurs during increased neuronal activity, or whether HSL participates in neuroinflammatory responses.
Bringing TrackMate into the era of machine-learning and deep-learning
Authors: Ershov Dmitry , Phan Minh-Son , Pylvänäinen Joanna W. , Rigaud Stéphane U. , Le Blanc Laure , Charles-Orszag Arthur , Conway James R. W. , Laine Romain F. , Roy Nathan H. , Bonazzi Daria , Duménil Guillaume , Jacquemet Guillaume , Tinevez Jean-Yves
Published: September 2021

TrackMate is an automated tracking software used to analyze bioimages and distributed as a Fiji plugin. Here we introduce a new version of TrackMate rewritten to improve performance and usability, and integrating several popular machine and deep learning algorithms to improve versatility. We illustrate how these new components can be used to efficiently track objects from brightfield and fluorescence microscopy images across a wide range of bio-imaging experiments.
Technology facilitation on inclusive learning; higher education institutions in Sri Lanka
Authors: Kirupainayagam David Shiyam , Sutha Jayaranjani
Published: September 2021

Purpose

The application of technology to higher education is contributing in many ways to create a highly adaptable, inclusive learning environment for all. This study intends to analyze the role of technology facilitation in creating an inclusive learning environment in the higher education institutions (HEIs), which would connect multi-ethnic students and academics effectively in the Sri Lankan context. Therefore, the primary aim of this study is to explore how technology facilitates inclusive learning in HEIs.

Design/methodology/approach

Based on the qualitative research approach, this study generated data from 30 undergraduates and 10 academics from 5 national universities in Sri Lanka to evaluate the effectiveness of technological facilitation in promoting inclusive learning. The data were then thematically analyzed using NVivo 10.

Findings

The nature of technology facilitation in HEIs and influencing factors such as the internet, search engines, mobile apps and software, cost involved, upgraded knowledge, time efficiency and technological devices. Further, the factors contribute to the HEIs and the benefits realized, such as information gathering, time-saving, cost reduction, information sharing, connective communication, easy learning and online services. On the other hand, challenges such as the involved parties’ resistance to technological change, inadequate infrastructure facilities, lack of technical knowledge, negative perceptions and behaviors, technical failures and health issues will also be assessed.

Research limitations/implications

Implications for policy and practice include a thorough understanding of the nature of technology facilitation in an inclusive environment. The researcher has recommended some strategies and mechanisms to the policymakers that will guide them to use technology as a tool to enhance the inclusive learning practices within HEIs.

Originality/value

This paper presents an original review and it contextualizes the technology facilitations in respect of the inclusive learning environment in HEIs.
Functional niches of cleanerfish species are mediated by habitat use, cleaning intensity and client selectivity
Authors: Côté Isabelle M. , Brandl Simon J.
Published: September 2021

An animal's functional niche is a complex, multidimensional construct, mediated by an individual's morphology, physiology and behaviour. Behavioural aspects of the niche can be difficult to quantify, as their expression is often subtle and tailored to an infinite number of different situations that involve sophisticated mechanisms such as mutualisms, species dominance or fear effects.

The extreme diversity of tropical fish assemblages has led to extensive debate over the extent to which species differ in their resource use and functional role. Ectoparasite removal by cleanerfish species is considered a behaviourally complex interspecific interaction in vertebrates, but differences in the services rendered by various species of cleanerfish, and potential consequences for the range of clients (i.e. resources) they attract, have rarely been examined.

Here, we quantify differences among three coexisting species of morphologically similar cleaner wrasses (Labroides bicolor, L. dimidiatus and L. pectoralis) in the global centre of marine biodiversity, the Coral Triangle.

We found no clear taxonomic partitioning of clients among cleanerfishes. However, the three cleanerfish species exhibited distinct habitat preferences, and differed in their cleaning intensity: L. bicolor serviced the fewest species and clients, while L. pectoralis serviced the most clients and spent the most time cleaning.

Accordingly, L. pectoralis showed no preference for clients based on client size or abundance, while both L. bicolor and L. dimidiatus had a higher likelihood of interacting with clients based on their size (larger client species in L. bicolor, smaller client species in L. dimidiatus) and abundance (more abundant client species for both).

Our results suggest that the services rendered by the three species of cleanerfishes differ in their spatial availability, quality and selectivity, thus permitting the coexistence of these species despite their ecological similarity. This, in turn, creates a complex seascape of species‐specific cleaning services that underpins crucial biotic interactions in the ocean's most diverse ecosystem.
Comparing opportunistic and strategic removal efforts to manage invasive fish species using a dynamic multi‐state occupancy model
Authors: Rogosch Jane S. , Olden Julian D.
Published: September 2021

Growing ecological and economic impacts of invasive species have heightened the need for new science to inform management that prevents and counteracts their impacts. A persistent challenge is to identify whether removal programs, which range widely in their approach, are successful. Given the variability in dynamic environmental conditions and complex biotic interactions among species, identifying the effectiveness of removal programs intended to lessen nonnative species impacts is inherently difficult. We were interested in whether strategic (i.e. significant coordination and investment) and opportunistic (i.e. temporally periodic and implemented at smaller spatial scales) removal programs result in measurable, and if so, comparable benefits to native fish conservation.

We applied a novel dynamic co‐occurrence model to evaluate nonnative fish removal efforts across the Lower Colorado River Basin (USA), while accounting for potential interspecific species interactions and variable hydrologic regimes. We examined the co‐occurrence of two native fishes of conservation concern and two other representative fishes of endemic assemblages, each paired with a nonnative species hypothesized to negatively affect the focal native species.

Our model results suggest that both strategic and opportunistic removal programs result in lower extinction probabilities for native fishes (1.2 times greater for strategic programs), especially species of conservation concern, when compared to locations and years not subject to removal. Nonnative species presence mediated native species dynamics, most notably by increasing native species extinction probability during drought years regardless of removal program. Removal efforts resulted in modest changes in extinction probabilities for nonnative fishes, but no measurable effect on colonization dynamics.

Synthesis and applications. Both strategic and opportunistic nonnative fish removal programs can help meet recovery goals for native fishes, even over large areas and long after nonnative species are established. Quantifying dynamics of native and nonnative fishes in a multi‐state dynamic co‐occurrence model highlights the collective management value of individual programs at regional scales. Increased evaluation of ongoing nonnative removal programs remains critical to ensuring that management actions are warranted and effective in meeting desired conservation outcomes.
Digestive tube of an herbivorous fish (Rhytiodus microlepis) from the Amazonian floodplain lakes: A morphological and histochemical study
Authors: de Matos Lorena Vieira , de Oliveira Maria Inês Braga , de Oliveira Malta José Celso , da Silva Grazyelle Sebrenski
Published: September 2021

This study describes the morphology and histochemistry of the digestive tube of the herbivorous fish Rhytiodus microlepis, which is commonly found in the Amazonian floodplain lakes, Brazil. Thirty‐eight fish were used in this study. The digestive tube was measured and dissected for anatomical description, and stained with (i) haematoxylin and eosin, for histological analyses; (ii) periodic acid–Schiff, for detected neutral mucins; and (iii) Alcian Blue (AB) pH 1.0 and 2.5 for acid and sulphated acid mucins. The oesophagus, with its secretory cells and taste buds, is adapted for lubrication of vegetable matter, resistance to friction and reception of stimuli. The stomach is U‐shaped and rich in gastric glands, particularly in cardiac and fundic regions, which are adapted to receive large amounts of food, and promotes the digestion. The intestine comprises more than 70% of the digestive tube. All portions of the intestine, except the rectum, have the same pattern of mucosal folds, and the goblet cells reacted positively to all histochemical methods (PAS, AB 1.0 and 2.5), while rodlet cells reacted only to periodic acid–Schiff (PAS) staining. Neutral mucins and sulphated acid mucins predominated in the anterior portion of the intestine and a high concentration of carboxylated acid mucosubstances were present in the other portions. The rectum showed a strong reaction to all histochemical methods. The muscular layer of the intestine consists of three layers, which showed features presumably related to the rigid nature of the food. A simple squamous epithelium constitutes the serous layer over the entire length of the tube.
Recruitment of adults with moderate eczema for a randomised trial: Comparison of traditional versus modern methods
Authors: Spada Fabrizio , Harrison Ian P. , Barnes Tanya M. , Greive Kerryn A. , Daniels Daisy , Townley Joshua P. , Mostafa Niyaz , Fong Andrew T. , Tong Philip L. , Shumack Stephen
Published: September 2021

Background

Clinical trial recruitment is challenging for investigators who often overestimate the pool of qualified, willing subjects. Moreover, there is a paucity of literature, particularly in dermatology, regarding recruitment and the comparative success of advertising strategies.

Methods

Both ‘traditional’ (physician referral, newspaper and radio advertisements, letterbox drops, posters/flyers, word‐of‐mouth) and ‘modern’ (patient recruitment services, social media, Google advertisements, websites, email) recruitment methods were used to enrol 100 patients (>18 years) diagnosed with moderate eczema for a randomised, double‐blind, placebo‐controlled trial investigating the efficacy and safety of a topical eczema treatment over 4 weeks. The relationships between recruitment method and patient age, sex, race, study completion and costs were analysed.

Results

The majority of patients recruited were young, with millennials and Gen Z comprising 77% of the study population. Both traditional and modern recruitment methods were equally successful in recruiting younger patients, with older patients predominately recruited by traditional methods. Eighty per cent more men were recruited by traditional compared to modern methods, whilst 67% more women than men were recruited by modern methods. Recruitment method neither appeared to be influenced by race, nor did it effect whether patients completed the study. Costs per enrolment were similar for both methods.

Conclusions

This study shows that despite the high proportion of young patients and the rising popularity of social media and increased internet use, a combination of both traditional and modern recruitment methods was required to successfully meet the trial enrolment target of 100 adult patients with moderate eczema.
Comparison between early surgical treatment and conservative treatment of appendicitis in cancer patients
Authors: Park Sin Hye , Park Sung Sil , Lee Dong Woon , Park Hyoung‐Chul , Park Sung Chan , Hong Chang Won , Sohn Dae Kyung , Han Kyung Su , Chang Hee Jin , Oh Jae Hwan
Published: September 2021

Backgrounds

In cancer patients, the optimal appendicitis treatment has not been established. Therefore, we aimed to determine the ideal treatment option for appendicitis in cancer patients.

Methods

This retrospective study included 185 cancer patients with acute appendicitis who were divided into the early surgical group (n = 152) involving surgery performed within 48 h following the appendicitis diagnosis or the conservative group (n = 33) involving intravenous antibiotics. We compared the appendicitis treatment efficacy between the groups.

Results

In the early surgical group, the antibiotic duration [5.5 days (4.0–8.0) vs. 17.0 days (12.5–25.0), p < 0.001] and hospital stay length [7.0 days (5.0–11.75) vs. 10.0 days (8.0–32.0), p < 0.001] were significantly shorter. Regarding pathology, 16/171 (9.4%) patients who underwent surgery exhibited appendiceal tumours. During the 1‐year follow‐up period, one recurrence occurred in each group [1/152 (0.7%) vs. 1/33 (3.0%), p = 0.326]. The 1‐year treatment success rate was higher in the early surgical group [99.3% (151/152) vs. 42.4% (14/33), p < 0.001].

Conclusion

Early surgical treatment yielded a significantly higher success rate than conservative treatment for appendicitis in cancer patients. Surgery for appendicitis in cancer patients should be considered not only for treatment but also for pathologic confirmation.
A journey of emotions from a young environmental activist
Authors: Halstead Florence , Parsons Lucie R. , Dunhill Ally , Parsons Katie
Published: September 2021

The Earth is currently undergoing a sixth global‐scale ecological crisis. The most recent Intergovernmental Panel on Climate Change (IPCC) report of 2021 highlighted a need to curb global heating at 1.5 degrees above the pre‐industrial baseline, and outlined a range of likely impacts of climate change on global societies should no action be taken, particularly in relation to reducing greenhouse gas emissions to net zero by 2050. Despite this need, policy‐based action at a nation state level is lacking, with talks at COP25 failing to reach necessary agreements. In response to this, and as we approach COP26, a significant global youth movement has been activated, with children and young people taking it upon themselves to highlight a need for climate and environmental action, calling for others to follow. This paper follows the emotional journey of one of its co‐authors, 11‐year‐old environmental activist, Lucie. Through the innovative approach of co‐production with Lucie, in this paper we detail the role of emotion in one youth activist’s journey. From her initial reactions watching BBC’sBlue Planet II, to the multifaceted highs and lows that have followed as she strives for change, we illuminate the emotional implications such experiences may have on children and young people.
Mass transport deposits in reflection seismic data offshore Oregon, USA
Authors: Lenz Brandi L. , Sawyer Derek E.
Published: September 2021

Submarine landslides associated with the Cascadia subduction zone offshore of the Pacific northwest United States and Canada represent significant natural geohazards. Mapping past submarine landslide deposits is critical for understanding present and future slope failure and tsunami hazard potential. We focus on the portion of Cascadia offshore Oregon to map the occurrences of submarine landslide deposits (mass transport deposits [MTDs]) in the subsurface using recent high‐resolution reflection seismic data. We identified 133 MTDs and categorized them based on their present morphology inferred from their acoustic characteristics as disintegrative or blocky. Interestingly, nearly 76% of the MTDs are located in the northern Oregon margin and many of these are non‐cohesive disintegrative deposits. MTDs are less common in the southern Oregon margin, however, they were also much larger and more cohesive than those found in the north. The differences are not likely to be related to differences in earthquake intensity but rather sedimentation rates and basin structures. Specifically, the northern Oregon margin is proximal to the sediment‐delivery systems of the Columbia River and has landward verging fold‐and‐thrust structures, whereas the southern Oregon margin is relatively sediment starved and has seaward verging structures resulting in fewer steep ridges. Because of the higher sedimentation rates, the northern Oregon margin may be prone to more frequent and disintegrative types of slope failures. In contrast, the southern margin may have enhanced slope stability due to seismic strengthening and lower sedimentation rates. However, when slope failures do occur in the southern Oregon margin, they tend to be more cohesive and blocky. Therefore, even though there are fewer slope failures in the southern Oregon margin, there is still hazard potential because fast‐moving cohesive slope failures can generate tsunami.
The Phoenix pay system and intention to quit the federal public service
Authors: Cooper Christopher A. , Turgeon Luc
Published: September 2021

The Phoenix pay system has been mired by an unending string of problems negatively affecting hundreds of thousands of bureaucrats and costing billions of dollars to fix. This article studies whether Phoenix’s negative consequences might also be weakening a core component of good governance: a permanent public service. Using data from the 2017 Public Service Employee Survey, this article finds that the greater the problems an employee has endured from Phoenix, the more likely they are to intend to quit the public service. Signifying a potential loss of future talent for the federal public service, this relationship is particularly pronounced among younger and more educated public servants.
Clonal dynamics of circulating tumor DNA during immune checkpoint blockade therapy for melanoma
Authors: Takai Erina , Omata Wataru , Totoki Yasushi , Nakamura Hiromi , Shiba Satoshi , Takahashi Akira , Namikawa Kenjiro , Mori Taisuke , Yamazaki Naoya , Shibata Tatsuhiro , Yachida Shinichi
Published: September 2021

Assessment of treatment efficacy of immune checkpoint inhibitors in melanoma patients is difficult as the response to these therapies varies among patients or lesions. The clonal evolution of cancer during immune checkpoint blockade therapy could cause treatment resistance. We investigated the potential of liquid biopsy in monitoring the mutational profiles of metastatic melanoma during immunotherapy. Plasma samples collected from 21 Japanese metastatic melanoma patients before immune checkpoint blockade therapy were subjected to whole‐exome sequencing (WES). Furthermore, 14 Japanese patients with melanoma were enrolled for longitudinal analysis of circulating tumor DNA (ctDNA). Plasma samples were collected prospectively before and during therapy and sequenced. WES of the pretreatment plasma from Japanese melanoma patients showed detectable ctDNA levels with wide ranges of variant allele frequencies within a sample, suggesting clonal and subclonal mutations in ctDNA. In targeted sequencing using longitudinal samples, ctDNA levels correlated with increased tumor size, while ctDNA content immediately decreased after a surge in a patient exhibiting pseudo‐progression, suggesting the potential of ctDNA analysis in discriminating between pseudo‐ and true progression. Mutant ctDNA levels showed different patterns within the clinical course of specific patients, suggesting that these mutations were derived from different tumor clones with distinct therapeutic responses. During further investigation, WES of plasma samples from 1 patient showed marked differences in the mutational profiles of ctDNA, including expansive tumor evolution during an acute exacerbation. Immunotherapy may induce characteristic clonal evolutions of tumors; longitudinal analysis of ctDNA has the potential of determining these tumor evolution patterns and therapeutic responses.
Mental health and school absenteeism in children with long‐term physical conditions: A secondary analysis of the British Child and Adolescent Mental Health Surveys 2004 and 2007
Authors: Finning Katie , Neochoriti Varvarrigou Irida , Ford Tamsin , Panagi Laura , Ukoumunne Obioha C.
Published: September 2021

Background

Children and young people (CYP) with long‐term physical conditions (LTCs) are more likely to have poorer mental health and more school absenteeism compared with CYP with no LTCs. However, there is limited longitudinal research, and the extent to which these difficulties persist in CYP with LTCs is unknown. Furthermore, little is known about the relative impact of different types of LTC on mental health and absenteeism.

Methods

We investigated cross‐sectional and longitudinal associations of different LTCs with mental health and school absenteeism in a large (N = 7977) nationally representative survey of CYP in Great Britain and its 3‐year follow‐up. Psychopathology was assessed using the parent‐reported Strengths and Difficulties Questionnaire (SDQ), and diagnosis of any psychiatric disorder using the Development and Wellbeing Assessment (DAWBA). Days absent and persistent absence (missing 10% or more of school days) were reported by parents.

Results

Compared with those with no LTCs, CYP with any LTC had higher SDQ total difficulties scores at baseline (adjusted mean difference 1.4, 1.1–1.6) and follow‐up (1.1, 0.8–1.4) and were more likely to have a psychiatric disorder at baseline (adjusted odds ratio [aOR] 1.59, 1.34–1.89) and follow‐up (1.75, 1.44–2.12). Children with any LTC also missed more days of school at baseline (adjusted incidence rate ratio 1.47, 1.31–1.64) and follow‐up (1.17, 1.00–1.36) and were more likely to be persistently absent (aOR baseline 1.78, 1.48–2.14; follow‐up 1.27, 1.00–1.61). Neurodevelopmental disorders, migraines and atopic conditions were particularly strongly associated with both mental health and absenteeism.

Conclusions

Children with LTCs had poorer mental health and more school absence than those with no LTCs. Clinicians should routinely enquire about mental health and school attendance in CYP with LTCs and should collaborate with families and schools to ensure these children are provided with sufficient mental health and educational support.
Novel KMT2B mutation causes cerebellar ataxia: Expanding the clinical phenotype
Authors: Damásio Joana , Santos Mariana , Samões Raquel , Araújo Maria , Macedo Mafalda , Sardoeira Ana , Cavaco Sara , Freitas Joel , Barros José , Oliveira Jorge , Sequeiros Jorge
Published: September 2021

Hereditary cerebellar ataxias comprise a heterogeneous group of neurodegenerative disorders affecting the cerebellum and/or cerebellar pathways. Next‐generation sequencing techniques have contributed substantially to the expansion of ataxia‐causing genes, including genes classically described in alternative phenotypes. Herein, we describe a patient with adult‐onset cerebellar ataxia, minor dystonia, neuropathy, seizure and ophthalmological pathology, who bears a novel variant in KMT2B (NM_014727.2:c.3334 + 1G > A). Bioinformatic analysis suggested this variant completely abolished the splice‐site at exon 8/intron 8, which was confirmed through analysis of mRNA extracted from fibroblasts. Exon 8 skipping would ultimately translate as an in‐frame deletion at the protein level, corresponding to the loss of 91 aminoacids [p.(Gly1020_Asn1111del)]. So far, KMT2B disease causing variants have been described in patients with dystonia or neurodevelopmental delay, with no reports of a cerebellar predominant phenotype. Our findings highlight the possible role of KMT2B as a gene involved in hereditary cerebellar ataxias.
Effects of social networks on interventions to change conservation behavior
Authors: de Lange Emiel , Milner‐Gulland E.J. , Keane Aidan
Published: September 2021

Social networks are critical to the success of behavioral interventions in conservation because network processes such as information flows and social influence can enable behavior change to spread beyond a targeted group. We investigated these mechanisms in the context of a social marketing campaign to promote a wildlife poisoning hotline in Cambodia. With questionnaire surveys we measured a social network and knowledge and constructs from the theory of planned behavior at 3 points over 6 months. The intervention initially targeted ∼11% (of 365) of the village, but after 6 months ∼40% of the population was knowledgeable about the campaign. The likelihood of being knowledgeable nearly doubled with each additional knowledgeable household member. In the short term, there was also a modest, but widespread improvement in proconservation behavioral intentions, but this did not persist after 6 months. Estimates from stochastic actor‐oriented models suggested that the influences of social peers, rather than knowledge, were driving changes in intention and contributed to the failure to change behavioral intention in the long term, despite lasting changes in attitudes and perceived norms. Our results point to the importance of accounting for the interaction between networks and behavior when designing conservation interventions.
Functional characterization of novel rare CYP2A6 variants and potential implications for clinical outcomes
Authors: El‐Boraie Ahmed , Tanner Julie‐Anne , Zhu Andy Z.X. , Claw Katrina G. , Prasad Bhagwat , Schuetz Erin G. , Thummel Kenneth E. , Fukunaga Koya , Mushiroda Taisei , Kubo Michiaki , Benowitz Neal L. , Lerman Caryn , Tyndale Rachel F.
Published: September 2021

CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviors, including cessation and smoking‐related disease risk. The heritability of the NMR is 60–80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30–35%. Rare variants (minor allele frequency <1%) are hypothesized to explain some of this missing heritability. We present two targeted sequencing studies where rare protein‐coding variants are functionally characterized in vivo, in silico, and in vitro to examine this hypothesis. In a smoking cessation trial, 1687 individuals were sequenced; characterization measures included the in vivo NMR, in vitro protein expression, and metabolic activity measured from recombinant proteins. In a human liver bank, 312 human liver samples were sequenced; measures included RNA expression, protein expression, and metabolic activity from extracted liver tissue. In total, 38 of 47 rare coding variants identified were novel; characterizations ranged from gain‐of‐function to loss‐of‐function. On a population level, the portion of NMR variation explained by the rare coding variants was small (~1%). However, upon incorporation, the accuracy of the wGRS was improved for individuals with rare protein‐coding variants (i.e., the residuals were reduced), and approximately one‐third of these individuals (12/39) were re‐assigned from normal to slow metabolizer status. Rare coding variants can alter an individual’s CYP2A6 activity; their integration into wGRSs through precise functional characterization is necessary to accurately assess clinical outcomes and achieve precision medicine for all. Investigation into noncoding variants is warranted to further explain the missing heritability in the NMR.