bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of COVID-19 pandemic on bronchiolitis (lower respiratory tract infection) due to respiratory syncytial virus: A systematic review and meta-analysis
Authors: Sabeena Sasidharanpillai , Ravishankar Nagaraja , Robin Sudandiradas , Pillai Sabitha Sasidharan
Published: April 2022

Background

The COVID-19 pandemic has changed the epidemiology of RSV infection which accounts for most bronchiolitis cases and viral pneumonias in infants.

Aim

This systematic review and meta-analysis aimed to quantitatively assess the effect of COVID-19 pandemic on respiratory syncytial virus (RSV) associated bronchiolitis among hospitalised infants globally.

Methods

The study protocol was registered in the PROSPERO database (CRD42022314000) and was designed based on PRISMA guidelines updated in May 2020. An electronic search of PubMed/MEDLINE, Scopus and Google Scholar was carried out for articles regarding the impact of the COVID-19 pandemic on bronchiolitis or lower respiratory tract infection due to the respiratory syncytial virus in English published between January 2019 and March 2022. The meta-analysis component was modified appropriately to synthesise the pooled proportion of infants having RSV-associated bronchiolitis before the COVID-19 pandemic in 2019 and during the pandemic with 95% confidence interval (CI).

Results

We screened 189 articles and systematically reviewed fifty studies reporting RSV-associated bronchiolitis cases in infants before the pandemic in 2019 and during the pandemic in 2020/2021. Eight qualified studies from Europe and China, which reported RSV-bronchiolitis both in 2019 and in 2020/21 were pooled by random-effects meta-analysis. These studies comprised 109,186 symptomatic cases of bronchiolitis before the pandemic in 2019 and 61,982 cases in 2020-2021. The quantitative analysis included laboratory-confirmed RSV infection in 7691 infants with bronchiolitis reported before the pandemic in 2019. Meanwhile, during the pandemic, 4964 bronchiolitis cases were associated with RSV infection. The pooled proportion of RSV-associated bronchiolitis cases before the pandemic in 2019 was 16.74% (95% CI 11.73, 22.43%, 95% prediction interval 0.032, 34.16). The pooled proportion of confirmed RSV cases during the pandemic in 2020/2021 was 19.20 % (95% CI 12.01, 27.59%, 95% prediction interval 0.046, 42.35).

Conclusion

There was an increase in RSV activity after the relaxation of stringent public health measures during the COVID-19 pandemic.

Key Messages (Provide appropriate messages of about 35-50 words to be printed in centre box)

This systematic review and meta-analysis reports the pooled proportion of RSV associated bronchiolitis cases in 2019 (before the COVID-19 pandemic) and during the pandemic.

Eight observational studies from China and Europe were qualified for the meta-analysis.

A decline in reported cases of bronchiolitis was observed during the COVID-19 pandemic which might be attributed to non-pharmaceutical measures and a fall in the hospitalisation rates of respiratory non-SARS-CoV-2 infections.

The pooled proportion of RSV positivity rate among bronchiolitis cases was more during the COVID-19 pandemic.
Neurofeedback training for improving motor performance in healthy adults: A systematic review and meta-analysis
Authors: Onagawa Ryoji , Muraoka Yoshihito , Hagura Nobuhiro , Takemi Mitsuaki
Published: April 2022

Neurofeedback training (NFT) refers to a training where the participants voluntarily aim to manipulate their own brain activity using the sensory feedback abstracted from their brain activity. NFT has attracted attention in the field of motor learning for its potential to become an alternative or additional training method for general physical training. In this study, a systematic review of NFT studies for motor performance improvements in healthy adults and a meta-analysis on the effectiveness of NFT were conducted. To identify relevant studies published between January 1st, 1990 to August 3rd, 2021, a computerized search was performed using the databases, Web of Science, Scopus, PubMed, JDreamIII, and Ichushi-Web. Thirty-two studies were identified for the qualitative synthesis and 13 randomized controlled trials (286 subjects) for the meta-analysis. The meta-analysis revealed significant effects of NFT for motor performance improvement examined at the timing after the last NFT session (standardized mean difference = 0.96, 95% CI = 0.40–1.53), but with the existence of publication biases and substantial heterogeneity among the trials. Subsequent subgroup meta-analysis demonstrated reliable benefits when the NFT is performed longer than 1 week. The effectiveness of NFT for each motor performance measurement (e.g., speed, accuracy, and hand dexterity) remains unclear because of high heterogeneity or due to small sample size. Further accumulation of empirical NFT studies for motor performance improvement will be necessary to provide reliable evidence about the NFT effects on specific motor skills and to safely incorporate NFT into real-world scenarios.
Ultrasensitivity of Microtubule severing rate on the concentration of free Tubulin
Authors: Shiff Chloe E. , Kondev Jane , Mohapatra Lishibanya
Published: April 2022

Cytoskeletal structures aid in cell polarization, motility, and intracellular transport. Their functions are predicated on the rapid turnover of cytoskeleton proteins, which is achieved by the coordinated effort of multiple regulatory proteins whose dynamics are not well understood. In-vitro experiments have shown that free tubulin can repair nanoscale damages of microtubules created by severing proteins. Based on this observation, we propose a model for microtubule severing as a competition between the processes of damage spreading and tubulin-induced repair. Using theory and simulations, we demonstrate that this model is in quantitative agreement with in vitro experiments. We predict the existence of a critical tubulin concentration above which severing becomes rare but fast, and hypersensitive to the concentration of free tubulin. Further we show that this hypersensitivity leads to a dramatic increase in the dynamic range of steady-state microtubule lengths, when lengths are controlled by severing. Our work demonstrates how synergy between tubulin and severing proteins can lead to novel dynamical properties of microtubules.
Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta
Authors: Kecheliev Vasil , Boss Leo , Maheshwari Upasana , Konietzko Uwe , Keller Annika , Razansky Daniel , Nitsch Roger M. , Klohs Jan , Ni Ruiqing
Published: April 2022

Neurovascular-glymphatic dysfunction plays an important role in Alzheimer’s disease and has been analyzed mainly in association with amyloid-beta (Aβ) pathology. The neurovascular-glymphatic link with tauopathies has not been well elucidated. Here, we aimed to investigate the alterations in the neurovasculature and map the aquaporin 4 (AQP4) distribution and depolarization associated with tau and Aβ. Perfusion, susceptibility weighted imaging and structural magnetic resonance imaging (MRI) were performed in the pR5 P301L mouse model of 4-repeat tau and the arcAβ mouse model of amyloidosis. Immunofluorescence staining was performed using antibodies against AQP4, CD31, astroglia (GFAP, s100β), phospho-tau (AT-8) and Aβ (6E10) in brain tissue slices from P301L, arcAβ and nontransgenic mice. P301L mice showed regional atrophy, preserved cerebral blood flow and reduced cerebral vessel density compared to nontransgenic mice, while arcAβ mice showed cerebral microbleeds and reduced cerebral vessel density. AQP4 depolarization and peri-tau enrichment in the hippocampus and increased AQP4 levels in the forebrain and hippocampus were detected in P301L mice compared to nontransgenic mice. In comparison, cortical AQP4 depolarization and cortical/hippocampal peri-plaque increases were observed in arcAβ mice. Increased s100β-GFAP fluorescence intensities indicative of reactive astrocytes were detected surrounding tau inclusions in P301L mice and Aβ plaques in arcAβ mice. In conclusion, we observed a divergent region-specific AQP4 increase and association with phospho-tau and Aβ pathologies.
Light diffusion in layered media: A numerical study in the spatial and time-domains
Authors: Helton Michael , Zerafa Samantha , Vishwanath Karthik , Mycek Mary-Ann
Published: April 2022

Accurate and efficient forward models of photon migration in heterogeneous geometries are important for many applications of light in medicine because many biological tissues exhibit a layered structure, with each layer having independent optical properties and thickness. Unfortunately, closed form analytical solutions are not readily available for layered tissue-models, and often are modeled using computationally expensive numerical techniques or theoretical approximations that limit accuracy and real-time analysis. Here, we develop an open-source accurate, efficient, and stable numerical routine to solve the diffusion equation in the steady-state and time-domain for a layered cylinder tissue model with an arbitrary number of layers and specified thickness and optical coefficients. We show that the steady-state (< 0.1 ms) and time-domain (< 0.5 ms) fluence (for an 8-layer medium) can be calculated with absolute numerical errors approaching machine precision. The numerical implementation increased computation speed by 3 to 4 orders of magnitude compared to previously reported theoretical solutions in layered media. We verify our solutions asymptotically to homogeneous tissue geometries using closed form analytical solutions to assess convergence and numerical accuracy. Approximate solutions to compute the reflected intensity are presented which can decrease the computation time by an additional 2-3 orders of magnitude. We also compare our solutions for 2, 3, and 5 layered media to gold-standard Monte Carlo simulations in layered tissue models of high interest in biomedical optics (e.g. skin/fat/muscle and brain). The presented routine could enable more robust real-time data analysis tools in heterogeneous tissues that are important in many clinical applications such as functional brain imaging and diffuse optical spectroscopy.
Diet induced obesity and type 2 diabetes drives exacerbated sex-associated disease profiles in K18-hACE2-mice challenged with SARS-CoV-2
Authors: Lee Katherine S. , Russ Brynnan P. , Wong Ting Y. , Horspool Alexander M. , Winters Michael T. , Barbier Mariette , Bevere Justin R. , Martinez Ivan , Damron F. Heath , Cyphert Holly A.
Published: April 2022

SARS-CoV-2 infection results in wide-ranging disease manifestation from asymptomatic to potentially lethal. Infection poses an increased threat of severity to at-risk populations including those with hypertension, diabetes, and obesity. Type 2 Diabetes (T2DM), is characterized, in part, by insulin insensitivity and impaired glucose regulation. T2DM patients have increased disease severity and poorer outcomes with COVID-19. We utilized the diet-induced obesity (DIO) model of Type 2 Diabetes in SARS-CoV-2-susceptible K18-hACE2 transgenic mice to better understand the obesity co-morbidity. Female DIO, but not male DIO mice challenged with SARS-CoV-2 were observed to have shortened time to morbidity compared to normal diet mice. Increase in susceptibility to SARS-CoV2 in female DIO was associated with increased total viral RNA burden compared to male mice. RNAseq analysis was performed on the lungs of non-challenged, challenged, females, males, of either normal diet or DIO cohorts to determine the disease specific transcriptional profiles. DIO female mice had more total activated genes than normal diet mice after challenge; however, male mice experienced a decrease. GO term analysis revealed the DIO condition increased interferon response signatures and interferon gamma production following challenge. Male challenged mice had robust expression of antibody-related genes suggesting antibody producing cell localization in the lung. DIO reduced antibody gene expression in challenged males. Collectively this study establishes a preclinical T2DM/obesity co-morbidity model of COVID-19 in mice where we observed sex and diet specific responses that begin to explain the effects of obesity and diabetes on COVID-19 disease.
CORTICOTROPIN-RELEASING FACTOR- DOPAMINE INTERACTIONS IN MALE AND FEMALE MACAQUE: BEYOND THE CLASSIC VTA
Authors: Kelly E.A. , Love T.M. , Fudge J.L.
Published: April 2022

Dopamine (DA) is involved in stress and stress-related illnesses, including many psychiatric disorders. Corticotropin-releasing factor (CRF) plays a role in stress responses and targets the ventral midbrain DA system which is composed of DA and non-DA cells, and divided into specific subregions. Although CRF inputs to the midline A10 nuclei ('classic VTA') are known, in monkeys, CRF-containing terminals are also highly enriched in the expanded A10 parabrachial pigmented nucleus (PBP) and in the A8 retrorubral field subregions. We characterized CRF-labeled synaptic terminals on DA (tyrosine hydroxylase, TH+) and non-DA (TH-) cell types in the PBP and A8 regions using immuno-reactive electron microscopy (EM) in male and female macaques. CRF labeling was present mostly in axon terminals, which mainly contacted TH-negative dendrites in both subregions. Most CRF-positive terminals had inhibitory (symmetric) profiles. In both PBP and A8, CRF symmetric (inhibitory) synapses onto TH-negative dendrites were significantly greater than asymmetric (excitatory) profiles. This overall pattern was similar in males and females, despite shifts in the size of these effects between regions depending on sex. Because stress and gonadal hormone shifts can influence CRF expression, we also did hormonal assays over a 6-month time period, and found little variability in basal cortisol across similarly housed animals at the same age. Together our findings suggest that at baseline, CRF-positive synaptic terminals in the primate PBP and A8 are poised to regulate DA indirectly through synaptic contacts onto non-DA neurons.
The Toll and Imd pathway, the complement system and lectins during immune response of the nemertean Lineus ruber
Authors: Orús-Alcalde Andrea , Børve Aina , Hejnol Andreas
Published: April 2022

Innate immunity is the first line of defense against pathogens. In animals, the Toll pathway, the Imd pathway, the complement system, and lectins are well-known mechanisms involved in innate immunity. Although these pathways and systems are well understood in vertebrates and arthropods, they are understudied in other invertebrates. In order to shed light on immunity in the nemertean Lineus ruber, we performed a transcriptomic survey and identified the main components of the Toll pathway (e.g. myD88, dorsal/dif/NFκB-p65), the Imd pathway (e.g. imd, relish/NFκB-p105/100), the complement system (e.g. C3, cfb) and some lectins (FreD-Cs and C-lectins). In situ hybridization showed that TLRβ1, TLRβ2 and imd and are expressed in the nervous system, the complement gene C3-1 is expressed in the gut and the lectins in the nervous system, the blood, and the gut. To reveal their potential role in defense mechanisms, we performed immune challenge experiments, in which Lineus ruber specimens were exposed to the gram-negative bacteria Vibrio diazotrophicus. Our results show the upregulation of specific components of the Toll pathway (TLRα3, TLRβ1, and TLRβ2), the complement system (C3-1), and lectins (c-lectin2 and fred-c5). Therefore, similarly to what occurs in other invertebrates, our study shows that components of the Toll pathway, the complement system and lectins are involved in the immune response in the nemertean Lineus ruber. The presence of these pathways and systems in Lineus ruber, but also in other spiralians, in protostomes and in deuterostomes suggest that these pathways and systems were involved in the immune response in the stem species of Bilateria.
Cost-efficient boundary-free surface patterning achieves high effective-throughput of time-lapse microscopy experiments
Authors: Liang Guohao , Yin Hong , Ding Fangyuan
Published: April 2022

Time-lapse microscopy plays critical roles in the studies of cellular dynamics. However, to set up a time-lapse movie experiments is not only laborious but also with low output, mainly due to the cell-losing problem (i.e., cell moving out of limited field of view), especially in a long time recording. To overcome these issues, we have designed a cost-efficient way that enables cell patterning on the imaging surfaces without any physical boundaries. Using mouse embryonic stem cells as an example system, we have demonstrated that our boundary-free patterned surface solves the cell-losing problem without disturbing their cellular phenotype. Statistically, the presented system increases the effective-throughput of time-lapse microscopy experiments by order of magnitude.
A systematic review of the experiences of minority language users in health and social care research
Authors: Spencer Dr Llinos Haf , Cooledge Mrs Beryl Ann , Hoare Dr Zoe
Published: April 2022

To obtain the most rigorous results in health and social care research (HSCR), it is important to have a representative sample. Culture can sometimes be overlooked but can be important to the individual concerned. Ethnic minorities are often not accounted for in HSCR. Migration, equality, and diversity issues are now important priorities and therefore need to be considered by researchers. Therefore, it is important to explore the literature examining the experiences of minority language users in HSCR. A systematic review (SR) of the literature was conducted to answer the research question. SPIDER framework and Cochrane principles were utilized for the SR. Five databases were searched, yielding 5311 papers initially. A SR protocol was developed and published in PROSPERO. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020225114analysis. Following the title and abstract review by two authors, 74 papers were included, and a narrative account was provided. Six themes were identified: 1. Disparities in health care; 2. Maternal health; 3. Mental health; 4. Methodology in health research; 5. Migrant and minority health care; 6. Racial and ethnic gaps in health care. It was evident that language barriers (including language proficiency) and cultural barriers still exist in terms of recruitment, possibly effecting the validity of the results. Several papers acknowledged language barriers but did not act on this information. Ethnic minorities’ needs are not completely addressed in HSCR. Despite research acknowledging different cultures over the past 40 years, there is a need for this to be fully acknowledged and embedded in the research process. We propose that future research should include details of ethnicity and languages spoken so that readers can understand the sample composition to be able to interpret the results in the best way, recognising the significance of culture and language.

2-4 Key messages, detailing the main points made in the paper

Ethnic minorities’ needs are not completely addressed in health and social care research. Despite research acknowledging different cultures over the past 40 years, there is a need for this to be fully acknowledged and embedded in the research process.

Ethnic background and languages spoken by the research participants should be identified and addressed throughout the research process (from design of the study to dissemination of findings).

Language and cultural preferences should be appropriately considered/included in the analysis.

Future research should include details of ethnicity and languages spoken so that readers can understand the sample composition to be able to interpret the results in the best way, recognising the significance of culture and language.
The Physical Exercise and Cardiovascular Adaptation Monitoring in Pregnancy (PE-CAMP) Randomised Controlled Trial Protocol
Authors: Roldan-Reoyo O. , Mackintosh K A. , McNarry M A. , Jones S. , Emery S. , Uzun O. , Lewis M J.
Published: April 2022

Background

Exercise can be beneficial to cardiovascular system function, but its influence during pregnancy is less well understood. Heterogeneity in research studies has led to a lack of consensus on whether physical exercise during pregnancy can elicit cardiovascular adaptations during a period in which the cardiovascular system is already being challenged. Furthermore, little research has been conducted regarding the influence of physical exercise on foetal heart rate (FHR). This paper presents the protocol for a randomised controlled trial which will evaluate the influence of supervised antenatal physical exercise on cardiovascular adaptations during and after pregnancy, as well as the FHR response to acute and chronic maternal exercise.

Methods

The PE-CAMP Study (Physical Exercise and Cardiovascular Adaptation Monitoring in Pregnancy) is a randomised controlled trial (RCT) in which pregnant women will be randomised into an intervention group (INT), which attended supervised physical exercise programme up to three days per week, or a comparison group (COMP) which followed standard health care. All participants were assessed at three time-points i) 18-22 weeks pregnant, time-point 1; ii) 33-37 weeks pregnant, time-point 2; and iii) 12-16 weeks postnatal, time-point 3. A standardised experimental protocol was used for data collection, including body composition assessment, upper-body flexibility and strength assessment, physical activity assessment via questionnaires and acceletometry, and haemodynamic and cardiovascular evaluation before, during and after an acute 10-minute exercise bout. Foetal heart rate will be assessed at the time-point 2 before, during and after acute exercise.

Discussion

Although it is necessary and informative to continue investigating the effects of exercise on maternal cardiac and haemodynamic responses using specific laboratory-based tests, it is also critical to evaluate these influences during activities that are more achievable and realistic for pregnant women. The PE-CAMP study will provide data on the cardiac and haemodynamic responses to a typical acute bout of exercise, which could help inform future decisions and policies on maternal exercise prescription made by maternity healthcare providers and exercise professionals.

Clinical Trials Registration Number

NCT03748888
Defining the age-dependent and tissue-specific circadian transcriptome in male mice
Authors: Wolff Christopher A. , Gutierrez-Monreal Miguel A. , Meng Lingsong , Zhang Xiping , Douma Lauren G. , Costello Hannah M. , Douglas Collin M. , Ebrahimi Elnaz , Alava Bryan R. , Morris Andrew R. , Endale Mehari M. , Crislip G. Ryan , Cheng Kit-yan , Schroder Elizabeth A. , Delisle Brian P. , Bryant Andrew J. , Gumz Michelle L. , Huo Zhiguang , Liu Andrew C. , Esser Karyn A.
Published: April 2022

Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence supports age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profiled the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in 3 age groups. We found age-dependent and tissue-specific clock output changes. Aging reduced the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. Many genes gained rhythmicity in old tissues, reflecting an adaptive response. REGs were enriched for the hallmarks of aging, adding a new dimension to our understanding of aging. Differential gene expression analysis found that there were temporally distinct clusters of genes in tissue-specific manner. Increased daily gene expression variability is a common feature of aged tissues. This novel analysis extends the landscape of the understanding of aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.

HIGHLIGHTS

- Rhythmically expressed genes (REGs) in Young, but not Old mice, are enriched for the aging hallmarks across all tissues.

- The numbers of REGs decline across all tissues with age implicating the circadian clock in altered homeostasis.

- Age- and tissue-specific differentially expressed genes (DEGs) cluster at specific times of the day.

- Increase in gene expression variability over a day is a common feature of aging tissues.
Chronic nicotine exposure alters sperm small RNA content in a C57BL/6J mouse model: Implications for multigenerational inheritance
Authors: Zeid Dana , Gould Thomas J.
Published: April 2022

Multigenerational inheritance is a non-genomic form of heritability characterized by altered phenotypes in the first generation born from the exposed parent. Multigenerational factors may account for inconsistencies and gaps in heritable nicotine addiction vulnerability. Our lab previously found that F1 offspring of male C57BL/6J mice chronically exposed to nicotine exhibited altered hippocampus functioning and related learning, nicotine-seeking, nicotine metabolism, and basal stress hormones. In an effort to identify germline mechanisms underlying these multigenerational phenotypes, the current study sequenced small RNA extracted from sperm of males chronically administered nicotine using our previously established exposure model. We identified 16 miRNAs whose expression in sperm was dysregulated by nicotine exposure. A literature review of previous research on these transcripts suggested an enrichment for regulation of psychological stress and learning. mRNAs predicted to be regulated by differentially expressed sperm small RNAs were further analyzed using biological enrichment analysis, which also supported enrichment of gene expression pathways involved in hippocampus-dependent learning. Our findings point to links between nicotine-exposed F0 sperm miRNA and altered F1 phenotypes in this multigenerational inheritance model. Specifically, differentially expressed F0 sperm miRNAs may regulate the previously observed changes in F1 learning and stress. These findings provide a valuable foundation for future functional validation of these hypotheses and characterization of mechanisms underlying male-line multigenerational inheritance.
Algorithmic design of 3D wireframe RNA polyhedra
Authors: Elonen Antti , Natarajan Ashwin K. , Kawamata Ibuki , Oesinghaus Lukas , Mohammed Abdulmelik , Seitsonen Jani , Suzuki Yuki , Simmel Friedrich C. , Kuzyk Anton , Orponen Pekka
Published: April 2022

We address the problem of de novo design and synthesis of nucleic acid nanostructures, a challenge that has been considered in the area of DNA nanotechnology since the 1980s and more recently in the area of RNA nanotechnology. Towards this goal, we introduce a general algorithmic design process and software pipeline for rendering 3D wireframe polyhedral nanostructures in single-stranded RNA. To initiate the pipeline, the user creates a model of the desired polyhedron using standard 3D graphic design software. As its output, the pipeline produces an RNA nucleotide sequence whose corresponding RNA primary structure can be transcribed from a DNA template and folded in the laboratory. As case examples, we design and characterize experimentally three 3D RNA nanostructures: a tetrahedron, a bipyramid and a prism. The design software is openly available, and also provides an export of the targeted 3D structure into the oxRNA molecular dynamics simulator for easy simulation and visualization.
Osteoclast-mediated resorption primes the skeleton for successful integration during axolotl limb regeneration
Authors: Riquelme-Guzmán Camilo , Tsai Stephanie L. , Paz Karen Carreon , Nguyen Congtin , Oriola David , Schuez Maritta , Brugués Jan , Currie Joshua D. , Sandoval-Guzmán Tatiana
Published: April 2022

Early events during axolotl limb regeneration include an immune response and the formation of a wound epithelium. These events are linked to a clearance of damaged tissue prior to blastema formation and regeneration of the missing structures. Here, we report the resorption of calcified skeletal tissue as an active, cell-driven and highly regulated event. This process, carried out by osteoclasts, is essential for a successful integration of the newly formed skeleton. Indeed, the extent of resorption is directly correlated with the integration efficiency. Moreover, we identified the wound epithelium as a major regulator of skeletal resorption, likely creating a zone of influence in which signals involved in recruitment/differentiation of osteoclasts are released. Finally, we reported a correlation between resorption and blastema formation, particularly, a coordination of resorption with cartilage condensation. In sum, our results identify resorption as a major event upon amputation, playing a critical role in the overall process of skeletal regeneration.
The molecular architecture of cell cycle arrest
Authors: Stallaert Wayne , Taylor Sovanny R. , Kedziora Katarzyna M. , Johnson Martha S. , Taylor Colin D. , Sobon Holly K. , Young Catherine L. , Limas Juanita C. , Holloway Jonah Varblow , Cook Jeanette Gowen , Purvis Jeremy E.
Published: April 2022

The cellular decision governing the transition between proliferative and arrested states is crucial to the development and function of every tissue. While the molecular mechanisms that regulate the proliferative cell cycle are well established, we know comparatively little about what happens to cells as they diverge into cell cycle arrest. We performed hyperplexed imaging of 49 cell cycle effectors to obtain a map of the molecular architecture that governs cell cycle exit and progression into reversible (“quiescent”) and irreversible (“senescent”) arrest states. Using this map, we found multiple points of divergence from the proliferative cell cycle; identified stress-specific states of arrest; and resolved the molecular mechanisms governing these fate decisions, which we validated by single-cell, time-lapse imaging. Notably, we found that cells can exit into senescence from either G1 or G2; however, both subpopulations converge onto a single senescent state with a G1-like molecular signature. Cells can escape from this “irreversible” arrest state through the upregulation of G1 cyclins. This comprehensive map provides a first glimpse of the overall organization of cell proliferation and arrest.
Regulated use of alternative Transcription Start Sites controls the production of cytosolic or mitochondrial forms of branched-chain aminotransferase in Kluyveromyces marxianus
Authors: Coral-Medina Angela , Fenton Darren A. , Varela Javier , Camarasa Carole , Baranov Pavel V. , Morrissey John P.
Published: April 2022

Following a whole genome duplication (WGD) event approximately 100 million years ago, the yeast lineage from which the model Saccharomyces cerevisiae derives maintained two copies of genes where it was necessary to synthesise proteoforms with different sub-cellular localisation. In contrast, yeasts that did not undergo the WGD event have a single gene that must encode both proteoforms. We adopted an integrated in silico and experimental approach to study how this is achieved with BAT1, a gene that encodes mitochondrial and cytosolic forms of a branched chain aminotransferase (BCAT) in pre-WGD yeast such as Kluyveromyces marxianus. We determined that condition-specific regulation of alternative transcription sites gives rise to mRNA isoforms that differ at the 5’end and that, when decoded, generate a mitochondrial or cytosolic proteoform. Furthermore, targeted mutants lacking specific transcription factors were generated to establish how this differentiation was regulated. As in S. cerevisiae, Gcn4 and Leu3 activated expression of the mRNA encoding the mitochondrial proteoform under conditions when branched chain amino acid synthesis was required. Unlike S. cerevisiae, however, K. marxianus lacked tight regulation of the mRNA encoding the cytosolic proteoform supporting the hypothesis that maintaining paralogous genes in post-WGD yeasts facilitated development of more sophisticated expression control mechanisms.
Molecular mechanism of Afadin substrate recruitment to the receptor phosphatase PTPRK via its pseudophosphatase domain
Authors: Hay Iain M. , Mulholland Katie E. , Graham Stephen C. , Sharpe Hayley J. , Deane Janet E.
Published: April 2022

Protein tyrosine phosphatase receptor-type kappa (PTPRK) is a transmembrane receptor that links extracellular homophilic interactions to intracellular catalytic activity. Previously we showed that PTPRK promotes cell-cell adhesion by selectively dephosphorylating several cell junction regulators including the protein Afadin (Fearnley et al., 2019). Here we demonstrate that Afadin is recruited for dephosphorylation by directly binding to the PTPRK D2 pseudophosphatase domain. We mapped this interaction to a putative coiled coil (CC) domain in Afadin that is separated by more than 100 amino acids from the substrate pTyr residue. We identify the residues that define PTP specificity, explaining how Afadin is selectively dephosphorylated by PTPRK yet not by the closely-related receptor tyrosine phosphatase PTPRM. Our work demonstrates that PTP substrate specificity can be determined by protein-protein interactions distal to the active site. This explains how PTPRK and other PTPs achieve substrate specificity despite a lack of specific sequence context at the substrate pTyr. Furthermore, by demonstrating that these interactions are phosphorylation-independent and mediated via binding to a non-catalytic domain, we highlight how receptor PTPs could function as intracellular scaffolds in addition to catalyzing protein dephosphorylation.
Robust cone-mediated signaling persists late into rod photoreceptor degeneration
Authors: Scalabrino Miranda L. , Thapa Mishek , Chew Lindsey A. , Zhang Esther , Xu Jason , Sampath A.P. , Chen Jeannie , Field Greg D.
Published: April 2022

Rod photoreceptor degeneration causes deterioration in the morphology and physiology of cone photoreceptors along with changes in retinal circuits. These changes could diminish visual signaling at cone-mediated light levels, thereby limiting the efficacy of treatments such as gene therapy for rescuing normal, cone-mediated vision. However, the impact of progressive rod death on cone-mediated signaling remains unclear. A mouse model of rod degeneration was used to investigate the fidelity of retinal ganglion cell (RGC) signaling throughout disease progression. Despite clear deterioration of cone morphology with rod death, cone-mediated signaling among RGCs remained surprisingly robust: spatiotemporal receptive fields changed little and the mutual information between stimuli and spiking responses was relatively constant. This relative stability held until nearly all rods had died and cones had completely lost well-formed outer segments. Interestingly, RGC information rates were higher and more stable for natural movies than checkerboard noise as degeneration progressed. The main change in RGC responses with photoreceptor degeneration was a decrease in response gain. These results suggest that gene therapies for rod degenerative diseases are likely to successfully prolong cone-mediated vision even if there are changes to cone morphology and density.
Hyperactive somatostatin interneurons near amyloid plaque and cell-type-specific firing deficits in a mouse model of Alzheimer’s disease
Authors: Algamal Moustafa , Russ Alyssa N. , Miller Morgan R. , Hou Steven S. , Maci Megi , Munting Leon P. , Zhao Qiuchen , Gerashchenko Dmitry , Bacskai Brian J. , Kastanenka Ksenia V.
Published: April 2022

Alzheimer’s disease (AD) is characterized by synaptic loss and neuronal network dysfunction. These network deficits are mediated by early alterations in neuronal firing rates that coincide with amyloid plaque accumulation. Mounting evidence supports that inhibitory networks are impaired in AD, but the mechanisms driving these inhibitory deficits are poorly understood. Here we use in vivo multiphoton calcium imaging to determine the relationship between amyloid accumulation and the spontaneous activity of excitatory neurons and inhibitory interneurons in an APP/PS1 mouse model of Alzheimer’s disease. We show that somatostatin-expressing (SOM) interneurons are hyperactive, while parvalbumin-expressing interneurons are hypoactive in APP/PS1 mice. Only SOM interneuron hyperactivity correlated with proximity to amyloid plaque. These inhibitory deficits were accompanied by decreased excitatory neurons activity and decreased pairwise activity correlations in APP/PS1 mice. Our study identifies cell-specific interneuronal firing deficits driven by amyloid pathology in APP/PS1 mice and provides new insights for targeting inhibitory circuits in Alzheimer’s disease.
Phenotyping technology for assessing protein content in seaweed by field spectroscopy and a machine learning algorithm
Authors: Shalev Niva Tadmor , Ghermandi Andrea , Tchernov Dan , Shemesh Eli , Israel Alvaro , Brook Anna
Published: April 2022

Determining seaweed protein concentration and the associated phenotype is critical for food industries that require precise tools to moderate concentration fluctuations and attenuate risks. Algal protein extraction and profiling have been widely investigated, but content determination involves a costly, time-consuming, and high-energy, laboratory-based fractionation technique. The present study examines the potential of field spectroscopy technology as a precise, high-throughput, non-destructive tool for on-site detection of red seaweed protein concentration. By using information from a large dataset of 144 Gracilaria sp. specimens, studied in a land-based cultivation set-up, under six treatment regimes during two cultivation seasons, and an artificial neural network, machine learning algorithm and diffuse visible–near infrared reflectance spectroscopy, predicted protein concentrations in the algae were obtained. The prediction results were highly accurate (R2 = 0.95; RMSE = 0.84), exhibiting a high correlation with the analytically determined values. External validation of the model derived from a separate trial, exhibited even better results (R2 = 0.99; RMSE = 0.45). This model, trained to convert phenotypic spectral measurements and pigment intensity into accurate protein content predictions, can be adapted to include diversified algae species and usages.

Highlight

Non-destructive determination of protein content in the edible red seaweed Gracilaria sp. by in-situ, VIS-NIR spectroscopy and a machine learning algorithm.
Neuropsychological assessments for dementia research in the COVID-19 era: comparing remote and face-to-face testing
Authors: Requena-Komuro Maï-Carmen , Jiang Jessica , Dobson Lucianne , Benhamou Elia , Russell Lucy , Bond Rebecca L , Brotherhood Emilie V , Greaves Caroline , Barker Suzie , Rohrer Jonathan D , Crutch Sebastian J , Warren Jason D , Hardy Chris JD
Published: April 2022

Objectives

We explored whether adapting traditional neuropsychological tests for online administration against the backdrop of COVID-19 was feasible for people with diverse forms of dementia and healthy older controls. We compared face-to-face and remote settings to ascertain whether remote administration affected performance.

Design

We used a longitudinal design for healthy older controls who completed face-to-face neuropsychological assessments between three and four years before taking part remotely. For patients, we used a cross-sectional design, contrasting a prospective remote cohort with a retrospective face-to-face cohort matched in age, education, and disease duration.

Setting

Remote assessments were performed using video-conferencing and online testing platforms, with participants using a personal computer or tablet and situated in a quiet room in their own home. Face-to-face assessments were carried out in dedicated testing rooms in our research centre.

Participants

The remote cohort comprised ten healthy older controls (also seen face-to-face 3-4 years previously) and 25 patients (n=8 Alzheimer’s disease (AD); n=3 behavioural variant frontotemporal dementia (bvFTD); n=4 semantic dementia (SD); n=5 progressive nonfluent aphasia (PNFA); n=5 logopenic aphasia (LPA)). The face-to-face patient cohort comprised 64 patients (n=25 AD; n=12 bvFTD; n=9 SD; n=12 PNFA; n=6 LPA).

Primary and secondary outcome measures

The outcome measures comprised the strength of evidence under a Bayesian analytic framework for differences in performances between face-to-face and remote testing environments on a general neuropsychological (primary outcomes) and neurolingustic battery (secondary outcomes).

Results

There was evidence to suggest comparable performance across testing environments for all participant groups, for a range of neuropsychological tasks across both batteries.

Conclusions

Our findings suggest that remote delivery of neuropsychological tests for dementia research is feasible.

Strengths and limitations of this study

Methodological strengths of this study include

Diverse patient cohorts representing rare dementias with specific communication difficulties

Sampling of diverse and relevant neuropsychological domains

Use of Bayesian statistics to quantify the strength of evidence for the putative null hypothesis (no effect between remote and face-to-face testing)

Limitations include

Relatively small cohort sizes

Lack of direct head-to-head comparisons of test environment in the same patients
Patient satisfaction in the use of non-pharmacological therapies in the management of postoperative pain: a study in a tertiary hospital, Ghana
Authors: Tano Priscilla Felicia , Apiribu Felix , Tano Emile Kouakou , Agambire Ramatu , Boateng Isaac , Sefah Victoria
Published: April 2022

Background

Non-pharmacological therapies are the non-medicinal methods used in postoperative pain (POP) management by health care practitioners such as massage, positioning, breathing exercise, music therapy, and distraction. It has been discovered that therapies that are non-pharmacological for the relief of pain are effective with minimal side effects. Studies have also revealed that non-pharmacological interventions in the management of pain lessen or alter pain perception by decreasing intensity and intensifying the tolerance of pain. This study, therefore, seeks to determine how frequently non-pharmacological methods (NPMs) are used in the management of POP and the influence of these NPMs on patient satisfaction

Methods

This study was a descriptive cross-sectional design. A quantitative approach was utilized with a structured questionnaire to obtain responses from patients from October to December 2019. The study was conducted in the female and male surgical wards of Komfo Anokye Teaching Hospital (KATH) in Kumasi, Ghana. 138 patients within the first 72 hours post-operative period who consented and fulfilled the inclusion criteria were enrolled in the study. A convenience sampling method was used to collect the data. Inferential and descriptive statistics were used in analyzing the data.

Results

The majority of the patients, 52.2% responded to using some form of (NPMs) for pain relief. The most widely used non-pharmacological method of pain relief was walking representing 79.2%, followed by relaxation 5 (6.8%), distraction 4 (5.6%), listening to music 3 (4.2%), deep breathing 2 (2.8%), and meditation 1 (1.4%). The male participants were observed to use more NPMs of pain relief as compared to the females. Most of the patients (51.4%) who used NPMs for their pain relief reported having their pain not relieved. A majority (90.6%) of the participants desired for more pain treatment. The type of surgery the patients underwent had a statistically significant negative correlation with the use of NPMs of pain relief (Spearman Correlation Coefficient = -0.233, p-value <0.05). A higher percentage (71%) of participants were highly satisfied with the overall pain treatment received.

Conclusion

Non-pharmacological management of POP have been proven to be efficient, inexpensive, and have little or no side effect on patients. There should be continuous education on non-pharmacological management of POP to nurses and other healthcare professionals to help promote the efficiency of intervening in postoperative pain with these methods.
Balancing selection on genomic deletion polymorphisms in humans
Authors: Aqil Alber , Speidel Leo , Pavlidis Pavlos , Gokcumen Omer
Published: April 2022

A key question in biology is why genomic variation persists in a population for extended periods. Recent studies have identified examples of genomic deletions that have remained polymorphic in the human lineage for hundreds of millennia, ostensibly owing to balancing selection. Nevertheless, genome-wide investigations of ancient and possibly adaptive deletions remain an imperative exercise. Here, we used simulations to show an excess of ancient allele sharing between modern and archaic human genomes that cannot be explained solely by introgression or ancient structure under neutrality. We identified 63 deletion polymorphisms that emerged before the divergence of humans and Neanderthals and are associated with GWAS traits. We used empirical and simulation-based analyses to show that the haplotypes that harbor these functional ancient deletions have likely been evolving under time- and geography-dependent balancing selection. Collectively, our results suggest that balancing selection may have maintained at least 27% of the functional deletion polymorphisms in humans for hundreds of thousands of years.
Cytoplasmic processing of human transfer RNAs
Authors: Akiyama Yasutoshi , Lyons Shawn M. , Abe Takaaki , Anderson Paul J. , Ivanov Pavel
Published: April 2022

Biogenesis of different classes of eukaryotic RNAs proceeds via different pathways that require strict spatiotemporal resolution. The intracellular organization has evolved to provide order for RNA processing to coordinate different maturation steps with specific enzymatic reaction. In higher eukaryotes, processing of transfer RNAs (tRNAs) is postulated to be almost entirely intranuclear, while in lower eukaryotes like yeast, tRNA maturation is both nuclear and cytoplasmic. Here, we show that tRNA processing is largely cytosolic event in human cells. After transcription, unprocessed precursors of tRNAs (pre-tRNAs) bound by La protein are exported from the nucleus into the cytoplasm. Using cell fractionation analysis and pre-tRNA-specific fluorescence in situ hybridization (FISH) protocol, we show tRNA splicing/ligation and end-processing takes place in the cytoplasm where majority of processing enzymes is also located. We propose here a model where processing of intron-less and intron-containing pre-tRNAs is cytoplasmic similarly to the observed in lower eukaryotes, although tRNA splicing precedes 5’- and 3’-end processing in human cells unlike in yeast.