bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and predictors of long-acting reversible contraceptive use among sexually active women in 26 sub-Saharan African countries
Authors: Bolarinwa Obasanjo Afolabi , Nwagbara Ugochinyere Ijeoma , Okyere Joshua , Ahinkorah Bright Opoku , Seidu Abdul-Aziz , Ameyaw Edward Kwabena , Igharo Victor
Published: August 2021

Background

Long-acting reversible contraceptives (LARCs) are associated with high efficacy rates and continuity of use. Based on the foregoing, we sought to examine the prevalence and factors associated with LARC use among sexually active women in 26 countries in sub-Saharan Africa(SSA).

Methods

Secondary data from Demographic and Health Surveys conducted in 26 countries in SSA between January 2010 and December 2019 were pooled and analysed. A total of 56 067 sexually active women 15–49 y of age met the inclusion criteria. Bivariate and multivariate regression analyses were performed to examine the association between selected factors and the use of LARCs in SSA. Results were presented as crude odds ratios and adjusted odds ratios (aORs) with statistical precision at <0.05.

Results

The prevalence of LARC use was 21.73%, ranging from 1.94% in Namibia to 54.96% in Benin. Sexually active women with secondary or higher education (aOR 1.19 [95% confidence interval {CI} 1.08 to 1.32]), those cohabiting (aOR 1.25 [95% CI 1.06 to 1.47]) and those with four or more children (aOR 2.22 [95% CI 1.78 to 2.78]) were more likely to use LARCs compared with those without education, never married and with no biological child.

Conclusions

The use of LARCs in the 26 countries in SSA was relatively low. Hence, the identified contributory factors of LARC use should be tackled with appropriate interventions. These include continuous campaigns on the efficacy of LARCs in reducing unintended pregnancy, maternal mortality and morbidity.
Reciprocal regulation of IgA and the gut microbiota: a key mutualism in the intestine
Authors: Takeuchi Tadashi , Ohno Hiroshi
Published: August 2021

The mammalian intestine is home to trillions of microbes, and their colonization contributes to host physiology through the production of indispensable metabolites and competition against pathogens. However, it is also important to balance this symbiotic relationship, as overgrowth and translocation of microbes could trigger a fatal infection. IgA is the major immunoglobulin class produced and secreted in the intestine and is considered to play a pivotal role in maintaining homeostasis. In this review, we summarize recent studies exploring the interactions between IgA and the gut microbiota and explain how different types of IgA could coexist to regulate the gut microbiota. In particular, we discuss two important aspects of IgA in controlling the gut microbes: function and specificity. Differences in these two aspects appear attributable to how IgA is induced and are associated with the functions of IgA as well. Together, our review delineates a recent understanding of IgA–microbiome interactions and proposes a future direction to clarify its complexity.
Hormonal orchestration of root apical meristem formation and maintenance in Arabidopsis
Authors: Yamoune Amel , Cuyacot Abigail Rubiato , Zdarska Marketa , Hejatko Jan
Published: August 2021

Plant hormones are key regulators of a number of developmental and adaptive responses in plants, integrating the control of intrinsic developmental regulatory circuits with environmental inputs. Here we provide an overview of the molecular mechanisms underlying hormonal regulation of root development. We focus on key events during both embryonic and post-embryonic development, including specification of the hypophysis as a future organizer of the root apical meristem (RAM), hypophysis asymmetric division, specification of the quiescent centre (QC) and the stem cell niche (SCN), RAM maturation and maintenance of QC/SCN activity, and RAM size. We address both well-established and newly proposed concepts, highlight potential ambiguities in recent terminology and classification criteria of longitudinal root zonation, and point to contrasting results and alternative scenarios for recent models. In the concluding remarks, we summarize the common principles of hormonal control during root development and the mechanisms potentially explaining often antagonistic outputs of hormone action, and propose possible future research directions on hormones in the root.
An African American Male Patient with Rare Type B Insulin Resistance Syndrome
Authors: Jialal Ishwarlal , Devaraj Sridevi
Published: August 2021

Syndromes of severe insulin resistance can result from mutations in the insulin receptor gene or autoantibodies to the insulin receptor. The type B syndrome of insulin resistance results from autoantibodies to the insulin receptor and occurs predominantly in women under age 50 years. Here we report on a 64 year old African American man with systemic lupus erythematosus (SLE) and acanthosis nigricans who had severe insulin resistance requiring up to 5000 units of insulin per day. He was diagnosed with type B insulin resistance syndrome based on his clinical presentation and demonstration of autoantibodies to the insulin receptor in his serum. This case study underscores the importance of assaying for autoantibodies to the insulin receptors especially in African American patients with severe insulin resistance and diabetes requiring excessive doses of insulin, in the setting of an autoimmune disease like SLE. It also behooves reference laboratories to develop and offer this assay because these patients have a very high mortality.
Best Practices, Enduring Challenges, and Opportunities for VSED
Authors: Quill Timothy E. , Menzel Paul T. , Pope Thaddeus M. , Schwarz Judith K.
Published: August 2021

VSED begins with excellent symptom management supported by experienced clinicians. VSED is largely patient controlled, but involvement of experienced palliative care providers and family is strongly recommended. Decision making capacity is frequently lost late in the process as death nears, so written advance directives to continue withholding food and fluids should be completed prior to initiating VSED to forestall any misunderstandings of the patient’s wishes. Challenges associated with VSED include its two week duration before death, the personal determination required, and the possibility of delirium in the latter stages that potentially compromises the commitment to forgo fluids. These challenges should be anticipated and planned for. The primary advantages of VSED include: 1) predictable two week duration from initiation to death; 2) alertness for the early phase, 3) no terminal illness requirement, 4) largely under the patient’s control, and 5) awareness of the possibility of VSED can provide comfort to those worried about unacceptable future suffering.
Adolescents and young adults
Authors: Korenblum Chana , Craig Finella
Published: August 2021

Adolescents and young adults (AYAs) receiving palliative care form a distinct group with physical, emotional, psychological, and social needs that are significantly different from those of either children or mature adults. In this chapter, we focus on the unique needs of AYAs and the transition to adulthood in the context of living with a life-limiting condition (LLC) or life-threatening illness (LTI). For all our patients, the experiences and principles on which their adult identity is formed will be very different from those of their peers. The task for professionals is to deliver palliative care while supporting and respecting a transition to adulthood that may never be completed.
Delivering care around the world
Authors: Downing Julia , Marston Joan
Published: August 2021

Children’s Palliative Care (CPC) is a relatively new and emerging field with great potential for helping children and families who are living with life-limiting conditions (LLC) globally. There is a growing recognition of the need to develop services for these children, but the overall picture remains one of huge variance in different parts of the world and even within countries. The evidence base is still small, there is a great need for more education, and considerable scope for further development. Broader awareness of the values and philosophy of CPC, its history and development, and its place in society will help promote CPC further. As the field increases, we will need to enhance the international roles of our own local children’s organizations, and continue to develop paediatric networks, as well as link into global priorities in healthcare such as public health, Universal Health Coverage (UHC), and the sustainable development goals (SDGs).
Religion, spirituality, and mental health: Setting the scene
Authors: Moreira-Almeida Alexander , Bhugra Dinesh
Published: August 2021

This chapter starts defining spirituality as a transcendent realm of reality, which is considered sacred, and religion as the institutional or communal aspect of that spirituality. Then, it explores whether and how issues relating to religion and spirituality (R/S) are relevant to the mental health of individuals. A large body of evidence is presented and discussed showing that R/S remain and probably will continue to be relevant in the contemporary world, and that R/S have marked and usually positive effects on mental health. Ethical concerns regarding approaching R/S in clinical care are addressed, arguing that this approach must be patient-centred. An evidence-based, and ethically sound, bio-psycho-socio-spiritual approach is proposed. In summary, in respect to the evidence available and the R/S beliefs, behaviours and values of most of the world’s population, it is not only appropriate but a scientific and ethical duty to integrate R/S into mental health research, training, prevention, and clinical practice.
Differentiating spiritual experiences from mental disorders
Authors: Machado Leonardo , Moreira-Almeida Alexander
Published: August 2021

It is not uncommon for patients with mental disorders to have symptoms with religious or spiritual (R/S) contents, and, on the other hand, spiritual experiences often involve psychotic-like phenomena. This frequently creates difficulties in differentiating between a non-pathological R/S experience and a mental disorder. Clinical differentiation between a non-pathological R/S experience and a mental disorder with R/S content brings risks in both extremes: to pathologize normal R/S experience (promoting iatrogenic suffering) or neglecting pathological symptoms (delaying proper treatment). In order to mitigate these risks, this chapter will gather the best current scientific evidence and propose clinical guidelines to help the distinction between R/S experiences and mental disorders with R/S content. Scientific studies in people who have spiritual experiences should be encouraged, especially investigations of the phenomenology, neurobiology, precipitants, and outcomes in order to enlarge the empirical base needed to advance the criteria for this differential diagnosis.
The light and the bulb: The psychology and neurophysiology of mystical experience
Authors: Cardeña Etzel , Lindström Lena
Published: August 2021

Throughout history, people have described alterations of consciousness in which they experienced a sense of transcendence, being part of a much larger unity, sometimes encompassing the whole universe, or of being pure awareness. These experiences have been foundational for many religious and spiritual practices, albeit they have sometimes been treated as suspect or outright psycho- and or neuro-pathological. This chapter defines various aspects of the self, self-transcendence, and mystical experiences (ME), discusses the relation of ME with other constructs, its prevalence, psychological and demographic correlates, and its relation to mental health, reviews brain-imaging research on it, and concludes with a discussion of its ontological implications. By doing so, it seeks to give an overview of both enlightenment experiences, ‘the light,’ and the underlying neurophysiological processes, ‘the bulb’.
A supernova remnant association for the fast-moving pulsar PSR J0908–4913
Authors: Johnston Simon , Lower Marcus E
Published: August 2021

A recent measurement of the proper motion of PSR J0908–4913 shows that it is a fast-moving object at a distance of some 3 kpc. Here, we present evidence that the pulsar is located at the edge of a previously unknown, filled-centre supernova remnant (SNR), G270.4–1.0. The velocity vector of the pulsar points directly away from the centre of the remnant. The putative association of the pulsar with SNR G270.4–1.0 implies the pulsar is ∼12 kyr old, significantly less than its characteristic age of 110 kyr. We show that the rotation axis of the pulsar points in the direction of the proper motion. Rotation measure and dispersion measure variations are seen over time, likely indicating the pulsar is passing behind a filament of the remnant.
The Rsm (Csr) post-transcriptional regulatory pathway coordinately controls multiple CRISPR–Cas immune systems
Authors: Campa Aroa Rey , Smith Leah M , Hampton Hannah G , Sharma Sahil , Jackson Simon A , Bischler Thorsten , Sharma Cynthia M , Fineran Peter C
Published: August 2021

CRISPR–Cas systems provide bacteria with adaptive immunity against phages and plasmids; however, pathways regulating their activity are not well defined. We recently developed a high-throughput genome-wide method (SorTn-seq) and used this to uncover CRISPR–Cas regulators. Here, we demonstrate that the widespread Rsm/Csr pathway regulates the expression of multiple CRISPR–Cas systems in Serratia (type I-E, I-F and III-A). The main pathway component, RsmA (CsrA), is an RNA-binding post-transcriptional regulator of carbon utilisation, virulence and motility. RsmA binds cas mRNAs and suppresses type I and III CRISPR–Cas interference in addition to adaptation by type I systems. Coregulation of CRISPR–Cas and flagella by the Rsm pathway allows modulation of adaptive immunity when changes in receptor availability would alter susceptibility to flagella-tropic phages. Furthermore, we show that Rsm controls CRISPR–Cas in other genera, suggesting conservation of this regulatory strategy. Finally, we identify genes encoding RsmA homologues in phages, which have the potential to manipulate the physiology of host bacteria and might provide an anti-CRISPR activity.
Steroids use in non-oxygen requiring COVID-19 patients: a systematic review and meta-analysis
Authors: Sahu A K , Mathew R , Bhat R , Malhotra C , Nayer J , Aggarwal P , Galwankar S
Published: August 2021

Background

Corticosteroids have become the mainstay treatment in severe COVID-19. However, its role is mild disease is controversial due to lack of robust scientific evidence. This systematic review and meta-analysis were conducted to assess effect of steroids in mild COVID-19 patients.

Methods

PubMed, EMBASE, Web of Science and medRxiv were searched from 31 December 2019 to 14 May 2021 for studies that reported effectiveness of steroids in non-oxygen requiring COVID-19 patients in terms of progressing to severe disease, mortality, duration of fever, duration of viral clearance and length of hospital stay (LOHS). Studies on inhalational steroids, case reports and reviews were excluded. Risk of bias (ROB) was assessed by the Cochrane's ROB tool and ROBANS tool. Quantitative data synthesis was done using the generic inverse variance method.

Results

A total of 6411 studies were identified, 2990 articles were screened after exclusion. Seven studies which fit the criteria (involving 2214 non-oxygen requiring COVID-19 patients) were included and analysed. Overall odds of progression to severe disease among the non-oxygen requiring COVID-19 patients receiving steroids was 5.97 [95% confidence interval (CI): 1.27–27.99, I2 = 0%] and odds of death (OR: 1.35, 95% CI: 1.01–1.79; I2 = 0%) as compared to the patients not receiving steroids. Mean duration of fever (7.4 days), duration to viral clearance (18.9 days) and LOHS (20.8 days) were significantly higher in the steroid arm, as compared to that in no-steroid arm (6.7, 16.5 and 15.2 days, respectively).

Conclusion

Steroids in non-oxygen requiring COVID-19 patients can be more detrimental than beneficial.

Protocol registration

The study was prospectively registered in PROSPERO (CRD 42021254951).
Growth of ‘CandidatusLiberibacter asiaticus’ in Commercial Grapefruit Juice-Based Media Formulations Reveals Common Cell Density-Dependent Transient Behaviors
Authors: Merfa Marcus V. , Naranjo Eber , Shantharaj Deepak , De La Fuente Leonardo
Published: August 2021

The phloem-restricted, insect-transmitted bacterium ‘Candidatus Liberibacter asiaticus’ (CLas) is associated with huanglongbing (HLB), the most devastating disease of citrus worldwide. The inability to culture CLas impairs the understanding of its virulence mechanisms and the development of effective management strategies to control this incurable disease. Previously, our research group used commercial grapefruit juice (GJ) to prolong the viability of CLas in vitro. In the present study, GJ was amended with a wide range of compounds and incubated under different conditions to optimize CLas growth. Remarkably, results showed that CLas growth ratios were inversely proportional to the initial inoculum concentration. This correlation is probably regulated by a cell density-dependent mechanism, because diluting samples between subcultures allowed CLas to resume growth. Moreover, strategies to reduce the cell density of CLas, such as subculturing at short intervals and incubating samples under flow conditions, allowed this bacterium to multiply and reach maximum growth as early as 3 days after inoculation, although no sustained exponential growth was observed under any tested condition. Unfortunately, cultures were only transient, because CLas lost viability over time; nevertheless, we obtained populations of about 105genome equivalents/ml repeatedly. Finally, we established an ex vivo system to grow CLas within periwinkle calli that could be used to propagate bacterial inoculum in the lab. In this study we determined the influence of a comprehensive set of conditions and compounds on CLas growth in culture. We hope our results will help guide future efforts toward the long-sought goal of culturing CLas axenically.
Microclimate and resource quality determine resource use in a range-expanding herbivore
Authors: Stewart James E. , Maclean Ilya M. D. , Edney Alice J. , Bridle Jon , Wilson Robert J.
Published: August 2021

The consequences of climate change for biogeographic range dynamics depend on the spatial scales at which climate influences focal species directly and indirectly via biotic interactions. An overlooked question concerns the extent to which microclimates modify specialist biotic interactions, with emergent properties for communities and range dynamics. Here, we use an in-field experiment to assess egg-laying behaviour of a range-expanding herbivore across a range of natural microclimatic conditions. We show that variation in microclimate, resource condition and individual fecundity can generate differences in egg-laying rates of almost two orders of magnitude in an exemplar species, the brown argus butterfly (Aricia agestis). This within-site variation in fecundity dwarfs variation resulting from differences in average ambient temperatures among populations. Although higher temperatures did not reduce female selection for host plants in good condition, the thermal sensitivities of egg-laying behaviours have the potential to accelerate climate-driven range expansion by increasing egg-laying encounters with novel hosts in increasingly suitable microclimates. Understanding the sensitivity of specialist biotic interactions to microclimatic variation is, therefore, critical to predict the outcomes of climate change across species' geographical ranges, and the resilience of ecological communities.
Classification of three corynebacterial strains isolated from a small paddock in North Rhine-Westphalia: proposal of Corynebacterium kalinowskii sp. nov., Corynebacterium comes sp. nov. and Corynebacterium occultum sp. nov.
Authors: Schaffert Lena , Ruwe Matthias , Milse Johanna , Hanuschka Katharina , Ortseifen Vera , Droste Julian , Brandt David , Schlüter Laura , Kutter Yvonne , Vinke Svenja , Viehöfer Prisca , Jacob Lucas , Lübke Nils-Christian , Schulte-Berndt Eva , Hain Carsten , Linder Marten , Schmidt Pascal , Wollenschläger Lars , Luttermann Tobias , Thieme Eric , Hassa Julia , Haak Markus , Wittchen Manuel , Mentz Almut , Persicke Marcus , Busche Tobias , Rückert Christian
Published: August 2021

Three novel corynebacterial species were isolated from soil sampled at a paddock in Vilsendorf, North Rhine-Westphalia, Germany. The strains were coccoid or irregular rod-shaped, catalase-positive and pale white to yellow-orange in colour. By whole genome sequencing and comparison of the 16S rRNA genes as well as the whole genome structure, it was shown that all three strains represent novel species of the familyCorynebacteriaceae, orderCorynebacteriales, classActinobacteria. This project describes the isolation, identification, sequencing, and phenotypic characterization of the three novelCorynebacteriumspecies. We propose the namesCorynebacterium kalinowskiisp. nov. (DSM 110639T=LMG 31801T),Corynebacterium comessp. nov. (DSM 110640T=LMG 31802T), andCorynebacterium occultumsp. nov. (DSM 110642T=LMG 31803T).
Chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A
Authors: Rahman Fryad , Libre Camille , Oleinikov Andrew , Tcherniuk Sergey
Published: August 2021

Human respiratory syncytial virus (hRSV) is a major cause of respiratory illness in young children and can cause severe infections in the elderly or in immunocompromised adults. To date, there is no vaccine to prevent hRSV infections, and disease management is limited to preventive care by palivizumab in infants and supportive care for adults. Intervention with small-molecule antivirals specific for hRSV represents a good alternative, but no such compounds are currently approved. The investigation of existing drugs for new therapeutic purposes (drug repositioning) can be a faster approach to address this issue. In this study, we show that chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A (long strain) and synergistically increase the anti-replicative effect of ribavirinin cellulo. Moreover, chloroquine, but not pyrimethamine, inhibits hRSV replication in the mouse model. Our results show that chloroquine can potentially be an interesting compound for treatment of hRSV infection in monotherapy or in combination with other antivirals.
Are flexible school start times associated with higher academic grades? A 4-year longitudinal study
Authors: Biller Anna M. , Molenda Carmen , Obster Fabian , Zerbini Giulia , Förtsch Christian , Roenneberg Till , Winnebeck Eva C.
Published: August 2021

The mismatch between teenagers’ late sleep phase and early school start time results in acute and chronic sleep reductions. This is not only harmful for students’ learning in the short-term but may impact on students’ career prospects and widen social inequalities. Delaying school start times has been shown to improve sleep but whether this translates to better achievement is unresolved. The current evidence is limited due to a plethora of outcome measures and the many factors influencing sleep and grade/score trajectories. Here, we studied whether 0.5-1.5 years of exposure to a flexible school start system, with the daily choice of an 8AM or 8:50AM-start (intervention), allowed secondary school students (n=63-157, 14-19 years) to improve their quarterly school grades in a 4-year longitudinal pre-post design. We investigated whether sleep, changes in sleep or frequency of later starts predicted grade improvements in the flexible system. Our mixed model regressions with 5,111-16,724 official grades as outcomes did not indicate meaningful grade improvements in the flexible system per se or with previously observed sleep variables (nor their changes) – the covariates academic quarter, discipline and grade level had a greater, more systematic effect in our sample. Importantly, this finding does not preclude improvements in learning and cognition in our sample. However, at the ‘dose’ received here, intermittent sleep benefits did not obviously translate into detectable grade changes, which is in line with several other studies and highlights that grades are suboptimal to evaluate timetabling interventions despite their importance for future success.

Significance statement

Early school start times worldwide clash with teenagers’ delayed sleep-wake rhythms. This mismatch results in sleep restrictions below healthy amounts, which compromises health and performance and further aggravates social disparities. Since adequate sleep is important for learning and concentration, there is the strong expectation that counteracting sleep deprivation with delayed school starts results in better academic achievement. We add important high-resolution, longitudinal data to this unresolved scientific debate. When controlling for confounders, our results do not support that improved sleep leads to grade changes within 1.5 years in a flexible start system. While grades are suboptimal to measure later school start effects on performance, they nevertheless open doors to higher education worldwide and thus determine future trajectories.
Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection
Authors: Ryan Feargal J. , Hope Christopher M. , Masavuli Makutiro G. , Lynn Miriam A. , Mekonnen Zelalem A. , Lip Yeow Arthur Eng , Garcia-Valtanen Pablo , Al-Delfi Zahraa , Gummow Jason , Ferguson Catherine , O’Connor Stephanie , Reddi Benjamin AJ , Shaw David , Kok-Lim Chuan , Gleadle Jonathan M. , Beard Michael R. , Barry Simon C. , Grubor-Bauk Branka , Lynn David J.
Published: August 2021

Increasing evidence suggests immune dysregulation in individuals recovering from SARS- CoV-2 infection. We have undertaken an integrated analysis of immune responses at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 individuals recovering from mild, moderate, severe, or critical COVID-19. Anti-Spike and anti-RBD IgG responses were largely stable up to 24wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3+monocytes) and adaptive immune populations (T helper, T follicular helper and regulatory T cells) in COVID-19 convalescents compared to healthy controls, which were most strongly evident at 12 and 16wpi. RNA sequencing suggested ongoing immune and metabolic dysregulation in convalescents months after infection. Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some individuals.
The Arabidopsis m6A-binding proteins ECT2 and ECT3 bind largely overlapping mRNA target sets and influence target mRNA abundance, not alternative polyadenylation
Authors: Arribas-Hernández Laura , Rennie Sarah , Schon Michael , Porcelli Carlotta , Enugutti Balaji , Andersson Robin , Nodine Michael , Brodersen Peter
Published: August 2021

Gene regulation viaN6-methyladenosine (m6A) in mRNA involves RNA-binding proteins that recognize m6A via a YT521-B homology (YTH) domain. The plant YTH domain proteins ECT2 and ECT3 act genetically redundantly in stimulating cell proliferation during organogenesis, but several fundamental questions regarding their mode of action remain unclear. Here, we use HyperTRIBE (targets of RNA-binding proteins identified by editing) to show that most ECT2 and ECT3 targets overlap, with only few examples of preferential targeting by either of the two proteins. HyperTRIBE in different mutant backgrounds also provides direct views of redundant and specific target interactions of the two proteins. We also show that contrary to conclusions of previous reports, ECT2 does not accumulate in the nucleus. Accordingly, inactivation ofECT2,ECT3and their surrogateECT4does not change patterns of polyadenylation site choice in ECT2/3 target mRNAs, but does lead to lower steady state accumulation of target mRNAs. In addition, mRNA and microRNA expression profiles show indications of stress response activation inect2/ect3/ect4mutants, likely via indirect effects. Thus, previous suggestions of control of alternative polyadenylation by ECT2 are not supported by evidence, and ECT2 and ECT3 act largely redundantly to regulate target mRNA, including its abundance, in the cytoplasm.
Eelbrain: A Python toolkit for time-continuous analysis with temporal response functions
Authors: Brodbeck Christian , Das Proloy , Gillis Marlies , Kulasingham Joshua P. , Bhattasali Shohini , Gaston Phoebe , Resnik Philip , Simon Jonathan Z.
Published: August 2021

1

Even though human experience unfolds continuously in time, it is not strictly linear; instead, it entails cascading processes building hierarchical cognitive structures. For instance, during speech perception, humans transform a continuously varying acoustic signal into phonemes, words, and meaning, and these levels all have distinct but interdependent temporal structures. Time-lagged regression usingtemporal response functions (TRFs)has recently emerged as a promising tool for disentangling electrophysiological brain responses related to such complex models of perception. Here we introduce the Eelbrain Python toolkit, which makes this kind of analysis easy and accessible. We demonstrate its use, using continuous speech as a sample paradigm, with a freely available EEG dataset of audiobook listening. A companion GitHub repository provides the complete source code for the analysis, from raw data to group level statistics. More generally, we advocate a hypothesis-driven approach in which the experimenter specifies a hierarchy of time-continuous representations that are hypothesized to have contributed to brain responses, and uses those as predictor variables for the electrophysiological signal. This is analogous to a multiple regression problem, but with the addition of a time dimension. TRF analysis decomposes the brain signal into distinct responses associated with the different predictor variables by estimating a multivariate TRF (mTRF), quantifying the influence of each predictor on brain responses as a function of time(-lags). This allows asking two questions about the predictor variables: 1) Is there a significant neural representation corresponding to this predictor variable? And if so, 2) what are the temporal characteristics of the neural response associated with it? Thus, different predictor variables can be systematically combined and evaluated to jointly model neural processing at multiple hierarchical levels. We discuss applications of this approach, including the potential for linking algorithmic/representational theories at different cognitive levels to brain responses through computational models with appropriate linking hypotheses.
The CHK-2 antagonizing phosphatase PPM-1.D regulates meiotic entry via catalytic and non-catalytic activities
Authors: Baudrimont Antoine , Paouneskou Dimitra , Mohammad Ariz , Lichtenberger Raffael , Blundon Joshua , Kim Yumi , Hartl Markus , Falk Sebastian , Schedl Tim , Jantsch Verena
Published: August 2021

The transition from the stem cell/progenitor fate to meiosis is mediated by several redundant post-transcriptional regulatory pathways in C. elegans. Interfering with all three branches causes tumorous germlines. SCFPROM-1 comprises one branch and mediates a scheduled degradation step at entry into meiosis. prom-1 mutants show defects in timely initiation of events of meiotic prophase I, resulting in high rates of embryonic lethality. Here, we identify the phosphatase PPM-1.D/Wip1 as crucial substrate for PROM-1. We report that PPM-1.D antagonizes CHK-2 kinase, a key regulator for meiotic prophase initiation e.g., DNA double strand breaks, chromosome pairing and synaptonemal complex formation. We propose that PPM-1.D controls the amount of active CHK-2 by both catalytic and non-catalytic activities, where strikingly the non-catalytic regulation seems to be crucial at meiotic entry. PPM-1.D sequesters CHK-2 at the nuclear periphery and programmed SCFPROM-1 mediated degradation of PPM-1.D liberates the kinase and promotes meiotic entry.
Structural Basis and Mode of Action for Two Broadly Neutralizing Antibodies Against SARS-CoV-2 Emerging Variants of Concern
Authors: Li Wenwei , Chen Yaozong , Prévost Jérémie , Ullah Irfan , Lu Maolin , Gong Shang Yu , Tauzin Alexandra , Gasser Romain , Vézina Dani , Anand Sai Priya , Goyette Guillaume , Chaterjee Debashree , Ding Shilei , Tolbert William D. , Grunst Michael W. , Bo Yuxia , Zhang Shijian , Richard Jonathan , Zhou Fei , Huang Rick K. , Esser Lothar , Zeher Allison , Côté Marceline , Kumar Priti , Sodroski Joseph , Xia Di , Uchil Pradeep D. , Pazgier Marzena , Finzi Andrés , Mothes Walther
Published: August 2021

Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here we elucidate the structural basis and mode of action for two potent SARS-CoV-2 Spike (S) neutralizing monoclonal antibodies CV3-1 and CV3-25 that remained effective against emerging variants of concern in vitro and in vivo. CV3-1 bound to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the “RBD-up” position and triggered potent shedding of the S1 subunit. In contrast, CV3-25 inhibited membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among β-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.
Monash DaCRA fPET-fMRI: A DAtaset for Comparison of Radiotracer Administration for high temporal resolution functional FDG-PET
Authors: Jamadar Sharna D , Liang Emma X , Zhong Shenjun , Ward Phillip GD , Carey Alexandra , McIntyre Richard , Chen Zhaolin , Egan Gary D
Published: August 2021

Background: Functional [18F]-fluorodeoxyglucose positron emission tomography (FDG-fPET) is a new approach for measuring glucose uptake in the human brain. The goal of FDG-fPET is to maintain a constant plasma supply of radioactive FDG in order to track, with high temporal resolution, the dynamic uptake of glucose during neuronal activity that occurs in response to a task or at rest. FDG-fPET has most often been applied in simultaneous BOLD-fMRI/FDG-fPET (blood oxygenation level dependent functional MRI fluorodeoxyglucose functional positron emission tomography) imaging. BOLD-fMRI/FDG-fPET provides the capability to image the two primary sources of energetic dynamics in the brain, the cerebrovascular haemodynamic response and cerebral glucose uptake. Findings: In this Data Note, we describe an open access dataset, Monash DaCRA fPET-fMRI, which contrasts three radiotracer administration protocols for FDG-fPET: bolus, constant infusion, and hybrid bolus/infusion. Participants (n=5 in each group) were randomly assigned to each radiotracer administration protocol and underwent simultaneous BOLD-fMRI/FDG-fPET scanning while viewing a flickering checkerboard. The Bolus group received the full FDG dose in a standard bolus administration; the Infusion group received the full FDG dose as a slow infusion over the duration of the scan, and the Bolus-Infusion group received 50% of the FDG dose as bolus and 50% as constant infusion. We validate the dataset by contrasting plasma radioactivity, grey matter mean uptake, and task-related activity in the visual cortex. Conclusions: The Monash DaCRA fPET-fMRI dataset provides significant re-use value for researchers interested in the comparison of signal dynamics in fPET, and its relationship with fMRI task-evoked activity.
The ER transmembrane complex (EMC) can functionally replace the Oxa1 insertase in mitochondria
Authors: Güngör Büsra , Flohr Tamara , Garg Sriram G. , Herrmann Johannes M.
Published: August 2021

Two multisubunit protein complexes for membrane protein insertion were recently identified in the endoplasmic reticulum (ER): The guided entry of tail anchor proteins (GET) complex and ER membrane complex (EMC). The structures of both of their hydrophobic core subunits, that are required for the insertion reaction, revealed an overall similarity to the YidC/Oxa1/Alb3 family members found in bacteria, mitochondria and chloroplasts. This suggests that these membrane insertion machineries all share a common ancestry. To test whether these ER proteins can functionally replace Oxa1 in yeast mitochondria, we generated strains that express mitochondria-targeted Get2-Get1 and Emc6-Emc3 fusion proteins in Oxa1 deletion mutants. Interestingly, the Emc6-Emc3 fusion was able to complement an Δoxa1 mutant and restored its respiratory competence. The Emc6-Emc3 fusion promoted the insertion of the mitochondrially encoded protein Cox2 as well as of nuclear encoded inner membrane proteins though was not able to facilitate the assembly of the Atp9 ring. Our observations indicate that protein insertion into the ER is functionally conserved to the insertion mechanism in bacteria and mitochondria and adheres to similar topological principles.
Transcriptome Profiles of Anopheles gambiae Harboring Natural Low-Level Plasmodium Infection Reveal Adaptive Advantages for the Mosquito
Authors: Carr Ann , Rinker David C. , Dong Yuemei , Dimopoulos George , Zwiebel Laurence J.
Published: August 2021

Anopheline mosquitoes are the sole vectors for the Plasmodium pathogens responsible for malaria, which is among the oldest and most devastating of human diseases. The continuing global impact of malaria reflects the evolutionary success of a complex vector-pathogen relationship that accordingly has been the long-term focus of both debate and study. An open question in the biology of malaria transmission is the impact of naturally occurring low-level Plasmodium infections of the vector on the mosquito’s health and longevity as well as critical behaviors such as host- preference/seeking. To begin to answer this, we have completed a comparative RNAseq-based transcriptome profile study examining the effect of biologically salient, salivary gland transmission- stage Plasmodium infection on the molecular physiology of Anopheles gambiae s.s. head, sensory appendage, and salivary glands. When compared with their uninfected counterparts, Plasmodium infected mosquitoes exhibit increased transcript abundance of genes associated with olfactory acuity as well as a range of synergistic processes that align with increased fitness based on both anti-aging and reproductive advantages. Taken together, these data argue against the long-held paradigm that malaria infection is pathogenic for anophelines and, instead, suggests there are biological and evolutionary advantages for the mosquito that drive the preservation of its high vectorial capacity.
Recombinant Lloviu virus as a model to study inaccessible zoonotic viruses
Authors: Hume Adam J , Heiden Baylee , Olejnik Judith , Suder Ellen L , Ross Stephen , Scoon Whitney A , Bullitt Esther , Ericsson Maria , White Mitchell R , Turcinovic Jacquelyn , Thao Tran TN , Hekman Ryan M , Kaserman Joseph E , Huang Jessie , Alysandratos Konstantinos-Dionysios , Toth Gabor E , Jakab Ferenc , Kotton Darrell N , Wilson Andrew A , Emili Andrew , Thiel Volker , Connor John H , Kemenesi Gabor , Cifuentes Daniel , Mühlberger Elke
Published: August 2021

Next generation sequencing has revealed the presence of many RNA viruses in animal reservoir hosts, including many closely related to known human pathogens. Despite their zoonotic potential, many of these viruses remain understudied due to not yet being cultured. While reverse genetic systems can facilitate virus rescue, this is often hindered by missing viral genome ends. A prime example is Lloviu virus (LLOV), an uncultured filovirus that is closely related to the highly pathogenic Ebola virus. Using minigenome systems, we complemented the missing LLOV genomic ends and identified cis-acting elements required for LLOV replication that were lacking in the published sequence. We leveraged these data to generate recombinant full-length LLOV clones and rescue infectious virus. Recombinant LLOV (rLLOV) displays typical filovirus features, as shown by electron microscopy. Known target cells of Ebola virus, including macrophages and hepatocytes, are permissive to rLLOV infection, suggesting that humans could be potential hosts. However, inflammatory responses in human macrophages, a hallmark of Ebola virus disease, are not induced by rLLOV. We also used rLLOV to test antivirals targeting multiple facets of the replication cycle. Rescue of uncultured viruses of pathogenic concern represents a valuable tool in our arsenal against pandemic preparedness.
A distinct inner nuclear membrane proteome in Saccharomyces cerevisiae gametes
Authors: Shelton Shary N. , Smith Sarah E. , Unruh Jay R. , Jaspersen Sue L.
Published: August 2021

The inner nuclear membrane (INM) proteome regulates gene expression, chromatin organization, and nuclear transport, however, it is poorly understood how changes in INM protein composition contribute to developmentally regulated processes, such as gametogenesis. Using a split-GFP complementation system, we compared the distribution of all C-terminally tagged transmembrane proteins in Saccharomyces cerevisiae in gametes to that of mitotic cells. Gametes contain a distinct INM proteome needed to complete gamete formation, including expression of genes linked to cell wall biosynthesis, lipid biosynthetic and metabolic pathways, protein degradation and unknown functions. Based on the inheritance pattern, INM components are made de novo in the gametes. Whereas mitotic cells show a strong preference for proteins with small extraluminal domains, gametes do not exhibit this size preference likely due to the changes in the nuclear permeability barrier during gametogenesis.
Heme stimulates platelet mitochondrial oxidant production via the activation of toll-like receptor 4 signaling to mediate targeted granule secretion
Authors: Annarapu Gowtham K. , Nolfi-Donegan Deirdre , Reynolds Michael , Wang Yinna , Kohut Lauren , Zuckerbraun Brian , Shiva Sruti
Published: August 2021

Hemolysis is a pathological component of many diseases and is associated with thrombosis and vascular dysfunction. Hemolytic products, including cell-free hemoglobin and free heme directly activate platelets. However, the effect of hemolysis on platelet degranulation, a central process in not only thrombosis, but also inflammatory and mitogenic signaling, remains less clear. Our group showed that hemoglobin-induced platelet activation involved the production of mitochondrial reactive oxygen species (mtROS). However, the molecular mechanism by which extracellular hemolysis induces platelet mtROS production, and whether the mtROS regulate platelet degranulation remains unknown. Here, we demonstrate using isolated human platelets that cell free heme is a more potent agonist for platelet activation than hemoglobin, and stimulates the release of a specific set of molecules from the α-granule of platelets, including the glycoprotein thrombospondin-1 (TSP-1). We uncover the mechanism of heme-mediated platelet mtROS production which is dependent on the activation of platelet TLR4 signaling and leads to the downstream phosphorylation of complex-V by the serine kinase Akt. Notably, inhibition of platelet TLR4 or Akt, or scavenging mtROS prevents heme-induced granule release in vitro. Further, heme-dependent granule release is significantly attenuated in vivo in mice lacking TLR4 or those treated with the mtROS scavenger MitoTEMPO. These data elucidate a novel mechanism of TLR4-mediated mitochondrial regulation, establish the mechanistic link between hemolysis and platelet degranulation, and begin to define the heme and mtROS-dependent platelet secretome. These data have implications for hemolysis-induced thrombo-inflammatory signaling and for the consideration of platelet mitochondria as a therapeutic target in hemolytic disorders.

Key points

Heme induces platelet mtROS production by inhibiting complex-V activity via TLR4 signaling.

Heme stimulated platelet granule secretion is regulated by mtROS.
Genome-wide RNA structure changes during human neurogenesis drive gene regulatory networks
Authors: Wang Jiaxu , Zhang Tong , Yu Zhang , Tan Wen Ting , Wen Ming , Shen Yang , Lambert Finnlay R.P. , Huber Roland G. , Wan Yue
Published: August 2021

The distribution, dynamics and function of RNA structures in human development is under- explored. Here, we systematically assayed RNA structural dynamics and its relationship with gene expression, translation and decay during human neurogenesis. We observed that the human ESC transcriptome is globally more structurally accessible than that of differentiated cells; and undergo extensive RNA structure changes, particularly in the 3’UTR. Additionally, RNA structure changes during differentiation is associated with translation and decay. We also identified stage-specific regulation as RBP and miRNA binding, as well as splicing is associated with structure changes during early and late differentiation, respectively. Further, RBPs serve as a major factor in structure remodelling and co-regulates additional RBPs and miRNAs through structure. We demonstrated an example of this by showing that PUM2-induced structure changes on LIN28A enable miR-30 binding. This study deepens our understanding of the wide-spread and complex role of RNA-based gene regulation during human development.
Entrepreneurship and sustainable innovation capabilities in platform enterprises: the mediating role of knowledge integration
Authors: Sun Xinbo , Zhao Donghui , Zhang Dapeng , Tian Feng
Published: August 2021

Purpose

The concept of entrepreneurship in platform enterprises has evolved and developed. The purpose of this paper is to explore how entrepreneurship in platform enterprises can be transformed into the sustainable innovation capability of enterprises based on knowledge integration.

Design/methodology/approach

This study adopts a questionnaire survey. The research samples are mainly from well-known domestic platform enterprises, EMBA students and professional online websites, 389 valid questionnaires were collected.

Findings

The results show that entrepreneurship has a positive impact on the sustainable innovation capability of platform enterprises, knowledge integration plays a partial mediating role between entrepreneurship and sustainable innovation capability of platform enterprises. Shared leadership plays a moderating role between entrepreneurship and knowledge integration and knowledge-sharing atmosphere plays a moderating role between knowledge integration and sustainable innovation capability of platform enterprises.

Originality/value

This paper emphasizes the key role of entrepreneurship in platform enterprises on the sustainable innovation capability and discusses the realization path of the sustainable innovation capability of platform enterprises from the perspective of knowledge integration, which is of great significance for developing the research system of entrepreneurship and promoting the construction of sustainable innovation capability of platform enterprises.