bluuebunny/crossref_metadata_2025 huggingface dataset:
Invasive neuromonitoring and neurological intensive care unit management in life-threatening central nervous system infections
Authors: Rass Verena , Kofler Mario , Beer Ronny , Helbok Raimund
Published: May 2021

Purpose of review

Patients with infectious diseases of the central nervous system (CNS) commonly require treatment in the intensive care unit (ICU). In a subset of patients with a life-threatening course, a more aggressive and invasive management is required. Treatment relies on the expertise of the intensivists as most recommendations are currently not based on a high level of evidence.

Recent findings

Published data suggest that an invasive brain-focused management should be considered in life-threatening CNS infections. Brain resuscitation by adequate control of intracranial pressure (ICP) and optimization of cerebral perfusion, oxygen and glucose delivery supports the idea of personalized medicine. Recent advances in monitoring techniques help to guide clinicians to improve neurocritical care management in these patients with severe disease. Robust data on the long-term effect of decompressive craniectomy and targeted temperature management are lacking, however, these interventions can be life-saving in individual patients in the setting of a potentially fatal situation such as refractory elevated ICP.

Advances in the neurocritical care management and progress in monitoring techniques in specialized neuro-ICUs may help to preserve brain function and prevent a deleterious cascade of secondary brain damage in life-threatening CNS infections.
Pathology of the Brain and the Eye in Severe Acute Respiratory Syndrome Coronavirus-2–Infected Patients: A Review
Authors: Champion Samantha N. , Williams Imani M. , Lage Maria Martinez , Stagner Anna M.
Published: May 2021

Background:

Patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may present or eventually develop central nervous system and ophthalmic signs and symptoms. Varying reports have emerged regarding isolation of viral RNA from these tissue sites, as well as largely autopsy-based histopathologic descriptions of the brain and the eye in patients with COVID-19.

Evidence Acquisition:

A primary literature search was performed in literature databases such as PubMed, Google Scholar, and Cochrane Library. Keywords were used alone and in combination including the following: SARS CoV-2, COVID-19, eye, brain, central nervous system, histopathology, autopsy, ocular pathology, aqueous, tears, vitreous, neuropathology, and encephalitis.

Results:

The reported ophthalmic pathologic and neuropathologic findings in patients with SARS-CoV-2 are varied and inconclusive regarding the role of direct viral infection vs secondary pathology. The authors own experience with autopsy neuropathology in COVID-19 patients is also described. There is a particular paucity of data regarding the histopathology of the eye. However, it is likely that the ocular surface is a potential site for inoculation and the tears a source of spread of viral particles.

Conclusions:

Additional large postmortem studies are needed to clarify the role of SARS-CoV in the ophthalmic and neuropathologic manifestations of COVID-19.
A New Score for Sharp Discharges in the EEG Predicts Epilepsy
Authors: Aanestad Eivind , Gilhus Nils E. , Brogger Jan
Published: May 2021

Purpose:

A challenge in EEG interpretation is to correctly classify suspicious focal sharp activity as epileptiform or not. A predictive score was developed from morphologic features of the first focal sharp discharge, which can help in this decision.

Methods:

From a clinical standard EEG database, the authors identified 2,063 patients without a previous epilepsy diagnosis who had a focal sharp discharge in their EEG. Morphologic features (amplitude, area of slow wave, etc.) were extracted using an open source one-click algorithm in EEGLAB, masked to clinical classification. A score was developed from these features and validated with the clinical diagnosis of epilepsy over 2 to 6 years of follow-up. Independent external validation was performed in Kural long-term video-EEG monitoring dataset.

Results:

The score for the first focal sharp discharge had a moderate predictive performance for the clinical designation as the EEG being epileptiform (area under the receiver operating characteristics curve = 0.86). Best specificity was 91% and sensitivity 55%. The score also predicted a future epilepsy diagnosis (area under the receiver operating characteristics curve = 0.70). Best specificity was 86% and sensitivity 38%. Validation on the external dataset had an area under the receiver operating characteristics curve = 0.80. Clinical EEG identification of focal interictal epileptiform discharges had an area under the receiver operating characteristics curve = 0.73 for prediction of epilepsy. The score was based on amplitude, slope, difference from background, slow after-wave area, and age. Interrater reproducibility was high (ICC = 0.91).

Conclusions:

The designation of the first focal sharp discharge as epileptiform depends on reproducible morphologic features. Characteristic features were amplitude, slope, slow after-wave area, and difference from background. The score was predictive of future epilepsy. Halford semiquantitative scale had similar diagnostic performance but lower reproducibility.
Who cares for women with children? Crossing the bridge between disciplines
Authors: Emmott Emily H. , Myers Sarah , Page Abigail E.
Published: May 2021

It has long been acknowledged that women with children require social support to promote their health and wellbeing, as well as that of their children. However, the dominant conceptualizations of support have been heavily influenced by Western family norms. The consequence, at best, has been to stifle our understanding of the nature and consequences of support for mothers and children. At worst, it has led to systematic discrimination negatively impacting maternal–child health. To fully engage with the complexities of social support, we must take multidisciplinary or interdisciplinary approaches spanning diverse cultural and geographical perspectives. However, multidisciplinary knowledge-processing can be challenging, and it is often unclear how different studies from different disciplines relate. To address this, we outline two epistemological frameworks—the scientific approach and Tinbergen's four questions—that can be useful tools in connecting research across disciplines. In this theme issue on ‘Multidisciplinary perspectives on social support and maternal–child health’, we attempt to foster multidisciplinary thinking by presenting work from a diverse range of disciplines, populations and cultures. Our hope is that these tools, along with papers in this issue, help to build a holistic understanding of social support and its consequences for mothers and their children. Overall, a multidisciplinary perspective points to how the responsibility of childrearing should not fall solely onto mothers. Indeed, this multidisciplinary issue demonstrates that successful childrearing is consistently an activity shared beyond the mother and the nuclear family: an insight that is crucial to harnessing the potential of social support to improve maternal–child health.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.
The male breadwinner nuclear family is not the ‘traditional’ human family, and promotion of this myth may have adverse health consequences
Authors: Sear Rebecca
Published: May 2021

The importance of social support for parental and child health and wellbeing is not yet sufficiently widely recognized. The widespread myth in Western contexts that the male breadwinner–female homemaker nuclear family is the ‘traditional’ family structure leads to a focus on mothers alone as the individuals with responsibility for child wellbeing. Inaccurate perceptions about the family have the potential to distort academic research and public perceptions, and hamper attempts to improve parental and child health. These perceptions may have arisen partly from academic research in disciplines that focus on the Western middle classes, where this particular family form was idealized in the mid-twentieth century, when many of these disciplines were developing their foundational research. By contrast, evidence from disciplines that take a cross-cultural or historical perspective shows that in most human societies, multiple individuals beyond the mother are typically involved in raising children: in evolutionary anthropology, it is now widely accepted that we have evolved a strategy of cooperative reproduction. Expecting mothers to care for children with little support, while expecting fathers to provide for their families with little support, is, therefore, likely to lead to adverse health consequences for mothers, fathers and children. Incorporating evidence-based evolutionary, and anthropological, perspectives into research on health is vital if we are to ensure the wellbeing of individuals across a wide range of contexts.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.
Male partner participation in maternity care and social support for childbearing women: a discussion paper
Authors: Daniele Marina Alice Sylvia
Published: May 2021

Male partners/fathers are key support persons for many childbearing women and their involvement in pregnancy, childbirth and the postpartum/postnatal period has beneficial effects on a wide range of outcomes related to maternal and child health and family wellbeing. Social support is implicated in the relevant causal pathway, but has received largely tangential attention in the public health literature. This discussion paper aims to reframe men's participation in maternity care as an opportunity to enhance their readiness and ability to provide social support to women, contributing to the debate on the definition and rationale for male partner involvement, and paving the way for further empirical work. I begin by presenting a theory of change illustrating the causal pathway leading from male partner participation, through the key intermediate step of social support, to improved health and wellbeing for women and children. I proceed by arguing that many people desire male partner participation in maternity care; however, in practice, this is often limited owing to cultural, social and institutional barriers. I use examples from the intervention literature to demonstrate how participation in care can boost men's motivation to support women and enhance their ability to do so by increasing their knowledge and skills. Finally, I draw up general implications for further male partner involvement programmes, suggesting that in order to achieve meaningful and sustainable gains, attention to design is crucial in order to avoid reinforcing patriarchal gender norms. Programmes should be implemented alongside other efforts to improve quality and promote woman-centred care.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.
Shaping birth: variation in the birth canal and the importance of inclusive obstetric care
Authors: Betti Lia
Published: May 2021

Regional variation in pelvic morphology and childbirth has long occurred alongside traditional labour support and an understanding of possible normal courses of childbirth for each population. The process of migration and globalization has broken down these links, while a European model of ‘normal’ labour has become widespread. The description of ‘normal’ childbirth provided within obstetrics and midwifery textbooks, in fact, is modelled on a specific pelvic morphology that is common in European women. There is mounting evidence, however, that this model is not representative of women's diversity, especially for women of non-white ethnicities. The human birth canal is very variable in shape, both within and among human populations, and differences in pelvic shapes have been associated with differences in the mechanism of labour. Normalizing a white-centred model of female anatomy and of childbirth can disadvantage women of non-European ancestry. Because they are less likely to fit within this model, pelvic shape and labour pattern in non-white women are more likely to be considered ‘abnormal’, potentially leading to increased rates of labour intervention. To ensure that maternal care is inclusive and as safe as possible for all women, obstetric and midwifery training need to incorporate women's diversity.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.
Childcare support and child social development in Japan: investigating the mediating role of parental psychological condition and parenting style
Authors: Morita Masahito , Saito Atsuko , Nozaki Mari , Ihara Yasuo
Published: May 2021

In humans, support from partners and alloparents is crucial for successful child-rearing and optimal child development. However, the complex relationships among childcare support, children's outcomes and parental characteristics have not been fully examined. We investigate how three sources of partner and alloparental support—partner's childcare participation, support from children's grandparents and support from non-kin—can be associated with child social development. We hypothesize that the associations between childcare support from partners/alloparents and child social development are partly mediated by parental psychological condition and parenting style. To test this, we conducted path analyses on online survey data collected in 2016 from parents of 3- to 5-year-old children in Japan. We found no evidence that childcare support had direct positive effects on child social development. Rather, the benefit of childcare support was mediated by its effects on parental psychological condition and parenting style, which in turn improved children's outcomes. At the same time, we found some evidence that greater availability of childcare support was directly associated with more behavioural difficulties in children. Our findings reveal the complex pathways between childcare support, parental characteristics and children's outcomes in Japan, showing potential mechanisms behind parental and alloparental effects in industrialized populations.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.
Children are important too: juvenile playgroups and maternal childcare in a foraging population, the Agta
Authors: Page Abigail E. , Emmott Emily H. , Dyble Mark , Smith Dan , Chaudhary Nikhil , Viguier Sylvain , Migliano Andrea B.
Published: May 2021

Non-maternal carers (allomothers) are hypothesized to lighten the mother's workload, allowing for the specialized human life history including relatively short interbirth intervals and multiple dependent offspring. Here, using in-depth observational data on childcare provided to 78 Agta children (a foraging population in the northern Philippines; aged 0–6 years), we explore whether allomaternal childcare substitutes and decreases maternal childcare. We found that allomother caregiving was associated with reduced maternal childcare, but the substitutive effect varied depending on the source and type of care. Children-only playgroups consistently predicted a decrease in maternal childcare. While grandmothers were rarely available, their presence was negatively associated with maternal presence and childcare, and grandmothers performed similar childcare activities to mothers. These results underscore the importance of allomothering in reducing maternal childcare in the Agta. Our findings suggest that flexibility in childcare sources, including children-only playgroups, may have been the key to human life-history evolution. Overall, our results reinforce the necessity of a broad conceptualization of social support in human childcare.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.
Social support, nutrition and health among women in rural Bangladesh: complex tradeoffs in allocare, kin proximity and support network size
Authors: Shenk Mary K. , Morse Anne , Mattison Siobhán M. , Sear Rebecca , Alam Nurul , Raqib Rubhana , Kumar Anjan , Haque Farjana , Blumenfield Tami , Shaver John , Sosis Richard , Wander Katherine
Published: May 2021

Malnutrition among women of reproductive age is a significant public health concern in low- and middle-income countries. Of particular concern are undernutrition from underweight and iron deficiency, along with overweight and obesity, all of which have negative health consequences for mothers and children. Accumulating evidence suggests that risk for poor nutritional outcomes may be mitigated by social support, yet how social support is measured varies tremendously and its effects likely vary by age, kinship and reproductive status. We examine the effects of different measures of social support on weight and iron nutrition among 677 randomly sampled women from rural Bangladesh. While we find that total support network size mitigates risk for underweight, other results point to a potential tradeoff in the effects of kin proximity, with nearby adult children associated with both lower risk for underweight and obesity and higher risk for iron deficiency and anaemia. Social support from kin may then enhance energy balance but not diet quality. Results also suggest that a woman's network of caregivers might reflect their greater need for help, as those who received more help with childcare and housework had worse iron nutrition. Overall, although some findings support the hypothesis that social support can be protective, others emphasize that social relationships often have neutral or negative effects, illustrating the kinds of tradeoffs expected from an evolutionary perspective. The complexities of these effects deserve attention in future work, particularly within public health, where what is defined as ‘social support' is often assumed to be positive.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health'.
Validating social support and prioritizing maternal wellbeing: beyond intensive mothering and maternal responsibility
Authors: Budds Kirsty
Published: May 2021

In this piece, I reflect on the current model of motherhood that prevails in Western countries, often termed ‘intensive mothering'. I will briefly trace the history of this approach, focusing in particular on how theory from developmental psychology has, to some extent, functioned to reinforce it by foregrounding the mother–child dyad and emphasizing the importance of maternal practices for children's developmental outcomes. I will then consider the particular implications of this cultural approach to motherhood for women's experiences of motherhood and maternal wellbeing. Finally, I reiterate that we need to continue to challenge this western-centric model of motherhood, which risks both isolating and overburdening women, by highlighting the ways in which both women and children benefit from wider social support systems, yet also by making it permissible for women to access social support without compromising a ‘good mother' identity.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health'.
Children's fingernail cortisol among BaYaka foragers of the Congo Basin: associations with fathers' roles
Authors: Gettler Lee T. , Lew-Levy Sheina , Sarma Mallika S. , Miegakanda Valchy , Doxsey Martha , Meyer Jerrold S. , Boyette Adam H.
Published: May 2021

Children and mothers’ cortisol production in response to family psychosocial conditions, including parenting demands, family resource availability and parental conflict, has been extensively studied in the United States and Europe. Less is known about how such family dynamics relate to family members' cortisol in societies with a strong cultural emphasis on cooperative caregiving. We studied a cumulative indicator of cortisol production, measured from fingernails, among BaYaka forager children (77 samples,
n
= 48 individuals) and their parents (78 samples,
n
= 49) in the Congo Basin. Men ranked one another according to locally valued roles for fathers, including providing resources for the family, sharing resources in the community and engaging in less marital conflict. Children had higher cortisol if their parents were ranked as having greater parental conflict, and their fathers were seen as less effective providers and less generous sharers of resources in the community. Children with lower triceps skinfold thickness (an indicator of energetic condition) also had higher cortisol. Parental cortisol was not significantly correlated to men's fathering rankings, including parental conflict. Our results indicate that even in a society in which caregiving is highly cooperative, children's cortisol production was nonetheless correlated to parental conflict as well as variation in locally defined fathering quality.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.
Was Cinderella just a fairy tale? Survival differences between stepchildren and their half-siblings
Authors: Schacht Ryan , Meeks Huong , Fraser Alison , Smith Ken R.
Published: May 2021

The death of a parent, particularly the mother, is linked to a suite of negative outcomes across the life-course. Compounding concerns for child outcomes are expectations of poor treatment by step-parents after parental remarriage. Indeed, folk tales of step-parental abuse abound cross-culturally and are embedded into stories taught to children. To understand why child outcomes might be sensitive to levels of relatedness within the household, evolutionary-oriented research targets patterning in parental expenditure in ways predicted to maximize inclusive fitness. In particular, parents are expected to prioritize investments in their biological children. However, stepfamilies are only formed after children experience multiple unfortunate events (e.g. parental loss, poverty), blurring causal interpretations between step-parental presence and stepchild outcomes. Moreover, stepchildren have been shown to be integral to household functioning, caring for their half-siblings and stabilizing relationships. These results challenge narrow views of adaptive behaviour; specifically, that step-parents, unlike biological parents, do no stand to reap fitness benefits from the care that they provide to their stepchildren. To evaluate these critiques, we analyse the survival outcomes of stepchildren. We include over 400 000 individuals from across a natural fertility period (1847–1940) in the United States state of Utah and examine the consequences of parental loss and step-parental introduction. Our analyses yield three key results: (i) exposure to maternal loss in childhood is associated with elevated mortality risk, (ii) parental remarriage does not increase the risk of mortality among stepchildren compared to non-stepchildren who too had lost a parent, and (iii) stepchildren enjoy higher survival than their half-siblings within the same family. Ultimately, this work contributes to the increasingly recognized importance of cooperative relationships among non-kin for childcare and household functioning.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.
The differential role of practical and emotional support in infant feeding experience in the UK
Authors: Myers S. , Page A. E. , Emmott E. H.
Published: May 2021

Social support is a known determinant of breastfeeding behaviour and is generally considered beneficial. However, social support encompasses a myriad of different supportive acts, providing scope for diverse infant feeding outcomes. Given the vulnerability of postpartum mental health, this paper aims to explore both how support prolongs breastfeeding and which forms of support promote the positive experience of all infant feeding. Using survey data collected online from 515 UK mothers with infants aged 0–108 weeks, Cox regression models assessed the relationship between receiving different types of support, support need and breastfeeding duration. Quasi-binomial logistic regression models assessed the relationship between receiving support, infant feeding mode and maternal experience of infant feeding. Rates of negative infant feeding experience indicate the widespread need for support: e.g. 38% of currently, 47% of no longer and 31% of never breastfeeding women found infant feeding stressful. Overall, practical support via infant feeding broadly predicted shorter breastfeeding durations and poorer feeding experience; results in relation to other forms of support were more complex. Our findings indicate different forms of support have different associations with infant feeding experience. They also highlight the wide range of individuals beyond the nuclear family on which postpartum mothers in the UK rely.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.
Does maternal grandmother's support improve maternal and child nutritional health outcomes? Evidence from Merida, Yucatan, Mexico
Authors: Vázquez-Vázquez Adriana , Fewtrell Mary S. , Chan-García Hidekel , Batún-Marrufo Carolina , Dickinson Federico , Wells Jonathan C.
Published: May 2021

In humans, high levels of investment are required to raise offspring, because of the prolonged developmental period and short interbirth intervals. The costs borne by individual mothers may be mitigated by obtaining social support from others. This strategy could be particularly valuable for first-time mothers, who lack first-hand experience and whose offspring have higher mortality risk than later-born siblings. As raising children is potentially stressful, mothers may gain from others sharing their experience, providing knowledge/information and emotional support. Being genetically related to both mother and grandchild, maternal grandmothers may be especially well placed to provide such support, while also gaining fitness benefits. We tested the over-arching hypothesis that first-time mothers and their young children supported by the maternal grandmother would have lower levels of stress and better health outcomes, compared to mother–infant dyads lacking such grandmaternal support. A cohort of 90 mother–infant dyads (52 with grandmaternal support, 38 without) was recruited in Merida, Mexico. We assessed anthropometry and body composition in both mother and child, along with maternally perceived stress and child temperament, and documented maternal social relationships. No differences were found in perceived stress/temperament or anthropometry of either mothers or children, according to the presence/absence of grandmaternal support. However, a composite score of whether grandmothers provided advice on infant feeding was positively associated with child nutritional status. Mothers without grandmaternal support reported seeking more informational and emotional support from other female relatives for childcare, potentially compensating for limited/absent grandmaternal support. Our findings may help develop interventions to improve maternal and child health by targeting the dynamics of maternal social networks.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.
Modulated TRPC1 expression predicts sensitivity of breast cancer to doxorubicin and magnetic field therapy: segue towards a precision medicine approach
Authors: Tai Yee Kit , Wing Chan Karen Ka , Hua Fong Charlene Hui , Ramanan Sharanya , Yee Yap Jasmine Lye , Yin Jocelyn Naixin , Yip Yun Sheng , Tan Wei Ren , Fern Koh Angele Pei , Tan Nguan Soon , Chan Ching Wan , Ju Huang Ruby Yun , Franco-Obregón Alfredo
Published: May 2021

Background

Chemotherapy is the mainstream treatment modality for invasive breast cancer. Nonetheless, chemotherapy-associated adverse events can result in a patient terminating treatment. We show that transient receptor potential channel 1 (TRPC1) expression level predicts breast cancer sensitivity to doxorubicin (DOX) and pulsed electromagnetic field (PEMF) therapies.

Methods

The effects of PEMFs were examined with respect to:1) the growth of MCF-7 cellsin vitro;2) MCF-7 tumors implanted into a chicken chorioallantoic membrane (CAM) model and;3) patient-derived and MCF-7 breast cancer xenografts in mice.

Potential synergisms between DOX and PEMF therapies were examined in these model systems and under conditions of TRPC1 overexpression or silencingin vitro.

Results

PEMF exposure impaired the survival of MCF-7 cells, but not that of nonmalignant MCF10A breast cells. The effects of PEMF- and DOX-therapies synergizedin vitroat compromising MCF-7 cell growth. Synergism could be corroboratedin vivowith patient-derived xenograft mouse models, wherein PEMF exposure alone or in combination with DOX reduced tumor size. Stable overexpression of TRPC1 enhanced the vulnerability of MCF-7 cells to both DOX and PEMF exposure and promoted proliferation, whereas chronic DOX exposure reduced TRPC1 expression, induced chemoresistance, precluded response to PEMF exposure and mitigated proliferation. Markers of metastasis includingSLUG, SNAIL, VIMENTIN, andE-CADHERINas well as invasiveness were also positively correlated with TRPC1 channel expression.

Conclusion

The presented data supports a potential role of PEMF-therapy as an effective companion therapy to DOX-based chemotherapy for the treatment of breast cancers characterized by elevated TRPC1 expression levels.
Coordinated changes in glycosylation regulate the germinal centre through CD22
Authors: Enterina Jhon R. , Sarkar Susmita , Streith Laura , Jung Jaesoo , Arlian Britni M. , Meyer Sarah J. , Takematsu Hiromu , Xiao Changchun , Baldwin Troy A. , Nitschke Lars , Shlomchick Mark J. , Paulson James C. , Macauley Matthew S.
Published: May 2021

Germinal centres (GC) are sites of B-cell expansion and selection, which are essential for antibody affinity maturation. Compared to naive follicular B-cells, GC B-cells have several notable changes in their cell surface glycans. While these changes are routinely used to identify the GC, functional roles for these changes have yet to be ascribed. Detection of GCs by the antibody GL7 reflects a reduction in the glycan ligands for CD22, which is an inhibitory co-receptor of the B-cell receptor (BCR). To test a functional role for downregulated CD22 ligands in the GC, we generated a mouse model that maintains CD22 ligands on GC B-cells. With this model, we demonstrate that glycan remodeling is crucial for proper GC B-cell response, including plasma cell output and affinity maturation of antibodies. The defect we observe in this model is dependent on CD22, highlighting that coordinated downregulation of CD22 ligands on B cells plays a critical function in the GC. Collectively, our study uncovers a crucial role for glycan remodeling and CD22 in B-cell fitness in the GC.
Mitotic checkpoint gene expression is tuned by coding sequences
Authors: Esposito Eric , Weidemann Douglas E. , Rogers Jessie M. , Morton Claire M. , Baybay Erod Keaton , Chen Jing , Hauf Silke
Published: May 2021

The mitotic checkpoint (also called spindle assembly checkpoint, SAC) is a signaling pathway that safeguards proper chromosome segregation. Proper functioning of the SAC depends on adequate protein concentrations and appropriate stoichiometries between SAC proteins. Yet very little is known about SAC gene expression. Here, we show in fission yeast (S. pombe) that a combination of short mRNA half-lives and long protein half-lives supports stable SAC protein levels. For the SAC genesmad2+andmad3+, their short mRNA half-lives are supported by a high frequency of non-optimal codons. In contrast,mad1+mRNA has a short half-life despite a low frequency of non-optimal codons and despite the lack of known destabilizing motifs. Hence, different SAC genes employ different strategies of expression. We further show that Mad1 homodimers form co-translationally, which may necessitate a certain codon usage pattern. Taken together, we propose that the codon usage of SAC genes is fine-tuned for proper SAC function. Our work shines light on gene expression features that promote spindle assembly checkpoint function and suggests that synonymous mutations may weaken the checkpoint.
Passive and active immunity in infants born to mothers with SARS-CoV-2 infection during pregnancy: Prospective cohort study
Authors: Song Dongli , Prahl Mary , Gaw Stephanie L. , Narasimhan SudhaRani , Rai Daljeet , Huang Angela , Flores Claudia , Lin Christine Y. , Jigmeddagva Unurzul , Wu Alan H.B. , Warrier Lakshmi , Levan Justine , Nguyen Catherine B.T. , Callaway Perri , Farrington Lila , Acevedo Gonzalo R. , Gonzalez Veronica J. , Vaaben Anna , Nguyen Phuong , Atmosfera Elda , Marleau Constance , Anderson Christina , Misra Sonya , Stemmle Monica , Cortes Maria , McAuley Jennifer , Metz Nicole , Patel Rupalee , Nudelman Matthew , Abraham Susan , Byrne James , Jegatheesan Priya
Published: May 2021

OBJECTIVE

To investigate maternal immunoglobulins’ (IgM, IgG) response to SARS-CoV-2 infection during pregnancy and IgG transplacental transfer, to characterize neonatal antibody response to SARS-CoV-2 infection, and to longitudinally follow actively- and passively-acquired SARS-CoV-2 antibodies in infants.

DESIGN

A prospective observational study.

SETTING

A public healthcare system in Santa Clara County (CA, USA).

PARTICIPANTS

Women with SARS-CoV-2 infection during pregnancy and their infants were enrolled between April 15, 2020 and March 31, 2021.

OUTCOMES

SARS-CoV-2 serology analyses in the cord and maternal blood at delivery and longitudinally in infant blood between birth and 28 weeks of life.

RESULTS

Of 145 mothers who tested positive for SARS-CoV-2 during pregnancy, 86 had symptomatic infections: 78 with mild-moderate symptoms, and eight with severe-critical symptoms. Of the 147 newborns, two infants showed seroconversion at two weeks of age with high levels of IgM and IgG, including one premature infant with confirmed intrapartum infection. The seropositivity rates of the mothers at delivery was 65% (95% CI 0.56-0.73) and the cord blood was 58% (95% CI 0.49-0.66). IgG levels significantly correlated between the maternal and cord blood (Rs= 0.93, p< 0.0001). IgG transplacental transfer ratio was significantly higher when the first maternal positive PCR was 60-180 days before delivery compared to <60 days (1.2 vs. 0.6, p=<0.0001). Infant IgG negative conversion rate over follow-up periods of 1-4, 5-12, and 13-28 weeks were 8% (4/48), 12% (3/25), and 38% (5/13), respectively. The IgG seropositivity in the infants was positively related to IgG levels in the cord blood and persisted up to six months of age.

CONCLUSIONS

Maternal SARS-CoV-2 IgG is efficiently transferred across the placenta when infections occur more than two months before delivery. Maternally-derived passive immunity may protect infants up to six months of life. Neonates mount a strong antibody response to perinatal SARS-CoV-2 infection.
Arrestin-mediated Desensitization Enables Olfactory Discrimination inC. elegans
Authors: Merritt Daniel M. , MacKay-Clackett Isabel , Almeida Sylvia M. T. , Tran Celina , Ansar Safa , van der Kooy Derek
Published: May 2021

In the mammalian olfactory system, crosstalk among diverse olfactory signals is minimized through labelled line coding: individual neurons express one or few olfactory receptors among those encoded in the genome. Labelled line coding allows for separation of stimuli during mammalian olfactory signal transduction, however, in the nematode wormCaenorhabditis elegans, 1,300 olfactory receptors are primarily expressed in only 32 neurons, precluding this strategy. Here we report genetic, pharmacological and behavioural evidence that β-arrestin-mediated desensitization of olfactory receptors, working downstream of the kinase GRK-1, enables discrimination between intra-neuronal olfactory stimuli, but that this discrimination relies on quantitative, rather than qualitative differences in signalling. Our findings suggest thatC. elegansexploits β-arrestin desensitization to maximize responsiveness to novel odors, allowing for behaviourally appropriate responses to olfactory stimuli despite the large number of olfactory receptors signalling in single cells. This represents a fundamentally different solution to the problem of olfactory discrimination than that which evolved in mammals, allowing for economical use of an extremely limited number of sensory neurons.
Quantifying the Tissue-Specific Regulatory Information within Enhancer DNA Sequences
Authors: Benner Philipp , Vingron Martin
Published: May 2021

Recent efforts to measure epigenetic marks across a wide variety of different cell types and tissues provide insights into the cell type-specific regulatory landscape. We use this data to study if there exists a correlate of epigenetic signals in the DNA sequence of enhancers and explore with computational methods to what degree such sequence patterns can be used to predict cell type-specific regulatory activity. By constructing classifiers that predict in which tissues enhancers are active, we are able to identify sequence features that might be recognized by the cell in order to regulate gene expression. While classification performances vary greatly between tissues, we show examples where our classifiers correctly predict tissue specific regulation from sequence alone. We also show that many of the informative patterns indeed harbor transcription factor footprints.
Genomic sequences and RNA binding proteins predict RNA splicing kinetics in various single-cell contexts
Authors: Hou Ruiyan , Huang Yuanhua
Published: May 2021

RNA splicing is a key step of gene expression in higher organisms. Accurate quantification of the two-step splicing kinetics is of high interests not only for understanding the regulatory machinery, but also for estimating the RNA velocity in single cells. However, the kinetic rates remain poorly understood due to the intrinsic low content of unspliced RNAs and its stochasticity across contexts. Here, we estimated the relative splicing efficiency across a variety of single-cell RNA-Seq data with scVelo. We further extracted three large feature sets including 92 basic genomic sequence features, 65,536 octamers and 120 RNA binding proteins features and found they are highly predictive to RNA splicing efficiency across multiple tissues on human and mouse. A set of important features have been identified with strong regulatory potentials on splicing efficiency. This predictive power brings promise to reveal the complexity of RNA processing and to enhance the estimation of single-cell RNA velocity.
Inferring species compositions of complex fungal communities from long- and short-read sequence data
Authors: Hu Yiheng , Irinyi Laszlo , Vi Hoang Minh Thuy , Eenjes Tavish , Graetz Abigail , Stone Eric , Meyer Wieland , Schwessinger Benjamin , Rathjen John P.
Published: May 2021

Background

The kingdom fungi is crucial for life on earth and is highly diverse. Yet fungi are challenging to characterize. They can be difficult to culture and may be morphologically indistinct in culture. They can have complex genomes of over 1 Gb in size and are still underrepresented in whole genome sequence databases. Overall their description and analysis lags far behind other microbes such as bacteria. At the same time, classification of species via high throughput sequencing without prior purification is increasingly becoming the norm for pathogen detection, microbiome studies, and environmental monitoring. However, standardized procedures for characterizing unknown fungi from complex sequencing data have not yet been established.

Results

We compared different metagenomics sequencing and analysis strategies for the identification of fungal species. Using two fungal mock communities of 44 phylogenetically diverse species, we compared species classification and community composition analysis pipelines using shotgun metagenomics and amplicon sequencing data generated from both short and long read sequencing technologies. We show that regardless of the sequencing methodology used, the highest accuracy of species identification was achieved by sequence alignment against a fungi-specific database. During the assessment of classification algorithms, we found that applying cut-offs to the query coverage of each read or contig significantly improved the classification accuracy and community composition analysis without significant data loss.

Conclusion

Overall, our study expands the toolkit for identifying fungi by improving sequence-based fungal classification, and provides a practical guide for the design of metagenomics analyses.
Fine-tuning of β-catenin in thymic epithelial cells is required for postnatal T cell development
Authors: Fujimori Sayumi , Ohigashi Izumi , Abe Hayato , Taketo Makoto M. , Takahama Yousuke , Takada Shinji
Published: May 2021

In the thymus, the thymic epithelium provides a microenvironment essential for the development of functionally competent and self-tolerant T cells. Previous findings showed that modulation of Wnt/β-catenin signaling in thymic epithelial cells (TECs) disrupts embryonic thymus organogenesis. However, the role of β-catenin in TECs for postnatal T cell development remains to be elucidated. Here, we analyzed gain-of-function (GOF) and loss-of-function (LOF) of β-catenin highly specific in TECs. We found that GOF of β-catenin in TECs results in severe thymic dysplasia and T cell deficiency beginning from the embryonic period. By contrast, LOF of β-catenin in TECs reduces the number of cortical TECs and thymocytes modestly and only postnatally. These results indicate that fine-tuning of β-catenin expression within a permissive range is required for TECs to generate an optimal microenvironment to support postnatal T cell development.
Frizzled3 inhibits Vangl2-Prickle3 association to establish planar cell polarity in the vertebrate neural plate
Authors: Chuykin Ilya , Itoh Keiji , Kim Kyeongmi , Sokol Sergei Y.
Published: May 2021

The orientation of epithelial cells in the plane of the tissue, known as planar cell polarity (PCP), is regulated by interactions of asymmetrically localized PCP protein complexes. In theXenopusneural plate, Van Gogh-like2 (Vangl2) and Prickle3 (Pk3) proteins form a complex at the anterior cell boundaries, but how this complex is regulatedin vivoremains largely unknown. Here we show that Vangl2-Pk3 association is inhibited by Frizzled3 (Fz3), a core PCP protein that is specifically expressed in the neuroectoderm and is essential for the establishment of PCP in this tissue. Proximity biotinylation and crosslinking studies revealed that the Vangl2-Pk3 interaction is suppressed by overexpressed Fz3, but enhanced in Fz3 morphants. In addition, Fz3 induced Vangl2 phosphorylation on T76 and T78, and this phosphorylation was required for Fz3-mediated inhibition of Vangl2-Pk3 complex formation. Consistent with this observation, the complex of Pk3 with nonphosphorylatable Vangl2 was not polarized in the neural plate. These findings provide evidence forin vivoregulation of the Vangl2-Pk3 complex formation and localization by a Frizzled receptor.
Density-dependent effects are the main determinants of variation in growth dynamics between closely related bacterial strains
Authors: Hilau Sabrin , Katz Sophia , Wasserman Tanya , Hershberg Ruth , Savir Yonatan
Published: May 2021

Although closely related genetically, bacterial strains belonging to the same species show significant variability in their growth and death dynamics. However, our understanding of the underlying processes that lead to this variability is still lacking. Here, we measured the growth and death dynamics of 11 strains ofE. colioriginating from different hosts and developed a mathematical model that captures their growth and death dynamics. Our model considers two environmental factors that determine growth dynamics: resource utilization efficiency and density-dependent growth inhibition. Here we show that both factors are required to capture the measured dynamics. Interestingly, our model results indicate that the main process that determines the major differences between the strains is the critical density at which they slow down their growth, rather than maximal growth rate or death rate. Finally, we found that bacterial growth and death dynamics can be reduced to only two dimensions and described by death rates and density-dependent growth inhibition alone.

Importance

Understanding the dynamics of bacterial growth has been an area of intense study. However, these dynamics have often been characterized through the narrow prism of describing growth rates, without considering parameters that may modulate these rates. Here, we generate a model that describes bacterial growth and death dynamics, incorporating two essential, growth-modulating factors: density-dependent reductions in growth rates and resource utilization efficiency. This model allows us to demonstrate that variation in the growth curves of closely related bacterial strains can be reduced to two dimensions and explained almost entirely by variation in the cellular density at which bacteria slow down their growth, combined with their death rates.
Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage accumulation
Authors: Ahrens-Nicklas Rebecca C. , Tecedor Luis , Hall Arron F. , Kane Owen , Chung Richard J. , Lysenko Elena , Marsh Eric D. , Stein Colleen S. , Davidson Beverly L.
Published: May 2021

Although neurologic symptoms occur in two-thirds of lysosomal storage disorders (LSDs), for most we do not understand the mechanisms underlying brain dysfunction. A major unanswered question is if the pathogenic hallmark of LSDs, storage accumulation, induces functional defects directly or is a disease bystander. Also, for most LSDs we do not know the impact of loss-of-function in individual cell types. Understanding these critical questions are essential to therapy development. Here, we determined the impact of genetic rescue in distinct cell types on neural circuit dysfunction in CLN3 disease, the most common pediatric dementia and a representative LSD. We restoredCln3expression via AAV-mediated gene delivery and conditional genetic rescue in a CLN3 mouse model. Surprisingly, we found that low-level rescue ofCln3expression in neurons alone normalized clinically-relevant electrophysiologic markers of network dysfunction, despite the presence of substantial residual histopathology, in contrast to restoring expression in astrocytes. Thus, loss of Cln3 function in neurons, not storage accumulation, underlies neurologic dysfunction in CLN3 disease, implying that storage clearance may be an inappropriate target for therapy development and an ineffectual biomarker.
cDNA Immunization of Mice, Rats, and Hamsters
Authors: Greenfield Edward A.
Published: May 2021

Genetic immunization has been useful in vaccine technology and can also be used to generate immune responses to novel proteins. It is particularly useful when a properly folded protein is difficult to isolate or make in recombinant form and the required antibody must recognize a conformational epitope. Injecting cDNA allows the protein to be expressed in native form by the animal's own cells in vivo and then presented to the immune system. Genetic immunization is most effective for the generation of antibodies if the cDNA encodes for secreted or cell-surface proteins to make them accessible to the immune system. It also has been successful in generating antibody responses to difficult protein targets such as G-coupled protein receptors, ion channel proteins, and other multiple membrane-spanning proteins. High-affinity antibodies tend to be favored because the proteins are expressed at low levels and are constantly present for presentation to the immune system. In addition, several months can be saved obtaining sufficient amounts of properly folded, soluble recombinant protein or high-expressing transfected cells.