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Summary: Pregnancy is a risk factor for increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory infections, but the mechanisms underlying this risk are poorly understood. To gain insight into the role of pregnancy in modulating immune responses at baseline and upon SARS-CoV-2 infection, we collected peripheral blood mononuclear cells and plasma from 226 women, including 152 pregnant individuals and 74 non-pregnant women. We find that SARS-CoV-2 infection is associated with altered T cell responses in pregnant women, including a clonal expansion of CD4-expressing CD8+ T cells, diminished interferon responses, and profound suppression of monocyte function. We also identify shifts in cytokine and chemokine levels in the sera of pregnant individuals, including a robust increase of interleukin-27, known to drive T cell exhaustion. Our findings reveal nuanced pregnancy-associated immune responses, which may contribute to the increased susceptibility of pregnant individuals to viral respiratory infection.

IntroductionThe Anaphase Promoting Complex (APC/C), an E3 ubiquitin ligase, plays a key role in cell cycle control, but it is also thought to operate in postmitotic neurons. Most studies linking APC/C function to neuron biology employed perturbations of the APC/C activators, cell division cycle protein 20 (Cdc20) and Cdc20 homologue 1 (Cdh1). However, multiple lines of evidence indicate that Cdh1 and Cdc20 can function in APC/C-independent contexts, so that the effects of their perturbation cannot strictly be linked to APC/C function.MethodsWe therefore deleted the gene encoding Anaphase Promoting Complex 4 (APC4), a core APC/C component, in neurons cultured from conditional knockout (cKO) mice.ResultsOur data indicate that several previously published substrates are actually not APC/C substrates, whereas ubiquitin specific peptidase 1 (USP1) protein levels are altered in APC4 knockout (KO) neurons. We propose a model where the APC/C ubiquitylates USP1 early in development, but later ubiquitylates a substrate that directly or indirectly stabilizes USP1. We further discovered a novel role of the APC/C in regulating the number of neurites exiting somata, but we were unable to confirm prior data indicating that the APC/C regulates neurite length, neurite complexity, and synaptogenesis. Finally, we show that APC4 SUMOylation does not impact the ability of the APC/C to control the number of primary neurites or USP1 protein levels.DiscussionOur data indicate that perturbation studies aimed at dissecting APC/C biology must focus on core APC/C components rather than the APC/C activators, Cdh20 and Cdh1.

Summary: Lyme disease is caused by the bacterial pathogen Borrelia burgdorferi, which can be readily modeled in laboratory mice. In order to understand the cellular and transcriptional changes that occur during B. burgdorferi infection, we conducted single-cell RNA sequencing (scRNA-seq) of ankle joints of infected C57BL/6 mice over time. We found that macrophages/monocytes, T cells, synoviocytes and fibroblasts all showed significant differences in gene expression of both inflammatory and non-inflammatory genes that peaked early and returned to baseline before the typical resolution of arthritis. Predictions of cellular interactions showed that macrophages appear to communicate extensively between different clusters of macrophages as well as with fibroblasts and synoviocytes. Our data give unique insights into the interactions between B. burgdorferi and the murine immune system over time and allow for a better understanding of mechanisms by which the dysregulation of the immune response may lead to prolonged symptoms in some patients.

Advances in genome sequencing technologies have favored the identification of rare de novo mutations linked to neurological disorders in humans. Recently, a de novo autosomal dominant mutation in NACC1 was identified (NM_052876.3: c.892C > T, NP_443108.1; p.Arg298Trp), associated with severe neurological symptoms including intellectual disability, microcephaly, and epilepsy. As NACC1 had never before been associated with neurological diseases, we investigated how this mutation might lead to altered brain function. We examined neurotransmission in autaptic glutamatergic mouse neurons expressing the murine homolog of the human mutant NACC1, i.e., Nacc1-R284W. We observed that expression of Nacc1-R284W impaired glutamatergic neurotransmission in a cell-autonomous manner, likely through a dominant negative mechanism. Furthermore, by screening for Nacc1 interaction targets in the brain, we identified SynGAP1, GluK2A, and several SUMO E3 ligases as novel Nacc1 interaction partners. At a biochemical level, Nacc1-R284W exhibited reduced binding to SynGAP1 and GluK2A, and also showed greatly increased SUMOylation. Ablating the SUMOylation of Nacc1-R284W partially restored its interaction with SynGAP1 but did not restore binding to GluK2A. Overall, these data indicate a role for Nacc1 in regulating glutamatergic neurotransmission, which is substantially impaired by the expression of a disease-associated Nacc1 mutant. This study provides the first functional insights into potential deficits in neuronal function in patients expressing the de novo mutant NACC1 protein.

SUMO1-conjugation of proteins at neuronal synapses is considered to be a major post-translational regulatory process in nerve cell and synapse function, but the published evidence for SUMO1-conjugation at synapses is contradictory. We employed multiple genetic mouse models for stringently controlled biochemical and immunostaining analyses of synaptic SUMO1-conjugation. By using a knock-in reporter mouse line expressing tagged SUMO1, we could not detect SUMO1-conjugation of seven previously proposed synaptic SUMO1-targets in the brain. Further, immunostaining of cultured neurons from wild-type and SUMO1 knock-out mice showed that anti-SUMO1 immunolabelling at synapses is non-specific. Our findings indicate that SUMO1-conjugation of synaptic proteins does not occur or is extremely rare and hence not detectable using current methodology. Based on our data, we discuss a set of experimental strategies and minimal consensus criteria for the validation of SUMOylation that can be applied to any SUMOylation substrate and SUMO isoform.

Most neuropsychological assessments of episodic memory bear little similarity to the events that patients actually experience as memories in daily life. The first aim of this study was to use a virtual environment to characterize episodic memory profiles in an ecological fashion, which includes memory for central and perceptual details, spatiotemporal contextual elements, and binding. This study included subjects from three different populations: healthy older adults, patients with amnestic mild cognitive impairment (aMCI) and patients with early to moderate Alzheimer's disease (AD). Second, we sought to determine whether environmental factors that can affect encoding (active vs. passive exploration) influence memory performance in pathological aging. Third, we benchmarked the results of our virtual reality episodic memory test against a classical memory test and a subjective daily memory complaint scale. Here, the participants were successively immersed in two virtual environments; the first, as the driver of a virtual car (active exploration) and the second, as the passenger of that car (passive exploration). Subjects were instructed to encode all elements of the environment as well as the associated spatiotemporal contexts. Following each immersion, we assessed the patient's recall and recognition of central information (i.e., the elements of the environment), contextual information (i.e., temporal, egocentric and allocentric spatial information) and lastly, the quality of binding. We found that the AD patients' performances were inferior to that of the aMCI and even more to that of the healthy aged groups, in line with the progression of hippocampal atrophy reported in the literature. Spatial allocentric memory assessments were found to be particularly useful for distinguishing aMCI patients from healthy older adults. Active exploration yielded enhanced recall of central and allocentric spatial information, as well as binding in all groups. This led aMCI patients to achieve better performance scores on immediate temporal memory tasks. Finally, the patients' daily memory complaints were more highly correlated with the performances on the virtual test than with their performances on the classical memory test. Taken together, these results highlight specific cognitive differences found between these three populations that may provide additional insight into the early diagnosis and rehabilitation of pathological aging. In particular, neuropsychological studies would benefit to use virtual tests and a multi-component approach to assess episodic memory, and encourage active encoding of information in patients suffering from mild or severe age-related memory impairment. The beneficial effect of active encoding on episodic memory in aMCI and early to moderate AD is discussed in the context of relatively preserved frontal and motor brain functions implicated in self-referential effects and procedural abilities. (Contains 5 figures and 3 tables.)

Animal groups can show consistent behaviors or personalities just like solitary animals. We studied the collective behavior of Temnothorax nylanderi ant colonies, including consistency in behavior and correlations between different behavioral traits. We focused on four collective behaviors (aggression against intruders, nest relocation, removal of infected corpses and nest reconstruction) and also tested for links to the immune defense level of a colony and a fitness component (per-capita productivity). Behaviors leading to an increased exposure of ants to micro-parasites were expected to be positively associated with immune defense measures and indeed colonies that often relocated to other nest sites showed increased immune defense levels. Besides, colonies that responded with low aggression to intruders or failed to remove infected corpses, showed a higher likelihood to move to a new nest site. This resembles the trade-off between aggression and relocation often observed in solitary animals. Finally, one of the behaviors, nest reconstruction, was positively linked to per-capita productivity, whereas other colony-level behaviors, such as aggression against intruders, showed no association, albeit all behaviors were expected to be important for fitness under field conditions. In summary, our study shows that ant societies exhibit complex personalities that can be associated to the physiology and fitness of the colony. Some of these behaviors are linked in suites of correlated behaviors, similar to personalities of solitary animals.

Information on a paper discussed at a congress on the history of medicine about the life and work of physician Stéphane Leduc from Nantes, France, is presented. Topics include his original theories on synthetic biology, his work on artificial cell growth and his approach on the origins of life. According to the article, the theories of Leduc were rejected by the Academy of science in the beginning of the 20th century.