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Since the outbreak of the SARS-CoV-2 pandemic, there have been intense structural studies on purified viral components and inactivated viruses. However, structural and ultrastructural evidence on how the SARS-CoV-2 infection progresses in the native cellular context is scarce, and there is a lack of comprehensive knowledge on the SARS-CoV-2 replicative cycle. To correlate cytopathic events induced by SARS-CoV-2 with virus replication processes in frozen-hydrated cells, we established a unique multi-modal, multi-scale cryo-correlative platform to image SARS-CoV-2 infection in Vero cells. This platform combines serial cryoFIB/SEM volume imaging and soft X-ray cryo-tomography with cell lamellae-based cryo-electron tomography (cryoET) and subtomogram averaging. Here we report critical SARS-CoV-2 structural events – e.g. viral RNA transport portals, virus assembly intermediates, virus egress pathway, and native virus spike structures, in the context of whole-cell volumes revealing drastic cytppathic changes. This integrated approach allows a holistic view of SARS-CoV-2 infection, from the whole cell to individual molecules. In this study, Peijun Zhang and colleagues use cryoFIB/SEM volume imaging and soft x-ray cryo-tomography with cryo-electron tomography (cryoET) of cellular periphery, lamellae, and subtomogram averaging to place critical structural events in the SARS-CoV-2 infection cycle in the context of whole-cell images.

Research on glutamatergic neurotransmission has focused mainly on the function of presynaptic and postsynaptic neurons, leaving astrocytes with a secondary role only to ensure successful neurotransmission. However, recent evidence indicates that astrocytes contribute actively and even regulate neuronal transmission at different levels. This review establishes a framework by comparing glutamatergic components between neurons and astrocytes to examine how astrocytes modulate or otherwise influence neuronal transmission. We have included the most recent findings about the role of astrocytes in neurotransmission, allowing us to understand the complex network of neuron-astrocyte interactions. However, despite the knowledge of synaptic modulation by astrocytes, their contribution to specific physiological and pathological conditions remains to be elucidated. A full understanding of the astrocyte’s role in neuronal processing could open fruitful new frontiers in the development of therapeutic applications.

AimsTo identify if COVID-19 has changed the experience for patients under the care of Crisis Resolution Home Treatment teams (HTT).To identify if COVID-19 altered the response for HTT patients in the context of Personality Disorder (PD).To provide useful demographic and experiential information about patients using HTT with PD during crisis.MethodsData regarding the demographics of patients with personality disorders under the care of the Croydon crisis home treatment team were collected retrospectively for two, predetermined time windows. The first window was pre-COVID-19 (26/03/2019–25/03/2020) and the second window was during COVID-19 (26/03/2020–25/03/2021). The demographics of patients with personality disorder referred to the team during these two time periods included were compared.ResultsMore patients with personality disorder were referred to the Croydon HTT during COVID-19 (n = 82) when compared with the window before (n = 58). The proportion of referred patients with Emotionally Unstable Personality Disorder (EUPD) was constant before and during COVID-19. The average length of stay reduced from 22.6 days before COVID-19 to 18.7 days during COVID-19. The proportion of rejected referrals to the HTT of patients with personality disorder increased during COVID-19. Finally, the proportion of BAME (Black, Asian, Minority Ethnicity) referrals of patients with personality disorder increased during COVID when compared with before, with this finding not being replicated in any other ethnic group.ConclusionIncreased numbers of referrals may indicate worsening mental health in the community. This may have been compounded by an inability of community mental health teams and inpatient services to meet such an increase in demand for services. An overall reduction in inpatient admissions during COVID-19 supports this idea. There was a relatively larger drop in duration of admission for patient with personality disorder during COVID-19, when compared with all patients. This may be due to staff feeling unable to offer quick management for patients with personality disorder. Subsequently, staff may have selectively discharged such patients earlier. The rate of rejected referrals to the Croydon HTT was consistently higher than the acceptances both pre- and post- COVID-19. Therefore, HTT clinicians may feel unable to adequately treat PD.In conclusion, the number of referrals to the HTT increased during COVID-19, however, with a reduced average duration of stay with HTT for patients. The rejection rates for personality disorder patients were consistently higher than for other patient groups, both before and during COVID-19. Additionally, the proportion of patients with personality disorder from BAME backgrounds increased during COVID-19.

Two books in C.S. Lewis’s young adult fantasy series Chronicles of Narnia - The Horse and His Boy and The Last Battle - paint an uncomfortable portrait of the Calormen, the traditional foil for the Narnians. Throughout the text, the Calormen are clearly marked both culturally and racially as Middle Eastern, perhaps specifically as Turkish or Arab in their socio-political power structure with harems, arranged marriages, and facial hair designating status. Even Tashbaan, the capital city of Calormen, reads somewhat like a description of Istanbul. Throughout these two books, the Calormen are portrayed as a sinister and conquest-driven culture threatening the freedom enjoyed by Narnia. This textual indictment is fairly consistent. In demonizing this group, Lewis took part in a literary tradition extending back hundreds of years, a tradition that has enjoyed renewed resonance with increased fears over the growth of Islam. From Sir John Mandeville to post-9/11 concerns over terrorism, western depictions of Islam have often revolved around fear and distrust. The Last Battle is particularly problematic in its allegorical depictions of Islam, as Lewis seems to suggest that salvation is only reserved for those who follow the lion Aslan, clearly marked throughout the series as a stand-in for Jesus Christ.

The human endogenous retrovirus K (HERV-K) is the most recently acquired endogenous retrovirus in the human genome and is activated and expressed in many cancers and amyotrophic lateral sclerosis. We present the immature HERV-K capsid structure at 3.2 Å resolution determined from native virus-like particles using cryo-electron tomography and subtomogram averaging. The structure shows a hexamer unit oligomerized through a 6-helix bundle, which is stabilized by a small molecule analogous to IP6 in immature HIV-1 capsid. The HERV-K immature lattice is assembled via highly conserved dimer and trimer interfaces, as detailed through all-atom molecular dynamics simulations and supported by mutational studies. A large conformational change mediated by the linker between the N-terminal and the C-terminal domains of CA occurs during HERV-K maturation. Comparison between HERV-K and other retroviral immature capsid structures reveals a highly conserved mechanism for the assembly and maturation of retroviruses across genera and evolutionary time. The hexagonal immature capsid lattice of human endogenous retrovirus K is determined at 3.2 Å resolution, which is an assembly of small molecule-stabilized hexamers via dimer and trimer interfaces, a highly conserved mechanism among retroviruses.

D3 receptors, a key component of the dopamine system, have emerged as a potential target of therapies to improve motor symptoms across neurodegenerative and neuropsychiatric conditions. In the present work, we evaluated the effect of D3 receptor activation on the involuntary head twitches induced by 2,5-dimethoxy-4-iodoamphetamine (DOI) at behavioral and electrophysiological levels. Mice received an intraperitoneal injection of either a full D3 agonist, WC 44 [4-(2-fluoroethyl)-N-[4-[4-(2-methoxyphenyl)piperazin 1-yl]butyl]benzamide] or a partial D3 agonist, WW-III-55 [N-(4-(4-(4-methoxyphenyl)piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamide] five minutes before the intraperitoneal administration of DOI. Compared to the control group, both D3 agonists delayed the onset of the DOI-induced head-twitch response and reduced the total number and frequency of the head twitches. Moreover, the simultaneous recording of neuronal activity in the motor cortex (M1) and dorsal striatum (DS) indicated that D3 activation led to slight changes in a single unit activity, mainly in DS, and increased its correlated firing in DS or between presumed cortical pyramidal neurons (CPNs) and striatal medium spiny neurons (MSNs). Our results confirm the role of D3 receptor activation in controlling DOI-induced involuntary movements and suggest that this effect involves, at least in part, an increase in correlated corticostriatal activity. A further understanding of the underlying mechanisms may provide a suitable target for treating neuropathologies in which involuntary movements occur.

In meiosis, cells undergo two sequential rounds of cell division, termed meiosis I and meiosis II. Textbook models of the meiosis I substage called pachytene show that nuclei have conspicuous 100-nm-wide, ladder-like synaptonemal complexes and ordered chromatin loops. It remains unknown if these cells have any other large, meiosis-related intranuclear structures. Here we present cryo-ET analysis of frozen-hydrated budding yeast cells before, during, and after pachytene. We found no cryo-ET densities that resemble dense ladder-like structures or ordered chromatin loops. Instead, we found large numbers of 12-nm-wide triple-helices that pack into ordered bundles. These structures, herein called meiotic triple helices (MTHs), are present in meiotic cells, but not in interphase cells. MTHs are enriched in the nucleus but not enriched in the cytoplasm. Bundles of MTHs form at the same timeframe as synaptonemal complexes (SCs) in wild-type cells and in mutant cells that are unable to form SCs. These results suggest that in yeast, SCs coexist with previously unreported large, ordered assemblies.

In meiosis, cells undergo two sequential rounds of cell division, termed meiosis I and meiosis II. Textbook models of the meiosis I substage called pachytene show that nuclei have conspicuous 100-nm-wide, ladder-like synaptonemal complexes and ordered chromatin loops. It remains unknown if these cells have any other large, meiosis-related intranuclear structures. Here we present cryo-ET analysis of frozen-hydrated budding yeast cells before, during, and after pachytene. We found no cryo-ET densities that resemble dense ladder-like structures or ordered chromatin loops. Instead, we found large numbers of 12-nm-wide triple-helices that pack into ordered bundles. These structures, herein called meiotic triple helices (MTHs), are present in meiotic cells, but not in interphase cells. MTHs are enriched in the nucleus but not enriched in the cytoplasm. Bundles of MTHs form at the same timeframe as synaptonemal complexes (SCs) in wild-type cells and in mutant cells that are unable to form SCs. These results suggest that in yeast, SCs coexist with previously unreported large, ordered assemblies.

In this case study, we present a novel approach to care within a Home Treatment Team, using a behavioural contract. This is a signed, written agreement that targets specific behaviours for change. The concept draws on social learning theory in that it requires social interaction and a relationship to work. In psychiatric settings, the behavioural contract often finds use in Democratic Therapeutic Communities but rarely in crisis or acute services. In this case study, we attempted to use a behavioural contract within our Home Treatment Team to help a patient address his alcohol dependence and its subsequent effect on his daily living activities. The behavioural contract provided an alternative way to manage a crisis episode. We hope that other crisis service staff reading this case study may use a behavioural contract in their work to a similar beneficial effect.

Cleft lip (CL) is a common malformation that has both genetic and exogenous causes. The main pharmaceutical cause is exposure to phenytoin during early facial development in the 5th to 6th weeks of gestation. Phenytoin also causes CL if administered to pregnant rats during the period of early facial development. Evidence is presented that in the pregnant rat, a teratogenic dose of phenytoin slows the early embryonic heart and causes a prolonged period of embryonic hypoxia. It is proposed that this hypoxia, through an undefined downstream mechanism, leads to the development of CL. The involvement of hypoxia in the pathogenesis of CL is in agreement with studies in mouse strains with a spontaneous rate of CL in which exposure to hypoxia has been shown to increase the rate and hyperoxia to decrease the rate. Other exogenous risk factors during pregnancy for human CL include maternal cigarette smoking, residence at high altitude and exposure to corticosteroids. It is suggested that these exposures all involve an increased risk of embryonic hypoxia. It has been proposed that phenytoin affects the embryonic heart by inhibition of the human-ether-a-go-go (HERG) potassium channel. Phenytoin also inhibits sodium and calcium channels and these properties may also be involved in the observed effect on the embryonic heart. Phenytoin-induced bradycardia leading to embryonic hypoxia may be an important mechanism by which phenytoin causes birth defects.