Deprivation-Induced Plasticity in the Early Central Circuits of the Rodent Visual, Auditory, and Olfactory Systems.

Activity-dependent neuronal plasticity is crucial for animals to adapt to dynamic sensory environments. Traditionally, it has been investigated using deprivation approaches in animal models primarily in sensory cortices. Nevertheless, emerging evidence emphasizes its significance in sensory organs and in subcortical regions where cranial nerves relay information to the brain. Additionally, critical questions started to arise. Do different sensory modalities share common cellular mechanisms for deprivation-induced plasticity at these central entry points? Does the deprivation duration correlate with specific plasticity mechanisms? This study systematically reviews and meta-analyzes research papers that investigated visual, auditory, or olfactory deprivation in rodents of both sexes. It examines the consequences of sensory deprivation in homologous regions at the first central synapse following cranial nerve transmission (vision - lateral geniculate nucleus and superior colliculus; audition - ventral and dorsal cochlear nucleus; olfaction - olfactory bulb). The systematic search yielded 91 papers (39 vision, 22 audition, 30 olfaction), revealing substantial heterogeneity in publication trends, experimental methods, measures of plasticity, and reporting across the sensory modalities. Despite these differences, commonalities emerged when correlating plasticity mechanisms with the duration of sensory deprivation. Short-term deprivation (up to 1 d) reduced activity and increased disinhibition, medium-term deprivation (1 d to a week) involved glial changes and synaptic remodeling, and long-term deprivation (over a week) primarily led to structural alterations. These findings underscore the importance of standardizing methodologies and reporting practices. Additionally, they highlight the value of cross-modal synthesis for understanding how the nervous system, including peripheral, precortical, and cortical areas, respond to and compensate for sensory inputs loss.

The Impact of Awe on Existential Isolation: Evidence for Contrasting Pathways.

We propose that awe has multifaceted relations with existential isolation, a feeling of separation between the self and others or the world. Three studies examined the relation between awe and existential isolation via feelings of small self (vastness, self-size, self-perspectives) and a sense of connectedness. Awe (vs. a control topic) was induced either using virtual reality (Study 1) or a recall task (Studies 2 and 3) and was indirectly associated with higher and lower levels of existential isolation through differing pathways. Awe was associated with lower feelings of existential isolation via an increased sense of vastness, which in turn predicted greater connectedness; whereas awe was associated with higher feelings of existential isolation via increased sense of feeling small, which in turn predicted lower connectedness. This work advances understanding of the complex nature of awe-revealing its competing effects on the self and the social connectedness pathways through which awe can influence existential isolation.

A Review on Microbiological Source Attribution Methods of Human Salmonellosis: From Subtyping to Whole-Genome Sequencing.

Salmonella is one of the main causes of human foodborne illness. It is endemic worldwide, with different animals and animal-based food products as reservoirs and vehicles of infection. Identifying animal reservoirs and potential transmission pathways of Salmonella is essential for prevention and control. There are many approaches for source attribution, each using different statistical models and data streams. Some aim to identify the animal reservoir, while others aim to determine the point at which exposure occurred. With the advance of whole-genome sequencing (WGS) technologies, new source attribution models will greatly benefit from the discriminating power gained with WGS. This review discusses some key source attribution methods and their mathematical and statistical tools. We also highlight recent studies utilizing WGS for source attribution and discuss open questions and challenges in developing new WGS methods. We aim to provide a better understanding of the current state of these methodologies with application to Salmonella and other foodborne pathogens that are common sources of illness in the poultry and human sectors.

Henipavirus Matrix Protein Employs a Non-Classical Nuclear Localization Signal Binding Mechanism.

Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic species from the Henipavirus genus within the paramyxovirus family and are harbored by Pteropus Flying Fox species. Henipaviruses cause severe respiratory disease, neural symptoms, and encephalitis in various animals and humans, with human mortality rates exceeding 70% in some NiV outbreaks. The henipavirus matrix protein (M), which drives viral assembly and budding of the virion, also performs non-structural functions as a type I interferon antagonist. Interestingly, M also undergoes nuclear trafficking that mediates critical monoubiquitination for downstream cell sorting, membrane association, and budding processes. Based on the NiV and HeV M X-ray crystal structures and cell-based assays, M possesses a putative monopartite nuclear localization signal (NLS) (residues 82KRKKIR87; NLS1 HeV), positioned on an exposed flexible loop and typical of how many NLSs bind importin alpha (IMPα), and a putative bipartite NLS (244RR-10X-KRK258; NLS2 HeV), positioned within an α-helix that is far less typical. Here, we employed X-ray crystallography to determine the binding interface of these M NLSs and IMPα. The interaction of both NLS peptides with IMPα was established, with NLS1 binding the IMPα major binding site, and NLS2 binding as a non-classical NLS to the minor site. Co-immunoprecipitation (co-IP) and immunofluorescence assays (IFA) confirm the critical role of NLS2, and specifically K258. Additionally, localization studies demonstrated a supportive role for NLS1 in M nuclear localization. These studies provide additional insight into the critical mechanisms of M nucleocytoplasmic transport, the study of which can provide a greater understanding of viral pathogenesis and uncover a potential target for novel therapeutics for henipaviral diseases.

Severe Legionella and Histoplasma Pneumonia Acquired From Spring Water.

Legionnaires' disease and pulmonary histoplasmosis are important causes of community-acquired pneumonia. Environmental reservoirs remain the primary source of infection and may persist since investigations are often reserved for large outbreaks. Our case highlights a source of both legionella and histoplasmosis not previously reported. It demonstrates the value of taking a thorough history while recognizing non-traditional sources of both infections.

Shades of expansiveness: Postural expression of dominance, high-arousal positive affect, and warmth.

In addition to the face, bodily posture plays an important role in communicating affective states. Postural expansion-how much space the body takes up-has been much studied as expressing and signaling dominance and pride. The present research aimed to expand research on the range of affect dimensions and affect-laden personality characteristics that are expressed via expansiveness, investigating specific forms of expansiveness and their interactions with other postural elements (e.g., arm position). Using an innovative expression-production method, Study 1 (N = 146) characterized full-body expressions of dominance, joy, hope, and awe; results indicated joy is communicated most expansively and suggested a signature arm position for most feelings. Studies 2 and 3 (Ns = 352 and 183) revealed that other postural features interact with expansiveness to signal dominance (arms akimbo, head raised, stability), as distinct from high-arousal positive affect (arms high up, head raised) and warmth (arms high up, head raised, instability). Together, this research adds needed data on full-body expressions of positive affect states and provides systematic analysis of different affective messages and varieties of postural expansiveness. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Hemophagocytic lymphohistiocytosis secondary to disseminated histoplasmosis, cytomegalovirus viremia, and nontuberculous mycobacteria bacteremia in a patient with recently diagnosed AIDS.

A 30-year-old Honduran male with recently diagnosed AIDS presented with a 1-month history of worsening abdominal pain, diarrhea, and fever. Initial investigations were notable for Cytomegalovirus viremia and diffuse lymphadenopathy. Axillary lymph node biopsy demonstrated necrotizing lymphadenitis with disseminated histoplasmosis. Despite aggressive antimicrobial therapy he continued to clinically deteriorate raising suspicion for hemophagocytic lymphohistiocytosis. The patient met 5 of 8 HLH-2004 diagnostic criteria and was successfully treated with dexamethasone and etoposide per the HLH-94 protocol. Despite the high mortality rates and poor clinical outcomes of hemophagocytic lymphohistiocytosis in patients living with HIV/AIDS, this case demonstrates that this high-risk patient population can be successfully treated and survive acquired hemophagocytic lymphohistiocytosis. Furthermore, our case stresses the importance of maintaining a broad differential diagnosis in patients living with HIV/AIDS who present with sepsis.

Marburg Virus VP30 Is Required for Transcription Initiation at the Glycoprotein Gene.

Marburg virus (MARV) is an enveloped, negative-sense RNA virus from the filovirus family that causes outbreaks of severe, frequently fatal illness in humans. Of the seven MARV proteins, the VP30 protein stands out because it is essential for viral growth but lacks a definitive function. Here, we used model MARV genome RNAs for one or two reporter genes and the MARV VP40, glycoprotein (GP), and VP24 genes to demonstrate that VP30 is dispensable for the transcription of some genes but critical for transcription reinitiation at the GP gene. This results in the loss of the expression of GP and downstream genes and the impaired production of infectious particles when VP30 is absent. Bicistronic minigenome assays demonstrate that the VP40 gene end/GP gene start junction specifically confers VP30 dependence. A region at the GP gene start site predicted to form a stem-loop contributes to VP30 dependence because the replacement of the GP stem-loop with corresponding sequences from the MARV VP35 gene relieves VP30 dependence. Finally, a Cys3-His zinc binding motif characteristic of filovirus VP30 proteins was demonstrated to be critical for reinitiation at GP. These findings address a long-standing gap in our understanding of MARV biology by defining a critical role for VP30 in MARV transcription. IMPORTANCE Marburg virus and Ebola virus encode VP30 proteins. While the role of VP30 in Ebola virus transcription has been well studied, the role of VP30 in the Marburg virus life cycle is not well understood. The work here demonstrates that different gene start sites within the Marburg viral genome have variable levels of dependence on Marburg virus VP30, with its expression being critical for transcription reinitiation at the GP gene start site. These findings address a long-standing question regarding Marburg virus VP30 function and further our understanding of how Marburg virus gene expression is regulated.

Bodily feedback: expansive and upward posture facilitates the experience of positive affect.

Most emotion theories recognise the importance of the body in expressing and constructing emotions. Focusing beyond the face, the present research adds needed empirical data on the effect of static full body postures on positive/negative affect. In Studies 1 (N = 110) and 2 (N = 79), using a bodily feedback paradigm, we manipulated postures to test causal effects on affective and physiological responses to emotionally ambiguous music. Across both studies among U.S. participants, we find the strongest support for an effect of bodily postures that are expansive and oriented upward on positive affect. In addition, an expansive and upward pose also led to greater cardiac vagal reactivity but these changes in parasympathetic activity were not related to affective changes (Study 2). In line with embodied theories, these results provide additional support for the role of postural input in constructing affect. Discussion highlights the relevance of these findings for the study of religious practices during which the postures studied are often adopted.

Divergent effects of social media use on meaning in life via loneliness and existential isolation during the coronavirus pandemic.

Stay-at-home orders issued to combat the growing number of infections during the coronavirus pandemic in 2020 had many psychological consequences for people including elevated stress, anxiety, and difficulty maintaining meaning in their lives. The present studies utilized cross-sectional designs and were conducted to better understand how social media usage related to people's subjective isolation (i.e., social loneliness, emotional loneliness, and existential isolation) and meaning in life (MIL) during the early months of the pandemic within the United States. Study 1 found that general social media use indirectly predicted higher MIL via lower existential isolation and social isolation. Study 2 replicated these patterns and found that social media use also predicted lower MIL via higher emotional loneliness, and that the aforementioned effects occurred with active, but not passive, social media use. Findings suggest social media use may be a viable means to validate one's experiences (i.e., reduce existential isolation) during the pandemic but may also lead to intensified feelings concerning missing others (i.e., increased emotional loneliness). This research also helps to identify potential divergent effects of social media on MIL and helps to clarify the relationships among varying types of subjective isolation.

Prevotella bivia cardiac implantable electronic device related endocarditis.

Cases of Gram-negative, anaerobic rod bacteremia and endocarditis have been increasingly recognized in recent years. This increase has been primarily observed in patients at risk for polymicrobial infections, such as those who use injection drugs and patients with diabetes mellitus. Despite a growing incidence, there are few published case reports of cardiac implantable electronic device related endocarditis secondary to Gram negative, anaerobic organisms. We present a unique case of Prevotella bivia cardiac implantable electronic device related endocarditis in a middle-aged woman with no history of injection drug use. This case highlights the increasing incidence of polymicrobial infections and anaerobic endocarditis. Additionally, it demonstrates how Prevotella bivia has the potential to cause native valve infective endocarditis as well as cardiac implantable electronic device related endocarditis.

MERS-CoV ORF4b employs an unusual binding mechanism to target IMPα and block innate immunity.

The MERS coronavirus (MERS-CoV) is a highly pathogenic, emerging virus that produces accessory proteins to antagonize the host innate immune response. The MERS-CoV ORF4b protein has been shown to bind preferentially to the nuclear import adapter IMPα3 in infected cells, thereby inhibiting NF-κB-dependent innate immune responses. Here, we report high-resolution structures of ORF4b bound to two distinct IMPα family members. Each exhibit highly similar binding mechanisms that, in both cases, lack a prototypical Lys bound at their P2 site. Mutations within the NLS region dramatically alter the mechanism of binding, which reverts to the canonical P2 Lys binding mechanism. Mutational studies confirm that the novel binding mechanism is important for its nuclear import, IMPα interaction, and inhibition of innate immune signaling pathways. In parallel, we determined structures of the nuclear binding domain of NF-κB component p50 bound to both IMPα2 and α3, demonstrating that p50 overlaps with the ORF4b binding sites, suggesting a basis for inhibition. Our results provide a detailed structural basis that explains how a virus can target the IMPα nuclear import adapter to impair immunity, and illustrate how small mutations in ORF4b, like those found in closely related coronaviruses such as HKU5, change the IMPα binding mechanism.

Multiple genetic paths including massive gene amplification allow Mycobacterium tuberculosis to overcome loss of ESX-3 secretion system substrates.

Mycobacterium tuberculosis (Mtb) possesses five type VII secretion systems (T7SS), virulence determinants that include the secretion apparatus and associated secretion substrates. Mtb strains deleted for the genes encoding substrates of the ESX-3 T7SS, esxG or esxH, require iron supplementation for in vitro growth and are highly attenuated in vivo. In a subset of infected mice, suppressor mutants of esxG or esxH deletions were isolated, which enabled growth to high titers or restored virulence. Suppression was conferred by mechanisms that cause overexpression of an ESX-3 paralogous region that lacks genes for the secretion apparatus but encodes EsxR and EsxS, apparent ESX-3 orphan substrates that functionally compensate for the lack of EsxG or EsxH. The mechanisms include the disruption of a transcriptional repressor and a massive 38- to 60-fold gene amplification. These data identify an iron acquisition regulon, provide insight into T7SS, and reveal a mechanism of Mtb chromosome evolution involving "accordion-type" amplification.

Evaluation of Genome Sequences of the Bacteriophages JeTaime and Luna22.

The mycobacteriophages JeTaime (E cluster) and Luna22 (Q cluster) were isolated from soil in Providence, Rhode Island, and Charleston, South Carolina, respectively, using a Mycobacterium smegmatis mc2 155 host. The genome of JeTaime is 75,099 bp (142 predicted genes), and that of Luna22 is 53,730 bp (87 predicted genes). Both phages exhibit Siphoviridae morphology.

Synthesis and antiviral activity of fatty acyl conjugates of remdesivir against severe acute respiratory syndrome coronavirus 2 and Ebola virus.

We report here the synthesis, purification, and characterization of mono- and di-fatty acyl conjugates of remdesivir (RDV) and their in vitro antiviral activity against SAR-CoV-2, an Ebola virus transcription- and replication-competent virus-like particle (trVLP) system, and infectious Ebola virus. The most potent monofatty acyl conjugate was 4b, containing a 4-oxatetradecanolyl at the 3' position. Monofatty acyl conjugates, 3'-O-tetradecanoyl (4a) (IC50(VeroE6) = 2.3 µM; IC50(Calu3) = 0.24 µM), 3'-O-4-oxatetradodecanoyl (4b) (IC50(VeroE6) = 2.0 µM; IC50(Calu3) = 0.18 µM), and 3'-O-(12-ethylthiododecanoyl) (4e) (IC50(VeroE6) = 2.4 µM; IC50(Calu3) = 0.25 µM) derivatives exhibited less activity than RDV (IC50(VeroE6) = 0.85 µM; IC50(Calu3) = 0.06 µM) in both VeroE6 and Calu3 cells. Difatty acylation led to a significant reduction in the antiviral activity of RDV (as shown in conjugates 5a and 5b) against SARS-CoV-2 when compared with monofatty acylation (3a-e and 4a-e). About 77.9% of 4c remained intact after 4 h incubation with human plasma while only 47% of parent RDV was observed at the 2 h time point. The results clearly indicate the effectiveness of fatty acylation to improve the half-life of RDV. The antiviral activities of a number of monofatty acyl conjugates of RDV, such as 3b, 3e, and 4b, were comparable with RDV against the Ebola trVLP system. Meanwhile, the corresponding physical mixtures of RDV and fatty acids 6a and 6b showed 1.6 to 2.2 times less antiviral activity than the corresponding conjugates, 4a and 4c, respectively, against SARS-CoV-2 in VeroE6 cells. A significant reduction in viral RNA synthesis was observed for selected compounds 3a and 4b consistent with the IC50 results. These studies indicate the potential of these compounds as long-acting antiviral agents or prodrugs of RDV.

Structural basis for nuclear import selectivity of pioneer transcription factor SOX2.

SOX (SRY-related HMG-box) transcription factors perform critical functions in development and cell differentiation. These roles depend on precise nuclear trafficking, with mutations in the nuclear targeting regions causing developmental diseases and a range of cancers. SOX protein nuclear localization is proposed to be mediated by two nuclear localization signals (NLSs) positioned within the extremities of the DNA-binding HMG-box domain and, although mutations within either cause disease, the mechanistic basis has remained unclear. Unexpectedly, we find here that these two distantly positioned NLSs of SOX2 contribute to a contiguous interface spanning 9 of the 10 ARM domains on the nuclear import adapter IMPα3. We identify key binding determinants and show this interface is critical for neural stem cell maintenance and for Drosophila development. Moreover, we identify a structural basis for the preference of SOX2 binding to IMPα3. In addition to defining the structural basis for SOX protein localization, these results provide a platform for understanding how mutations and post-translational modifications within these regions may modulate nuclear localization and result in clinical disease, and also how other proteins containing multiple NLSs may bind IMPα through an extended recognition interface.

Relaxed predation theory: size, sex and brains matter.

Australia's wildlife is being considerably impacted by introduced mammalian predators such as cats (Felis catus), dogs (Canis lupus familiaris), and foxes (Vulpes vulpes). This is often attributed to native wildlife being naïve to these introduced predators. A systematic review of the literature reveals that native metatherians (body mass range 0.02-25 kg) do not recognise, and show relaxed antipredator behaviours towards, native and some introduced mammalian predators. Native eutherians (all with body mass < 2 kg), however, do appear to recognise and exhibit antipredator behaviours towards both native and introduced predators. Based on our findings, we propose a novel theory, the 'Relaxed Predation Theory'. Our new theory is based on the absence of large mammalian predators leading to reduced predation pressure in Australia during the past 40000-50000 years, and on three key differences between Australian metatherians and eutherians: size, sex, and brains. In light of this Relaxed Predation Theory, we make a number of recommendations for the conservation of Australian wildlife: (i) predator avoidance training of suitable species; (ii) exclusion fencing to exclude some, but not all, predators to facilitate the development of antipredator behaviours; (iii) captive breeding programs to prevent the extinction of some species; and (iv) reintroduction of Australia's larger predators, potentially to compete with and displace introduced predators. A more detailed understanding of the responses of Australian mammals to predators will hopefully contribute to the improved conservation of susceptible species.

Upward spirals of positive emotions and religious behaviors.

Positive emotions feel good and build psychological, social, and biological resources (Broaden-and-Build Theory, Fredrickson, 1998, 2013). People who identify as religious or spiritual value them and report feeling them frequently. They are also prevalent in religious and spiritual practices, such as prayer, meditation, and collective worship. We review the literature on the reciprocal relationship between positive emotions and religion/spirituality and identify individual differences predicting greater positive emotions derived from engaging in religious practices. We suggest that beyond building religious/spiritual people's well-being, positive emotions play a role in sustaining otherwise costly religious behaviors. We integrate our review in the proposed Upward Spiral Theory of Sustained Religious Practice.

Interactions of the Nipah Virus P, V, and W Proteins across the STAT Family of Transcription Factors.

The Nipah virus (NiV) phosphoprotein (P) gene encodes four proteins. Three of these-P, V, and W-possess a common N-terminal domain but distinct C termini. These proteins interact with immune modulators. Previous studies demonstrated that P, V, and W bind STAT1 and STAT4 and that V also interacts with STAT2 but not with STAT3. The STAT1 and STAT2 interactions block interferon (IFN)-induced STAT tyrosine phosphorylation. To more fully characterize the interactions of P, V, and W with the STATs, we screened for interaction of each viral protein with STATs 1 to 6 by coimmunoprecipitation. We demonstrate that NiV P, V, and W interact with STAT4 through their common N-terminal domain and block STAT4 activity, based on a STAT4 response element reporter assay. Although none of the NiV proteins interact with STAT3 or STAT6, NiV V, but not P or W, interacts with STAT5 through its unique C terminus. Furthermore, the interaction of NiV V with STAT5 was not disrupted by overexpression of the N-terminal binding STAT1 or the C-terminal binding MDA5. NiV V also inhibits a STAT5 response element reporter assay. Residues 114 to 140 of the common N-terminal domain of the NiV P gene products were found to be sufficient to bind STAT1 and STAT4. Analysis of STAT1-STAT3 chimeras suggests that the P gene products target the STAT1 SH2 domain. When fused to GST, the 114-140 peptide is sufficient to decrease STAT1 phosphorylation in IFN-ß-stimulated cells, suggesting that this peptide could potentially be fused to heterologous proteins to confer inhibition of STAT1- and STAT4-dependent responses.IMPORTANCE How Nipah virus (NiV) antagonizes innate immune responses is incompletely understood. The P gene of NiV encodes the P, V, and W proteins. These proteins have a common N-terminal sequence that is sufficient to bind to STAT1 and STAT2 and block IFN-induced signal transduction. This study sought to more fully understand how P, V, and W engage with the STAT family of transcription factors to influence their functions. The results identify a novel interaction of V with STAT5 and demonstrate V inhibition of STAT5 function. We also demonstrate that the common N-terminal residues 114 to 140 of P, V, and W are critical for inhibition of STAT1 and STAT4 function, map the interaction to the SH2 region of STAT1, and show that a fusion construct with this peptide significantly inhibits cytokine-induced STAT1 phosphorylation. These data clarify how these important virulence factors modulate innate antiviral defenses.