bluuebunny/crossref_metadata_2025 huggingface dataset:
Human olfactory communication: current challenges and future prospects
Authors: Roberts S. Craig , Havlíček Jan , Schaal Benoist
Published: April 2020

Although anthropologists frequently report the centrality of odours in the daily lives and cultural beliefs of many small-scale communities, Western scholars have historically considered the sense of smell as minimally involved in human communication. Here, we suggest that the origin and persistence of this latter view might be a consequence of the fact that most research is conducted on participants from Western societies who, collectively, were ratherold(adults),deodorizedanddesensitized(ODD) to various aspects of olfactory perception. The view is rapidly changing, however, and this themed issue provides a timely overview of the current state-of-the-art on human chemocommunication. Based on evolutionary models of communication, the papers cover both general mechanisms of odour production by ‘senders’ and odour perception by ‘receivers’. Focus on specific functional contexts includes reciprocal impact of odours between infants and mothers, the role of odour in mate choice and how odours communicate emotion and disease. Finally, a position paper outlines pitfalls and opportunities for the future, against the context of the replication crisis in psychology. We believe a more nuanced view of human chemical communication is within our grasp if we can continue to develop inter-disciplinary insights and expand research activities beyond ODD people.

This article is part of the Theo Murphy meeting issue ‘Olfactory communication in humans’.
Decoding the social volatilome by tracking rapid context-dependent odour change
Authors: Roberts S. Craig , Misztal Pawel K. , Langford Ben
Published: April 2020

Odours can have a significant influence on the outcome of social interactions. However, we have yet to characterize the chemical signature of any specific social cue in human body odour, and we know little about how changes in social context influence odour chemistry. Here, we argue that adoption of emerging analytical techniques from other disciplines, such as atmospheric chemistry, might become game-changing tools in this endeavour. First, we describe the use of online chemical ionization time-of-flight mass spectrometry to sensitively measure many hundreds of gas-phase volatile organic compounds in real time. By analysing ambient air emanating from undisturbed individuals or groups, the technique enables a continuous recording of an instantaneous odour change in response to external stimuli and changing social context. This has considerable advantages over the traditional approach of periodic sampling for analysis by gas chromatography. We also discuss multivariate statistical approaches, such as positive matrix factorization, that can effectively sift through this complex datastream to identify linked groups of compounds that probably underpin functional chemosignals. In combination, these innovations offer new avenues for addressing outstanding questions concerning olfactory communication in humans and other species, as well as in related fields using odour, such as biometrics and disease diagnostics.

This article is part of the Theo Murphy meeting issue ‘Olfactory communication in humans’.
Major histocompatibility complex-associated odour preferences and human mate choice: near and far horizons
Authors: Havlíček Jan , Winternitz Jamie , Roberts S. Craig
Published: April 2020

The major histocompatibility complex (MHC) is a core part of the adaptive immune system. As in other vertebrate taxa, it may also affect human chemical communication via odour-based mate preferences, with greater attraction towards MHC-dissimilar partners. However, despite some well-known findings, the available evidence is equivocal and made complicated by varied approaches to quantifying human mate choice. To address this, we here conduct comprehensive meta-analyses focusing on studies assessing: (i) genomic mate selection, (ii) relationship satisfaction, (iii) odour preference, and (iv) all studies combined. Analysis of genomic studies reveals no association between MHC-dissimilarity and mate choice in actual couples; however, MHC effects appear to be independent of the genomic background. The effect of MHC-dissimilarity on relationship satisfaction was not significant, and we found evidence for publication bias in studies on this area. There was also no significant association between MHC-dissimilarity and odour preferences. Finally, combining effect sizes from all genomic, relationship satisfaction, odour preference and previous mate choice studies into an overall estimate showed no overall significant effect of MHC-similarity on human mate selection. Based on these findings, we make a set of recommendations for future studies, focusing both on aspects that should be implemented immediately and those that lurk on the far horizon. We need larger samples with greater geographical and cultural diversity that control for genome-wide similarity. We also need more focus on mechanisms of MHC-associated odour preferences and on MHC-associated pregnancy loss.

This article is part of the Theo Murphy meeting issue ‘Olfactory communication in humans’.
Body odours as a chemosignal in the mother–child relationship: new insights based on an human leucocyte antigen-genotyped family cohort
Authors: Schäfer Laura , Sorokowska Agnieszka , Sauter Jürgen , Schmidt Alexander H. , Croy Ilona
Published: April 2020

Mothers are able to identify the body odour (BO) of their own child and prefer this smell above other BOs. It has hence been assumed that the infantile BO functions as a chemosignal promoting targeted parental care. We tested this hypothesis and examined whether children's BOs signal genetic similarity and developmental status to mothers. In addition, we assessed whether BOs facilitate inbreeding avoidance (Westermarck effect). In a cross-sectional design,
N
= 164 mothers participated with their biological children (
N
= 226 children, aged 0–18 years) and evaluated BO probes of their own and four other, sex-matched children. Those varied in age and in genetic similarity, which was assessed by human leucocyte antigen profiling. The study showed not only that mothers identified and preferred their own child's BO, but also that genetic similarity and developmental status are transcribed in BOs. Accordingly, maternal preference of their own child's odour changes throughout development. Our data partly supported the Westermarck effect: mothers' preference of pubertal boys' BOs was negatively related to testosterone for the own son, but not for unfamiliar children.

This article is part of the Theo Murphy meeting issue ‘Olfactory communication in humans’.
Interdisciplinary challenges for elucidating human olfactory attractiveness
Authors: Ferdenzi Camille , Richard Ortegón Stéphane , Delplanque Sylvain , Baldovini Nicolas , Bensafi Moustafa
Published: April 2020

Many species use chemicals to communicate. In humans, there is increasing evidence that chemicals conveyed by the body are extremely important in interpersonal relationships. However, many aspects of chemical communication remain to be explored to fully understand this function in humans. The aim of this article is to identify relevant challenges in this field, with a focus on human attractiveness in the context of reproduction, and to put forward roadmaps for future studies that will hopefully extend to a wider range of social interactions. The first challenge consists in not being limited to body (mal)odours from the axilla. Preliminary data on how the odour of the face and head is perceived are presented. Second, there is a crucial need to increase our knowledge of the chemical bases of human chemical communication. Third, cross-cultural approaches must not be overlooked, because they have a major input in understanding the universal and culture-specific aspects of chemical communication. Fourth, the influence of specific cultural practices such as contraceptive and fragrance use is likely to be prominent and, therefore, needs to be well described. The fifth and last challenge for research projects in this field is the integration of different disciplines such as behavioural sciences, social sciences, neurosciences and microbiology.

This article is part of the Theo Murphy meeting issue ‘Olfactory communication in humans’.
People expressing olfactory and visual cues of disease are less liked
Authors: Sarolidou Georgia , Axelsson John , Kimball Bruce A. , Sundelin Tina , Regenbogen Christina , Lundström Johan N. , Lekander Mats , Olsson Mats J.
Published: April 2020

For humans, like other social animals, behaviour acts as a first line of defence against pathogens. A key component is the ability to detect subtle perceptual cues of sick conspecifics. The present study assessed the effects of endotoxin-induced olfactory and visual sickness cues on liking, as well as potential involved mechanisms. Seventy-seven participants were exposed to sick and healthy facial pictures and body odours from the same individual in a 2 × 2 factorial design while disgust-related facial electromyography (EMG) was recorded. Following exposure, participants rated their liking of the person presented. In another session, participants also answered questionnaires on perceived vulnerability to disease, disgust sensitivity and health anxiety. Lower ratings of liking were linked to both facial and body odour disease cues as main effects. Disgust, as measured by EMG, did not seem to be the mediating mechanism, but participants who perceived themselves as more prone to disgust, and as more vulnerable to disease, liked presented persons less irrespectively of their health status. Concluding, olfactory and visual sickness cues that appear already a few hours after the experimental induction of systemic inflammation have implications for human sociality and may as such be a part of a behavioural defence against disease.

This article is part of the Theo Murphy meeting issue ‘Olfactory communication in humans’.
Limitations in odour simulation may originate from differential sensory embodiment
Authors: Arshamian Artin , Manko Patricia , Majid Asifa
Published: April 2020

Across diverse lineages, animals communicate using chemosignals, but only humans communicateaboutchemical signals. Many studies have observed that compared with other sensory modalities, communication about smells is relatively rare and not always reliable. Recent cross-cultural studies, on the other hand, suggest some communities are more olfactorily oriented than previously supposed. Nevertheless, across the globe a general trend emerges where olfactory communication is relatively hard. We suggest here that this is in part because olfactory representations are different in kind: they have a low degree of embodiment, and are not easily expressed as primitives, thereby limiting the mental manipulations that can be performed with them. New exploratory data from Dutch children (9–12 year-olds) and adults support that mental imagery from olfaction is weak in comparison with vision and audition, and critically this is not affected by language development. Specifically, while visual and auditory imagery becomes more vivid with age, olfactory imagery shows no such development. This is consistent with the idea that olfactory representations are different in kind from representations from the other senses.

This article is part of the Theo Murphy meeting issue ‘Olfactory communication in humans’.
Use of Physician Global Assessment (PGA) in Systemic lupus erythematosus: a systematic review of its psychometric properties
Authors: Chessa Elisabetta , Piga Matteo , Floris Alberto , Devilliers Hervé , Cauli Alberto , Arnaud Laurent
Published: April 2020

Background

Physician Global Assessment (PGA) is a visual analogue score (VAS) that reflects the clinician’s judgment of overall Systemic Lupus Erythematosus (SLE) disease activity. The aim of this systematic literature review (SLR) is to describe and analyse the psychometric properties of PGA.

Methods

This SLR was conducted by two independent reviewers in accordance with the PRISMA statement. All articles published until the 1st of July 2019 in Pubmed were screened with no limitation about years of publication, language or patients’ age. Psychometric properties data were analysed according to the OMERACT Filter methodology version 2.1.

Results

The literature search identified 91 studies. Face validity was reported in all the articles retrieved, in which the PGA was used alone or as part of composite indices (SRI, SFI, LLDAS, DORIS remission criteria). Content validity was reported in 89 studies. Construct validity was demonstrated by a good correlation (r≥0.50) between the PGA with the SLEDAI (12 studies), SLAM (4 studies), LAI, BILAG and ECLAM (2 studies each). Criterion validity was assessed exploring the PGA correlation with quality of life measurements, biomarkers levels and treatment changes in 28 studies, while no study has evaluated correlation with damage. A good responsiveness for PGA was shown in 8 studies. A high variability in scales was found, causing a wide range of reliability (ICC=0.67-0.98).

Conclusion

PGA is a valid, responsive and feasible instrument, while its reliability was impacted by the scale adopted, suggesting the major need for a standardization of its scoring.
Piloting Forensic Tele-Mental Health Evaluations of Asylum Seekers
Authors: Green Aliza S. , Ruchman Samuel G. , Katz Craig L. , Singer Elizabeth K.
Published: April 2020

Problem

Forensic mental health evaluations can provide critical evidence in the legal cases of individuals seeking asylum and other forms of protected immigration status. While the number of academically affiliated medical human rights programs has increased in recent years, there is still substantial unmet need for pro bono evaluations throughout the United States, especially for individuals in detention.

Approach

The Mount Sinai Human Rights Program launched its pilot Remote Evaluation Network in September 2019, with the aim to coordinate forensic mental health evaluations by telephone or video call for individuals who are unable to access in-person services. The authors recruited mental health clinicians from across the country, trained them in best practices in conducting forensic evaluations using telehealth platforms, and coordinated pro bono mental health evaluations of individuals seeking immigration relief. Remote forensic services have been a particularly relevant solution in the context of the COVID-19 pandemic.

Outcomes

The Remote Evaluation Network consists of seventeen active evaluators. From December 2019 to April 2020, the pilot program has coordinated fifteen forensic evaluations of individuals seeking asylum and other forms of protected immigration status in six different states. All clinicians participated in a training module on best practices in conducting forensic evaluations by telephone; respondents to optional pre-and-post-module surveys reported an increase in comfort level with conducting telephonic evaluations after participating in the module.

Next Steps

We will formally evaluate this pilot program’s services by assessing the quality of medico-legal affidavits from telephonic evaluations, tracking legal outcomes and qualitative feedback from attorneys, and investigating the acceptability of telephonic mental health evaluations among legal professionals. Future directions include expansion to new geographies, including individuals affected by the Migrant Protection Protocols or “Remain in Mexico” program.
Disentangling fine-scale effects of environment on malaria detection and infection to design risk-based disease surveillance systems in changing landscapes
Authors: Fornace Kimberly M , Reyes Ralph A , Macalinao Maria Lourdes M , Bareng Alison Paolo N , Luchavez Jennifer S , Hafalla Julius Clemence R , Espino Fe Esperanza J , Drakeley Chris J
Published: April 2020

Landscape changes have complex effects on malaria transmission, disrupting social and ecological systems determining the spatial distribution of risk. Within Southeast Asia, forested landscapes are associated with both increased malaria transmission and reduced healthcare access. Here, we adapt an ecological modelling framework to identify how local environmental factors influence the spatial distributions of malaria infections, diagnostic sensitivity and detection probabilities in the Philippines. Using convenience sampling of health facility attendees and Bayesian latent process models, we demonstrate how risk-based surveillance incorporating forest data increases the probability of detecting malaria foci over three-fold and enables estimation of underlying distributions of malaria infections. We show the sensitivity of routine diagnostics varies spatially, with the decreased sensitivity in closed canopy forest areas limiting the utility of passive reporting to identify spatial patterns of transmission. By adjusting for diagnostic sensitivity and targeting spatial coverage of health systems, we develop a model approach for how to use landscape data within disease surveillance systems. Together, this illustrates the essential role of environmental data in designing risk-based surveillance to provide an operationally feasible and cost-effective method to characterise malaria transmission while accounting for imperfect detection.
Exploring health in the UK Biobank: associations with sociodemographic characteristics, psychosocial factors, lifestyle and environmental exposures
Authors: Mutz Julian , Roscoe Charlotte J. , Lewis Cathryn M.
Published: April 2020

A greater understanding of factors associated with good health may help increase longevity and healthy life expectancy. Here we report associations between multiple health indicators and sociodemographic (age, sex, ethnicity, education, income and deprivation), psychosocial (loneliness and social isolation), lifestyle (smoking, alcohol intake, sleep, BMI, physical activity and stair climbing) and environmental (air pollution, noise and greenspace) factors, using data from 307,378 UK Biobank participants. Low income, being male, neighbourhood deprivation, loneliness, social isolation, short or long sleep duration, low or high BMI and smoking was associated with poor health. Walking, vigorous-intensity physical activity and more frequent alcohol intake was associated with good health. There was some evidence that airborne pollutants (PM2.5, PM10, and NO2) and noise (Lden) were associated with poor health, though findings were inconsistent in adjusted models. Our findings highlight the multifactorial nature of health, the importance of non-medical factors, such as loneliness, healthy lifestyle behaviours and weight management, and the need to examine efforts to improve health outcomes of individuals with low income.
Analysis of the mitigation strategies for COVID-19: from mathematical modelling perspective
Authors: Kassa S. M. , Njagarah H.J.B. , Terefe Y. A.
Published: April 2020

In this article, a mathematical model for the transmission of COVID-19 disease is formulated and analysed. It is shown that the model exhibits a backward bifurcation at ℛ0 = 1 when recovered individuals do not develop a permanent immunity for the disease. In the absence of reinfection, it is proved that the model is without backward bifurcation and the disease free equilibrium is globally asymptotically stable for ℛ0 < 1. By using available data, the model is validated and parameter values are estimated. The sensitivity of the value of ℛ0 to changes in any of the parameter values involved in its formula is analysed. Moreover, various mitigation strategies are investigated using the proposed model and it is observed that the asymptomatic infectious group of individuals may play the major role in the re-emergence of the disease in the future. Therefore, it is recommended that in the absence of vaccination, countries need to develop capacities to detect and isolate at least 30% of the asymptomatic infectious group of individuals while treating in isolation at least 50% of symptomatic patients to control the disease.
Objective olfactory testing in patients presenting with sudden onset olfactory dysfunction as the first manifestation of confirmed COVID-19 infection
Authors: Lechien Jerome R. , Cabaraux Pierre , Chiesa-Estomba Carlos M. , Khalife Mohamad , Plzak Jan , Hans Stéphane , Martiny Delphine , Calvo-Henriquez Christian , Hopkins Claire , Saussez Sven
Published: April 2020

Background

The aims of this study are to investigate the COVID-19 status of patients with initial sudden olfactory anosmia (ISOA) using nasopharyngeal swabs for RT-PCR analysis and to explore their olfactory dysfunctions with psychophysical olfactory evaluation.

Methodology

This prospective study included 78 ISOA patients who fulfilled a patient-reported outcome questionnaire and underwent a nasopharyngeal swabs. Among these, 46 patients performed psychophysical olfactory evaluation using sniffing tests. Based on the duration of the ISOA, two groups of patients were compared: patients with anosmia duration ≤12 days (group 1) and those with duration >12 days (group 2).

Results

Among group 1, 42 patients (87.5%) had a positive viral load regarding RT-PCR while 6 patients (12.5%) were negative. In group 2, 7 patients (23%) had a positive viral load and 23 patients (77%) were negative. Among the 46 patients having performed a psychophysical olfactory evaluation, we observed anosmia in 52% (N=24), hyposmia in 24% (N=11) and normosmia in 24% (N=11) of patients. The viral load significantly decreased throughout the 14-days following the onset of the olfactory disorder.

Conclusions

Our results support that a high proportion of ISOA patients are Covid+. Our study supports the need to add anosmia to the list of symptoms used in screening tools for possible COVID-19 infection.
Social Isolation as a predictor for mortality: Implications for COVID-19 prognosis
Authors: Banerjee Sri , Burkholder Gary , Sana Beyan , Szirony G. Mihalyi
Published: April 2020

The health benefits of social support have been widely documented. However, the social distancing practices from the COVID-19 pandemic is causing social disruption on a grand scale, potentially causing poor health outcomes. Through Google Trends analysis, we found a COVID-19-related surge in interest surrounding “loneliness.” We assessed if social isolation and loneliness increase the risk for all-cause and cardiovascular disease (CVD) mortality (ICD-10: I00–I99) and used the data to create a conceptual framework. Using the 10-year overall and cardiovascular mortality follow-up data (n = 12,019) from the National Health and Nutrition Examination Survey (1999–2008), we conducted survival analyses and found that individuals who experience social isolation or loneliness have a significantly higher likelihood of overall and CVD mortality than those without support. These effects generally remained strong with further adjustment for NHANES-detected health and demographic differences showing the need to address COVID-19 related loneliness through increasing social nearing.
Epigenomic profiles of African American Transthyretin Val122Ile carriers reveals putatively dysregulated amyloid mechanisms
Authors: Pathak Gita A , Wendt Frank R , De Lillo Antonella , Nunez Yaira Z. , Goswami Aranyak , De Angelis Flavio , Fuciarelli Maria , Kranzler Henry R , Gelernter Joel , Polimanti Renato
Published: April 2020

The Val122Ile mutation in Transthyretin (TTR) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure and several other non-cardiac phenotypes such as carpal tunnel syndrome, peripheral edema, and arthroplasty which are top reasons for ambulatory/outpatient surgeries in the country. We conducted first-ever epigenome-wide association study in Val122Ile carriers of African descent for heart disease (HD) and multiple outpatient surgeries (OS) - an early disease indicator. Five differentially methylated sites (p≤2.1e-08) in genes – FAM129B, SKI, WDR27, GLS, and an intergenic site near RP11-550A5.2 and one differentially methylated region containing KCNA6 and GALNT3 (p=1.1e-12) were associated with HD. For OS, we observe four sites – two sites in UBE2E3 and SEC14L5, and other two in intergenic regions (p≤1.8e-07) and three regions overlapping SH3D21, EVA1B, LTB4R2 and CIDEB (p≤3.9e-07). Functional PPI module analysis identified ABCA1 (p=0.001) for HS. Six cis-mQTLs were associated with one of the significant CpG sites (FAM129B; p=4.1e-24). We replicated two CpG sites (cg18546846 and cg06641417; p<0.05) in an external cohort of biopsy-confirmed cases of TTR amyloidosis. The genes identified are involved in transport and clearance of amyloid deposits (GLS, ABCA1, FAM129B); cardiac fibrosis (SKI); and muscle tissue regulation (SKI, FAM129B). These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.
The role of motor and environmental visual rhythms in structuring auditory cortical excitability
Authors: O’Connell M.N. , Barczak A. , McGinnis T. , Mackin K. , Mowery T. , Schroeder C.E. , Lakatos P.
Published: April 2020

One of the ways we perceive our external world is through the process of active sensing in which biological sensors (e.g. fingers and eyes) sample the environment utilizing mostly rhythmic motor routines. Previous studies indicate that these motor sampling patterns modulate neuronal excitability in sensory brain regions by entraining brain rhythms, a process termed motor-initiated entrainment. Additionally, rhythms of the external environment, that are independent of internal motor commands, are also capable of entraining rhythmic brain activity. The goal of our study was twofold. First, we aimed to investigate the properties of motor-initiated entrainment in the auditory system using the most prominent motor sampling pattern in primates, eye movements. Second, we wanted to determine whether/how motor-initiated entrainment by eye movements interacts with visual environmental entrainment. By examining laminar profiles of neuronal ensemble activity in the primary auditory cortex of non-human primates, we found that while motor-initiated entrainment has a suppressive, visual environmental entrainment has an enhancive effect. We also found that the two processes are temporally coupled during free viewing, and their temporal relationship ensures that their effect on neuronal ensemble excitability is complementary rather than interfering. Taken together, our results provide strong evidence that motor and sensory systems continuously interact in orchestrating the brain’s rhythmic context for the optimal sampling of our multisensory environment.
RNA-seq of Human T-Cells After Hematopoietic Stem Cell Transplantation Identifies Linc00402 as a Novel Regulator of T-Cell Alloimmunity
Authors: Peltier Daniel , Radosevich Molly , Hou Guoqing , Zajac Cynthia , Oravecz-Wilson Katherine , Sokol David , Henig Israel , Wu Julia , Kim Stephanie , Taylor Austin , Fujiwara Hideaki , Sun Yaping , Reddy Pavan
Published: April 2020

Mechanisms governing allogeneic T-cell responses after allogeneic hematopoietic stem cell (HSC) and solid organ transplantation are incompletely understood. Long non-coding RNAs (lncRNA) do not code for, but control gene expression with tissue specificity. However, their role in T-cell alloimmunity is unknown. We performed RNA-seq on donor T-cells from HSCT patients and found that increasing strength of allogeneic stimulation caused greater differential expression of lncRNAs. The differential expression was validated in an independent patient cohort, and also following ex vivo allogeneic stimulation of healthy human T-cells. Linc00402, a novel, conserved lncRNA, was identified as the most differentially expressed and was enriched 88 fold in human T-cells. Mechanistically, it was mainly located in the cytoplasm, and its expression was rapidly reduced following T-cell activation. Consistent with this, tacrolimus preserved the expression of Linc00402 following T-cell activation, and lower levels of Linc00402 were found in patients who subsequently went on to develop acute graft versus host disease (GVHD). The dysregulated expression of Linc00402 was also validated in murine T-cells, both in vitro and in vivo. Functional studies using multiple modalities to deplete Linc00402 in both mouse and human T-cells, demonstrated a critical role for Linc00402 in the T-cell proliferative response to an allogeneic stimulus but not a non-specific anti-CD3/CD28 stimulus. Thus, our studies identified Linc00402 as a novel, conserved regulator of allogeneic T-cell function. Because of its T-cell specific expression and its impact on allogeneic T-cell responses, targeting Linc00402 may improve outcomes after allogeneic HSC and solid organ transplantation.

One sentence summary

LncRNAs are differentially expressed by allogeneic antigen-stimulated T-cells, and the novel lncRNA, Linc00402, is a specific regulator of mouse and human allogeneic T-cells.
Corticostriatal Plasticity Established by Initial Learning Persists After Behavioral Reversal
Authors: Ghosh Sanchari , Zador Anthony M
Published: April 2020

The neural mechanisms that allow animals to adapt their previously learned associations in response to changes in the environment remain poorly understood. To probe the synaptic mechanisms that mediate such adaptive behavior, we trained mice on an auditory-motor reversal task, and tracked changes in the strength of corticostriatal synapses associated with the formation of learned associations. Using a ChR2-based electrophysiological assay in acute striatal slices, we measured the strength of these synapses after animals learned to pair auditory stimuli with specific actions. Here we report that the pattern of synaptic strength initially established by learning remains unchanged even when the task contingencies are reversed. Our results suggest that synaptic changes associated with the initial acquisition of this task are not erased or over-written, and that behavioral reversal of learned associations may recruit a separate neural circuit.
Loss of Caspase-8 function in combination with SMAC mimetic treatment sensitizes Head and Neck Squamous Carcinoma to radiation through induction of necroptosis
Authors: Uzunparmak Burak , Gao Meng , Lindemann Antje , Erikson Kelly , Wang Li , Lin Eric , Frank Steven J. , Gleber-Netto Frederico O. , Zhao Mei , Skinner Heath D. , Newton Jared , Sikora Andrew G. , Myers Jeffrey N. , Pickering Curtis R.
Published: April 2020

Caspase-8 (CASP8) is one of the most frequently mutated genes in head and neck squamous carcinomas (HNSCC), and mutations ofCASP8are associated with poor overall survival. The distribution of these mutations in HNSCC suggests that they are likely to be inactivating. Inhibition ofCASP8has been reported to sensitize cancer cells to necroptosis, a unique cell death mechanism. Here, we evaluated howCASP8regulates necroptosis in HSNCC using cell line models and syngeneic mouse xenografts.In vitro, knockdown ofCASP8rendered HNSCCs susceptible to necroptosis induced by a second mitochondria-derived activator of caspase (SMAC) mimetic, Birinapant, when combined with pan-caspase inhibitors Z-VAD-FMK or Emricasan. Strikingly, inhibition ofCASP8function via knockdown or Emricasan treatment was associated with enhanced radiation killing by Birinapant through induction of necroptosis. In a syngeneic mouse model of oral cancer, Birinapant, particularly when combined with radiation delayed tumor growth and enhanced survival underCASP8loss. Exploration of molecular underpinnings of necroptosis sensitivity confirmed that the level of functional receptor-interacting serine/threonine-protein kinase-3 (RIP3), a key enzyme in the necroptosis pathway was crucial in determining susceptibility to this mode of death. Although anin vitroscreen revealed that many HNSCC cell lines were resistant to necroptosis due to low levels of RIP3, patient tumors maintain RIP3 expression and should therefore remain sensitive. Collectively, these results suggest that targeting the necroptosis pathway with SMAC mimetics, especially in combination with radiation, may be a relevant therapeutic approach in HNSCC with compromisedCASP8status, provided that RIP3 function is maintained.

Significance

CASP8status regulates necroptotic death in HNSCC and this pathway can be exploited therapeutically.
Anin silicomap of the SARS-CoV-2 RNA Structurome
Authors: Andrews Ryan J. , Peterson Jake M. , Haniff Hafeez S. , Chen Jonathan , Williams Christopher , Grefe Maison , Disney Matthew D. , Moss Walter N.
Published: April 2020

SARS-CoV-2 is a positive-sense single-stranded RNA virus that has exploded throughout the global human population. This pandemic coronavirus strain has taken scientists and public health researchers by surprise and knowledge of its basic biology (e.g. structure/function relationships in its genomic, messenger and template RNAs) and modes for therapeutic intervention lag behind that of other human pathogens. In this report we used a recently-developed bioinformatics approach, ScanFold, to deduce the RNA structural landscape of the SARS-CoV-2 transcriptome. We recapitulate known elements of RNA structure and provide a model for the folding of an essential frameshift signal. Our results find that the SARS-CoV-2 is greatly enriched in unusually stable and likely evolutionarily ordered RNA structure, which provides a huge reservoir of potential drug targets for RNA-binding small molecules. Our results also predict regions that are accessible for intermolecular interactions, which can aid in the design of antisense therapeutics. All results are made available via a public database (the RNAStructuromeDB) where they may hopefully drive drug discovery efforts to inhibit SARS-CoV-2 pathogenesis.
Nonallosteric Sirtuin Enzyme Activation: Characterization of Hit Compounds
Authors: Upadhyay A , Guan X , Munshi S , Chakrabarti R
Published: April 2020

Mammalian sirtuins (SIRT1-SIRT7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases that play critical roles in lifespan and age-related diseases. The physiological importance of sirtuins has stimulated intense interest in designing sirtuin-activating compounds. However, except for allosteric activators of SIRT1-catalyzed reactions that are limited to particular substrates, a general framework for the design of sirtuin-activating compounds has been lacking. Recently, we introduced a general mode of sirtuin activation that is distinct from the known modes of enzyme activation, establishing biophysical properties of small molecule modulators that can, in principle, result in enzyme activation for various sirtuins and substrates. Here, we characterize small molecules reported in the literature to activate the SIRT3 enzyme using a variety of computational, biochemical and biophysical techniques including protein-ligand docking, molecular dynamics simulation, nonlinear reaction dynamics simulation, kinetic assays and thermodynamic assays with multiple substrates and protocols. In particular, we identify the mechanism of action of the compound honokiol on the human SIRT3 enzyme, modeling its effect on active site conformational degrees of freedom and demonstrating how it nonallosterically activates the human SIRT3 enzyme under physiologically relevant conditions. We show that honokiol constitutes a hit compound for the design of a new generation of nonallosteric activators that can activate SIRT3 through the proposed mechanism-based mode of activation.
Lisdexamfetamine alters BOLD-fMRI activations induced by odor cues in impulsive children
Authors: Hidalgo Tobón Silvia S. , Suárez Pilar Dies , Barragán Pérez Eduardo , Hernández López Javier M. , García Julio , de Celis Alonso Benito
Published: April 2020

Introduction

Lisdexamfetamine (LDX) is a drug used to treat ADHD/impulsive patients. Impulsivity is known to affect inhibitory, emotional and cognitive function. On the other hand, smell and odor processing are known to be affected by neurological disorders, as they are modulators of addictive and impulsive behaviors specifically. We hypothesize that, after LDX ingestion, inhibitory pathways of the brain would change, and complementary behavioral regulation mechanisms would appear to regulate decision-making and impulsivity.

Methods

20 children were studied in an aleatory crossover study. Imaging of BOLD-fMRI activity, elicited by olfactory stimulation in impulsive children, was performed after either LDX or placebo ingestion.

Results

Findings showed that all subjects that underwent odor stimulation presented activations of similar intensities in the olfactory centers of the brain. This contrasted with inhibitory regions of the brain such as the cingulate cortex and frontal lobe regions, which demonstrated changed activity patterns and intensities. While some differences between the placebo and medicated states were found in motor areas, precuneus, cuneus, calcarine, supramarginal, cerebellum and posterior cingulate cortex, the main changes were found in frontal, temporal and parietal cortices. When comparing olfactory cues separately, pleasant food smells like chocolate seemed not to present large differences between the medicated and placebo scenarios, when compared to non-food-related smells.

Conclusions

We demonstrated that LDX, first, altered the inhibitory pathways of the brain, second, increased activity in large amounts of brain regions which were not activated by smell in drug-naïve patients, third, facilitated a complementary behavioral regulation mechanism, run by the cerebellum, which regulated decision-making and impulsivity in motor and frontal structures.
Extensive hybridization between pig and humanAscarisidentifies a highly interbred species complex infecting humans
Authors: Easton Alice V. , Gao Shenghan , Lawton Scott P , Bennuru Sasisekhar , Khan Asis , Dahlstrom Eric , Oliveira Rita G , Kepha Stella , Porcella Steve F , Webster Joanne P , Anderson Roy M , Grigg Michael E. , Davis Richard E , Wang Jianbin , Nutman Thomas B
Published: April 2020

Human ascariasis is a major neglected tropical disease caused by the nematodeAscaris lumbricoides. We report a 296 megabase (Mb) reference quality genome comprised of 17902 protein-coding genes derived from a single, representativeAscarisworm collected from 60 human hosts in Kenyan villages where pig husbandry is rare. Notably, the majority of human isolates (63/68) possessed mitochondrial genomes that clustered closer to the pig parasiteAscaris suumthan toA. lumbricoides. Comparative phylogenomic analyses identified over 11 million nuclear-encoded SNPs but just two distinct genetic types that had recombined across the genomes analysed. The nuclear genomes had extensive heterozygosity and all samples existed as genetic mosaics with eitherA. suum-like orA. lumbricoides-like inheritance patterns supporting a highly interbredAscarisspecies genetic complex. As no barriers appear to exist for anthroponotic transmission of these “hybrid” worms, a one-health approach to control the spread of human ascariasis will be necessary.
Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity
Authors: Heer Collin D. , Sanderson Daniel J. , Voth Lynden S. , Alhammad Yousef M.O. , Schmidt Mark S. , Trammell Samuel A.J. , Perlman Stanley , Cohen Michael S. , Fehr Anthony R. , Brenner Charles
Published: April 2020

Poly-ADP-ribose polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using nicotinamide adenine dinucleotide (NAD) as the source of ADPR. While the well-known poly-ADP-ribosylating (PARylating) PARPs primarily function in the DNA damage response, many non-canonical mono-ADP-ribosylating (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust upregulation of several PARPs following infection with Murine Hepatitis Virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly upregulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while downregulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+and NADP+. Finally, we show that NAMPT activation, NAM and NR dramatically decrease the replication of an MHV virus that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD, and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.
Distinct Structural Flexibility within SARS-CoV-2 Spike Protein Reveals Potential Therapeutic Targets
Authors: Chen Serena H. , Young M. Todd , Gounley John , Stanley Christopher , Bhowmik Debsindhu
Published: April 2020

The emergence and rapid worldwide spread of the novel coronavirus disease, COVID-19, has prompted concerted efforts to find successful treatments. The causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), uses its spike (S) protein to gain entry into host cells. Therefore, the S protein presents a viable target to develop a directed therapy. Here, we deployed an integrated artificial intelligence with molecular dynamics simulation approach to provide new details of the S protein structure. Based on a comprehensive structural analysis of S proteins from SARS-CoV-2 and previous human coronaviruses, we found that the protomer state of S proteins is structurally flexible. Without the presence of a stabilizing beta sheet from another protomer chain, two regions in the S2 domain and the hinge connecting the S1 and S2 subunits lose their secondary structures. Interestingly, the region in the S2 domain was previously identified as an immunodominant site in the SARS-CoV-1 S protein. We anticipate that the molecular details elucidated here will assist in effective therapeutic development for COVID-19.
Significant expression of FURIN and ACE2 on oral epithelial cells may facilitate the efficiency of SARS-CoV-2 entry
Authors: Zhong Mei , Lin Bing-peng , Gao Hong-bin , Young Andrew J , Wang Xin-hong , Liu Chang , Wu Kai-bin , Liu Ming-xiao , Chen Jian-ming , Huang Jiang-yong , Lee Learn-han , Qi Cui-ling , Ge Lin-hu , Wang Li-jing
Published: April 2020

Background

Leading to a sustained epidemic spread with >2,000,000 confirmed human infections, including >100,000 deaths, COVID-19 was caused by SARS-CoV-2 and resulted in acute respiratory distress syndrome (ARDS) and sepsis, which brought more challenges to the patient’s treatment. The S-glycoprotein, which recognized as the key factor for the entry of SARS-CoV-2 into the cell, contains two functional domains: an ACE2 receptor binding domain and a second domain necessary for fusion of the coronavirus and cell membranes. FURIN activity, exposes the binding and fusion domains, is essential for the zoonotic transmission of SARS-CoV-2. Moreover, it has been reported that ACE2 is likely to be the receptor for SARS-CoV-2. In addition, FURIN enzyme and ACE2 receptor were expressed in airway epithelia, cardiac tissue, and enteric canals, which considered as the potential target organ of the virus. However, report about the expression of FURIN and ACE2 in oral tissues was limited.

Methods

In order to investigate the potential infective channel of new coronavirus in oral cavity, we analyze the expression of ACE2 and FURIN that mediate the new coronavirus entry into host cells in oral mucosa using the public single-cell sequence datasets. Furthermore, immunohistochemical staining experiment was performed to confirm the expression of ACE2 and FURIN in the protein level.

Results

The bioinformatics results indicated the differential expression of ACE2 and FURIN on epithelial cells of different oral mucosal tissues and the proportion of FURIN-positive cells was obviously higher than that of ACE2-positive cells. IHC experiments revealed that both the ACE2-positive and FURIN-positive cells in the target tissues were mainly positioned in the epithelial layers, partly expressed in fibroblasts, which further confirm the bioinformatics results.

Conclusions

Based on these findings, we speculated that SARS-CoV-2 could effectively invade oral mucosal cells though two possible routes: binding to the ACE2 receptor and fusion with cell membrane activated by FURIN protease. Our results indicated that oral mucosa tissues are susceptible to SARS-CoV-2, which provides valuable information for virus-prevention strategy in clinical care as well as daily life.
Lysosomal nucleotide metabolism regulates ER proteostasis through mTOR signaling
Authors: Mak Keng Hou , Zhao Qian , Hu Pei-Wen , Au-Yeung Chi-Lam , Yang Jin , Duraine Lita , Yu Yong , Abu-Remaileh Monther , Sabatini David , Wang Jue D. , Wang Meng C.
Published: April 2020

Organelles in eukaryotic cells are compartmentalized to carry out different functions, and require specific mechanisms governing their coordination. Two of these organelles, the lysosome and the endoplasmic reticulum (ER), play crucial roles in regulating cellular homeostasis and organismal health. The lysosome contains various enzymes devoted to the hydrolysis of specific substrates, and dysfunctions of these hydrolases and their related metabolic processes are implicated in many diseases1. On the other hand, ER is essential for protein synthesis and utilizes quality control mechanisms to maintain proteostasis. The metabolic status of the lysosome is now known to actively influence nuclear transcription and mitochondrial signaling2–4. However, whether and how mechanistically lysosomal metabolic activities regulate ER proteostasis remain unclear. Here, we reported that RSH-1, theCaenorhabditis elegansRelA/SpoT Homolog (RSH) protein, carries a lysosomal NADPH phosphatase activity and acts through the mammalian/mechanistic target of rapamycin (mTOR) signaling to regulate ER proteostasis. We discovered that RSH-1 is localized to the lysosome. Its mutation reduces NADPH hydrolysis by the lysosome, leading to a protection against ER stress-induced lethality. We further revealed that this ER stress tolerance requires lysosomal vacuolar-type H+-ATPase (v-ATPase), and Rag GTPases and ribosomal protein S6 kinase (S6K) in the mTOR signaling pathway. Through transcriptome analysis, we discovered that the S6K activation by the RSH-1 mutation increases the basal expression of X-box binding protein 1 (XBP-1) and peptidyl-prolyl cis-trans isomerases, which is necessary for improving ER proteostasis. Moreover, we demonstrated the lysosomal localization of RSH-1 mammalian homolog and its conserved role in regulating mTOR signaling. Together, our findings reveal the key role of a specific lysosomal nucleotide hydrolase in regulating organellar coordination and also signaling mechanisms underlying this active regulation, and suggest that diseases resulted from deficiency in lysosomal hydrolases may be attributed to the distortion of signal transduction and organelle homeostasis.