The relationship between modifiable lifestyle behaviours and self-reported health in children and adolescents in the United Kingdom.

Obesity, along with its associated health issues, is closely tied to lifestyle habits. While certain elements affecting childhood health, such as genetics and ethnicity, are beyond individuals' control, there exists modifiable lifestyle behaviours that can facilitate healthier living. This study employed multiple regression analysis to investigate the relationship between specific modifiable lifestyle behaviours and self-reported health. The independent variables considered included days of moderate to vigorous physical activity (MVPA), fruit and vegetable consumption, breakfast frequency, school night sleep duration, and non-school night sleep duration. These variables were chosen for their practical modifiability within participants' daily lives. The analysis revealed a highly significant overall model (F(13,11363) = 191.117, p < .001), explaining 17.9% of the variance in self-reported health. Notably, higher MVPA levels were associated with improved self-reported health (B = 0.136 to 0.730, p < .001). Additionally, regular breakfast consumption and increased fruit and vegetable intake exhibited positive associations with self-reported health (B = 0.113 to 0.377, p < .001), while girls reported lower self-reported health (B = -0.079, p < .001). School night sleep duration was positively linked to self-reported health (B = 0.071, p < .001). Furthermore, a dose-response relationship between MVPA, dietary habits, and health was identified. These findings hold substantial potential for public health campaigns to promote healthy behaviours and prevent chronic diseases in young individuals. It is imperative to emphasise that all the variables considered in this study are readily modifiable aspects of individuals' lives, offering a promising avenue for personal health and well-being enhancement.

Mutation of highly conserved residues in loop 2 of the coronavirus macrodomain demonstrates that enhanced ADP-ribose binding is detrimental to infection.

All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in nonstructural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown that Mac1 is important for virus replication and pathogenesis. Within Mac1, there are several regions that are highly conserved across CoVs, including the GIF (glycine-isoleucine-phenylalanine) motif. To determine how the biochemical activities of these residues impact CoV replication, the isoleucine and the phenylalanine residues were mutated to alanine (I-A/F-A) in both recombinant Mac1 proteins and recombinant CoVs, including murine hepatitis virus (MHV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The F-A mutant proteins had ADP-ribose binding and/or hydrolysis defects that led to attenuated replication and pathogenesis in cell culture and mice. In contrast, the I-A mutations had normal enzyme activity and enhanced ADP-ribose binding. Despite increased ADP-ribose binding, I-A mutant MERS-CoV and SARS-CoV-2 were highly attenuated in both cell culture and mice, indicating that this isoleucine residue acts as a gate that controls ADP-ribose binding for efficient virus replication. These results highlight the function of this highly conserved residue and provide unique insight into how macrodomains control ADP-ribose binding and hydrolysis to promote viral replication and pathogenesis.

Four-year longitudinal associations of physical activity, waist circumference, and blood pressure in UK adolescents.

BACKGROUND: This study assessed the specific influence of physical activity (PA) and waist circumference (WC) on the 4-year growth trajectory of blood pressure in UK high-school students. METHODS: Four-year longitudinal monitoring of 1501 adolescents was conducted as part of the EoEHHS. Measurements were taken in Grades (G)7, 9, and 11. RESULTS: Systolic (SBP) and diastolic blood pressure (DBP) increased over the 4-year period (SBP G7 114.6 ± 8.9 mmHg, G9 118.1 ± 9.7 mmHg, G11 122.8 ± 7.8 mmHg; DBP G7 66.7 ± 6.6 mmHg, G9 68.0 ± 6.4 mmHg, G11 70.0 ± 5.2 mmHg). Baseline WC predicted baseline and growth in SBP, but the strongest contribution to SBP came from changes in WC (ß = 0.084, p = 0.002). Baseline PAQ-A score (ß = -0.822, p = 0.020) and changes in PAQ-A score (ß = -0.650, p = 0.019) were associated with smaller increases in DBP over the 4-year measurement period. CONCLUSIONS: Baseline and change in WC predicted the growth trajectory of SBP, while baseline and change in PA predicted the growth trajectory of DBP. PA and WC have a prognostic value in predicting changes in blood pressure in adolescents. Increasing PA during adolescence could slow the rise in DBP over time. This is meaningful for future hypertension and CVD risk reduction into adulthood. IMPACT: Hypertension in adolescents is a growing health problem that is often overlooked. Baseline and changes in waist circumference over a 4-year period predicted development of systolic blood pressure, while baseline and changes in physical activity predicted development of diastolic blood pressure. Physical activity and waist circumference have a prognostic value in predicting changes in blood pressure in adolescents and could be valuable in planning programmes to prevent hypertension in similar communities and reduce the risk of future adult hypertension.

PARP12 is required to repress the replication of a Mac1 mutant coronavirus in a cell- and tissue-specific manner.

ADP-ribosyltransferases (ARTs) mediate the transfer of ADP-ribose from NAD+ to protein or nucleic acid substrates. This modification can be removed by several different types of proteins, including macrodomains. Several ARTs, also known as PARPs, are stimulated by interferon indicating ADP-ribosylation is an important aspect of the innate immune response. All coronaviruses (CoVs) encode for a highly conserved macrodomain (Mac1) that is critical for CoVs to replicate and cause disease, indicating that ADP-ribosylation can effectively control coronavirus infection. Our siRNA screen indicated that PARP12 might inhibit the replication of a murine hepatitis virus (MHV) Mac1 mutant virus in bone-marrow-derived macrophages (BMDMs). To conclusively demonstrate that PARP12 is a key mediator of the antiviral response to CoVs both in cell culture and in vivo, we produced PARP12-/-mice and tested the ability of MHV A59 (hepatotropic/neurotropic) and JHM (neurotropic) Mac1 mutant viruses to replicate and cause disease in these mice. Notably, in the absence of PARP12, Mac1 mutant replication was increased in BMDMs and mice. In addition, liver pathology was also increased in A59-infected mice. However, the PARP12 knockout did not restore Mac1 mutant virus replication to WT virus levels in all cell or tissue types and did not significantly increase the lethality of Mac1 mutant viruses. These results demonstrate that while PARP12 inhibits MHV Mac1 mutant virus infection, additional PARPs or innate immune factors must contribute to the extreme attenuation of this virus in mice. IMPORTANCE Over the last decade, the importance of ADP-ribosyltransferases (ARTs), also known as PARPs, in the antiviral response has gained increased significance as several were shown to either restrict virus replication or impact innate immune responses. However, there are few studies showing ART-mediated inhibition of virus replication or pathogenesis in animal models. We found that the CoV macrodomain (Mac1) was required to prevent ART-mediated inhibition of virus replication in cell culture. Using knockout mice, we found that PARP12, an interferon-stimulated ART, was required to repress the replication of a Mac1 mutant CoV both in cell culture and in mice, demonstrating that PARP12 represses coronavirus replication. However, the deletion of PARP12 did not fully rescue Mac1 mutant virus replication or pathogenesis, indicating that multiple PARPs function to counter coronavirus infection.

SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice.

Several coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies for COVID-19. Included in these drug targets is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein encoded as a small domain at the N terminus of nonstructural protein 3. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical for both murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV virulence. However, as a potential drug target, it is imperative to understand how a complete Mac1 deletion impacts the replication and pathogenesis of different CoVs. To this end, we created recombinant bacterial artificial chromosomes (BACs) containing complete Mac1 deletions (ΔMac1) in MHV, MERS-CoV, and SARS-CoV-2. While we were unable to recover infectious virus from MHV or MERS-CoV ΔMac1 BACs, SARS-CoV-2 ΔMac1 was readily recovered from BAC transfection, indicating a stark difference in the requirement for Mac1 between different CoVs. Furthermore, SARS-CoV-2 ΔMac1 replicated at or near wild-type levels in multiple cell lines susceptible to infection. However, in a mouse model of severe infection, ΔMac1 was quickly cleared causing minimal pathology without any morbidity. ΔMac1 SARS-CoV-2 induced increased levels of interferon (IFN) and IFN-stimulated gene expression in cell culture and mice, indicating that Mac1 blocks IFN responses which may contribute to its attenuation. ΔMac1 infection also led to a stark reduction in inflammatory monocytes and neutrophils. These results demonstrate that Mac1 only minimally impacts SARS-CoV-2 replication, unlike MHV and MERS-CoV, but is required for SARS-CoV-2 pathogenesis and is a unique antiviral drug target.

PARP12 is required to repress the replication of a Mac1 mutant coronavirus in a cell and tissue specific manner.

ADP-ribosyltransferases (ARTs) mediate the transfer of ADP-ribose from NAD + to protein or nucleic acid substrates. This modification can be removed by several different types of proteins, including macrodomains. Several ARTs, also known as PARPs, are stimulated by interferon, indicating ADP-ribosylation is an important aspect of the innate immune response. All coronaviruses (CoVs) encode for a highly conserved macrodomain (Mac1) that is critical for CoVs to replicate and cause disease, indicating that ADP-ribosylation can effectively control coronavirus infection. Our siRNA screen indicated that PARP12 might inhibit the replication of a MHV Mac1 mutant virus in bone-marrow derived macrophages (BMDMs). To conclusively demonstrate that PARP12 is a key mediator of the antiviral response to CoVs both in cell culture and in vivo , we produced PARP12 -/- mice and tested the ability of MHV A59 (hepatotropic/neurotropic) and JHM (neurotropic) Mac1 mutant viruses to replicate and cause disease in these mice. Notably, in the absence of PARP12, Mac1 mutant replication was increased in BMDMs and in mice. In addition, liver pathology was also increased in A59 infected mice. However, the PARP12 knockout did not restore Mac1 mutant virus replication to WT virus levels in all cell or tissue types and did not significantly increase the lethality of Mac1 mutant viruses. These results demonstrate that while PARP12 inhibits MHV Mac1 mutant virus infection, additional PARPs or innate immune factors must contribute to the extreme attenuation of this virus in mice. IMPORTANCE: Over the last decade, the importance of ADP-ribosyltransferases (ARTs), also known as PARPs, in the antiviral response has gained increased significance as several were shown to either restrict virus replication or impact innate immune responses. However, there are few studies showing ART-mediated inhibition of virus replication or pathogenesis in animal models. We found that the CoV macrodomain (Mac1) was required to prevent ART-mediated inhibition of virus replication in cell culture. Here, using knockout mice, we found that PARP12, an interferon-stimulated ART, was required to repress the replication of a Mac1 mutant CoV both in cell culture and in mice, demonstrating that PARP12 represses coronavirus replication. However, the deletion of PARP12 did not fully rescue Mac1 mutant virus replication or pathogenesis, indicating that multiple PARPs function to counter coronavirus infection.

A Randomized Controlled Pilot Trial Comparing Effects of Qigong and Exercise/Nutrition Training on Fatigue and Other Outcomes in Female Cancer Survivors.

Cancer-related fatigue (CRF) is a common and burdensome, often long-term side effect of cancer and its treatment. Many non-pharmacological treatments have been investigated as possible CRF therapies, including exercise, nutrition, health/psycho-education, and mind-body therapies. However, studies directly comparing the efficacy of these treatments in randomized controlled trials are lacking. To fill this gap, we conducted a parallel single blind randomized controlled pilot efficacy trial with women with CRF to directly compare the effects of Qigong (a form of mind-body intervention) (n = 11) to an intervention that combined strength and aerobic exercise, plant-based nutrition and health/psycho-education (n = 13) in a per protocol analysis. This design was chosen to determine the comparative efficacy of 2 non-pharmacologic interventions, with different physical demand intensities, in reducing the primary outcome measure of self-reported fatigue (FACIT "Additional Concerns" subscale). Both interventions showed a mean fatigue improvement of more than double the pre-established minimal clinically important difference of 3 (qigong: 7.068 ± 10.30, exercise/nutrition: 8.846 ± 12.001). Mixed effects ANOVA analysis of group × time interactions revealed a significant main effect of time, such that both groups significantly improved fatigue from pre- to post-treatment (F(1,22) = 11.898, P = .002, generalized eta squared effect size = 0.116) There was no significant difference between fatigue improvement between groups (independent samples t-test: P = .70 ), suggesting a potential equivalence or non-inferiority of interventions, which we could not definitively establish due to our small sample size. This study provides evidence from a small sample of n = 24 women with CRF that qigong improves fatigue similarly to exercise-nutrition courses. Qigong additionally significantly improved secondary measures of mood, emotion regulation, and stress, while exercise/nutrition significantly improved secondary measures of sleep/fatigue. These findings provide preliminary evidence for divergent mechanisms of fatigue improvement across interventions, with qigong providing a gentler and lower-intensity alternative to exercise/nutrition.

SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in mice.

Several coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies for COVID-19. Included in this set of proteins is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical for both murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV virulence. However, as a potential drug target, it is imperative to understand how a complete Mac1 deletion impacts the replication and pathogenesis of different CoVs. To this end, we created recombinant bacterial artificial chromosomes (BACs) containing complete Mac1 deletions (ΔMac1) in MHV, MERS-CoV, and SARS-CoV-2. While we were unable to recover infectious virus from MHV or MERS-CoV ΔMac1 BACs, SARS-CoV-2 ΔMac1 was readily recovered from BAC transfection, indicating a stark difference in the requirement for Mac1 between different CoVs. Furthermore, SARS-CoV-2 ΔMac1 replicated at or near wild-type levels in multiple cell lines susceptible to infection. However, in a mouse model of severe infection, ΔMac1 was quickly cleared causing minimal pathology without any morbidity. ΔMac1 SARS-CoV-2 induced increased levels of interferon (IFN) and interferon-stimulated gene (ISG) expression in cell culture and mice, indicating that Mac1 blocks IFN responses which may contribute to its attenuation. ΔMac1 infection also led to a stark reduction in inflammatory monocytes and neutrophils. These results demonstrate that Mac1 only minimally impacts SARS-CoV-2 replication, unlike MHV and MERS-CoV, but is required for SARS-CoV-2 pathogenesis and is a unique antiviral drug target. SIGNIFICANCE: All CoVs, including SARS-CoV-2, encode for a conserved macrodomain (Mac1) that counters host ADP-ribosylation. Prior studies with SARS-CoV-1 and MHV found that Mac1 blocks IFN production and promotes CoV pathogenesis, which has prompted the development of SARS-CoV-2 Mac1 inhibitors. However, development of these compounds into antivirals requires that we understand how SARS-CoV-2 lacking Mac1 replicates and causes disease in vitro and in vivo . Here we found that SARS-CoV-2 containing a complete Mac1 deletion replicates normally in cell culture but induces an elevated IFN response, has reduced viral loads in vivo , and does not cause significant disease in mice. These results will provide a roadmap for testing Mac1 inhibitors, help identify Mac1 functions, and open additional avenues for coronavirus therapies.

Thyroid nodules of indeterminate cytology in Hispanic/Latinx patients.

BACKGROUND: Behavior of differentiated thyroid cancer (DTC) varies among ethnic groups. Recommended management of thyroid nodules with indeterminate cytology (TN-IC) is based on molecular analysis from predominantly non-Hispanic white patients. We hypothesized that TN-IC in Hispanic/Latinx patients would have different features, management, and outcomes and that molecular testing might perform differently in Hispanic/Latinx patients. METHODS: Retrospective chart review was performed on 127 TN-IC analyzed with Afirma. Patient characteristics were compared using linear model ANOVA and Fisher's exact test. RESULTS: Out of 127 TN-IC, 71 (56%) were Hispanic/Latinx. Hispanic/Latinx had a greater prevalence of diabetes, but Afirma results (benign or suspicious) were similar between ethnic groups. Fourteen patients had malignant pathology. Their management and outcomes were similar across groups. The negative predictive value for our cohort (97.9%) was similar to published data. CONCLUSIONS: Data from our predominantly-Hispanic/Latinx cohort suggest that Afirma performs similarly in Hispanic/Latinx and non-Hispanic white patients with TN-IC.

Obese individuals do not underreport dietary intake to a greater extent than nonobese individuals when data are allometrically-scaled.

OBJECTIVE: The aim of this study was to assess the extent of misreporting in obese and nonobese adults on an absolute, ratio-scaled, and allometrically-scaled basis. METHOD: Self-reported daily energy intake (EI) was compared with total energy expenditure (TEE) in 221 adults (106 male, 115 female; age 53 ± 17 years, stature 1.68 ± 0.09 m, mass 79.8 ± 17.2 kg) who participated in a doubly-labeled water (DLW) subsection of 2013-2015 National Diet and Nutrition Survey. Data were log transformed and expressed as absolute values, according to simple ratio-standards (per kg body mass) and adjusted for body mass allometrically. Absolute and ratio-scaled misreporting were examined using full-factorial General Linear Models with repeated measures of the natural logarithms of TEE or EI as the within-subjects factor. The natural logarithm of body mass was included as a covariate in the allometric method. The categorical variables of gender, age, obesity, and physical activity level (PAL) were the between-factor variables. RESULTS: On an absolute-basis, self-reported EI (2759 ± 590 kcal·d-1 ) was significantly lower than TEE measured by DLW (2759 ± 590 kcal·d-1 : F1,205  = 598.81, p < .001, ηp 2 =0.75). We identified significantly greater underreporting in individuals with an obese BMI (F1,205  = 29.01, p <.001, ηp 2 =0.12), in more active individuals (PAL > 1.75; F1,205  = 34.15, p <.001, ηp 2 =0.14) and in younger individuals (≤55 years; F1,205  = 14.82, p < .001, ηp 2 =0.07), which are all categories with higher energy needs. Ratio-scaling data reduced the effect sizes. Allometric-scaling removed the effect of body mass (F1,205 =0.02, p = 0.887, ηp 2 =0.00). CONCLUSION: In weight-stable adults, obese individuals do not underreport dietary intake to a greater extent than nonobese individuals. These results contradict previous research demonstrating that obesity is associated with a greater degree of underreporting.

The associations between physical activity intensity, cardiorespiratory fitness, and non-alcoholic fatty liver disease.

BACKGROUND AND AIM: High levels of physical activity and cardiorespiratory fitness may protect against non-alcoholic fatty liver disease. We investigated whether different physical activity intensities and cardiorespiratory fitness were independent predictors of non-alcoholic fatty liver disease. METHODS: We included healthy adults with no prior diagnosis of liver dysfunction. Non-alcoholic fatty liver disease prevalence was estimated based on fatty liver index scores. We created tertiles of self-reported low, moderate, and vigorous physical activity. Participants completed an incremental treadmill test to estimate cardiorespiratory fitness, and data were subsequently separated into quintile groups (Q1 [least fit] through Q5 [most fit]). RESULTS: Non-alcoholic fatty liver disease prevalence in our sample of 7111 adults was 28.3% in male adults and 6.5% in female adults. Logistic regression showed the relative odds of non-alcoholic fatty liver disease were 42% lower if > 60 min/week of vigorous physical activity was maintained (odds ratio [OR] = 0.58, confidence interval [CI]: 0.49-0.68). There was a negative dose-response association between cardiorespiratory fitness and non-alcoholic fatty liver disease between Q1 and Q4. Compared with Q1, odds were 39% (OR = 0.61, CI: 0.51-0.73) lower in Q2, through to 51% lower in Q5 (OR = 0.49, CI: 0.41-0.60). Moderate physical activity did not reduce the odds of non-alcoholic liver disease. CONCLUSIONS: We found the lowest prevalence of non-alcoholic fatty liver disease in adults achieving > 60 min/week of vigorous physical activity. However, a stronger dose-response relationship existed between cardiorespiratory fitness and non-alcoholic fatty liver disease. Improving cardiorespiratory fitness as a potential therapeutic target for treatment and prevention of non-alcoholic fatty liver disease warrants further investigation.

Unique Mutations in the Murine Hepatitis Virus Macrodomain Differentially Attenuate Virus Replication, Indicating Multiple Roles for the Macrodomain in Coronavirus Replication.

All coronaviruses (CoVs) contain a macrodomain, also termed Mac1, in nonstructural protein 3 (nsp3) that binds and hydrolyzes mono-ADP-ribose (MAR) covalently attached to proteins. Despite several reports demonstrating that Mac1 is a prominent virulence factor, there is still a limited understanding of its cellular roles during infection. Currently, most of the information regarding the role of CoV Mac1 during infection is based on a single point mutation of a highly conserved asparagine residue, which makes contact with the distal ribose of ADP-ribose. To determine if additional Mac1 activities contribute to CoV replication, we compared the replication of murine hepatitis virus (MHV) Mac1 mutants, D1329A and N1465A, to the previously mentioned asparagine mutant, N1347A. These residues contact the adenine and proximal ribose in ADP-ribose, respectively. N1465A had no effect on MHV replication or pathogenesis, while D1329A and N1347A both replicated poorly in bone marrow-derived macrophages (BMDMs), were inhibited by PARP enzymes, and were highly attenuated in vivo. Interestingly, D1329A was also significantly more attenuated than N1347A in all cell lines tested. Conversely, D1329A retained some ability to block beta interferon (IFN-ß) transcript accumulation compared to N1347A, indicating that these mutations have different effects on Mac1 functions. Combining these two mutations resulted in a virus that was unrecoverable, suggesting that the combined activities of Mac1 are essential for MHV replication. We conclude that Mac1 has multiple functions that promote the replication of MHV, and that these results provide further evidence that Mac1 is a prominent target for anti-CoV therapeutics. IMPORTANCE In the wake of the COVID-19 epidemic, there has been a surge to better understand how CoVs replicate and to identify potential therapeutic targets that could mitigate disease caused by SARS-CoV-2 and other prominent CoVs. The highly conserved macrodomain, also termed Mac1, is a small domain within nonstructural protein 3. It has received significant attention as a potential drug target, as previous studies demonstrated that it is essential for CoV pathogenesis in multiple animal models of infection. However, the functions of Mac1 during infection remain largely unknown. Here, using targeted mutations in different regions of Mac1, we found that Mac1 has multiple functions that promote the replication of MHV, a model CoV, and, therefore, is more important for MHV replication than previously appreciated. These results will help guide the discovery of these novel functions of Mac1 and the development of inhibitory compounds targeting this domain.

An MHV macrodomain mutant predicted to lack ADP-ribose binding activity is severely attenuated, indicating multiple roles for the macrodomain in coronavirus replication.

All coronaviruses (CoVs) contain a macrodomain, also termed Mac1, in non-structural protein 3 (nsp3) which binds and hydrolyzes ADP-ribose covalently attached to proteins. Despite several reports demonstrating that Mac1 is a prominent virulence factor, there is still a limited understanding of its cellular roles during infection. Currently, most of the information regarding the role of CoV Mac1 during infection is based on a single point mutant of a highly conserved asparagine-to-alanine mutation, which is known to largely eliminate Mac1 ADP-ribosylhydrolase activity. To determine if Mac1 ADP-ribose binding separately contributes to CoV replication, we compared the replication of a murine hepatitis virus (MHV) Mac1 mutant predicted to dramatically reduce ADP-ribose binding, D1329A, to the previously mentioned asparagine mutant, N1347A. D1329A and N1347A both replicated poorly in bone-marrow derived macrophages (BMDMs), were inhibited by PARP enzymes, and were highly attenuated in vivo . However, D1329A was significantly more attenuated than N1347A in all cell lines tested that were susceptible to MHV infection. In addition, D1329A retained some ability to block IFN-ß transcript accumulation compared to N1347A, indicating that these two mutants impacted distinct Mac1 functions. Mac1 mutants predicted to eliminate both binding and hydrolysis activities were unrecoverable, suggesting that the combined activities of Mac1 may be essential for MHV replication. We conclude that Mac1 has multiple roles in promoting the replication of MHV, and that these results provide further evidence that Mac1 could be a prominent target for anti-CoV therapeutics. IMPORTANCE: In the wake of the COVID-19 epidemic, there has been a surge to better understand how CoVs replicate, and to identify potential therapeutic targets that could mitigate disease caused by SARS-CoV-2 and other prominent CoVs. The highly conserved macrodomain, also termed Mac1, is a small domain within non-structural protein 3. It has received significant attention as a potential drug target as previous studies demonstrated that it is essential for CoV pathogenesis in multiple animal models of infection. However, the various roles and functions of Mac1 during infection remain largely unknown. Here, utilizing recombinant Mac1 mutant viruses, we have determined that different biochemical functions of Mac1 have distinct roles in the replication of MHV, a model CoV. These results indicate that Mac1 is more important for CoV replication than previously appreciated, and could help guide the development of inhibitory compounds that target unique regions of this protein domain.

Feasibility of training service providers on the AMBIANCE-Brief measure for use in community settings.

The Atypical Maternal Behavior Instrument for Assessment and Classification-Brief (AMBIANCE-Brief) was developed to provide a clinically useful and psychometrically sound assessment of disrupted parenting behavior for community practitioners. With prior evidence of this tool's reliability and validity in laboratory settings, this study aimed to determine whether providers from family service agencies could become reliable in the use of the level of disrupted communication following a brief training. Providers (N = 46) from three agency sites participated in a 2-day AMBIANCE-Brief training and, at the end of the training, coded eight videotaped mother-child interactions. Novice participant coding was compared to expert consensus ratings using intraclass correlations. On average, participants' interrater agreement was good (ICCmean  = .84, SD = 0.10), with 89% meeting the reliability standards of ICC ≥ .70. In response to queries, 100% of participants indicated that they would recommend the AMBIANCE-Brief training to their colleagues, 85% reported that the AMBIANCE-Brief measure would be useful or very useful for their clinical practice, and 56% of participant clinicians believed that parents would find the measure acceptable or very acceptable for integration into intervention or support planning. Altogether, these findings speak to the feasibility of using the AMBIANCE-Brief in community settings. Future studies are needed in diverse clinical and community contexts to evaluate whether use of this assessment tool can inform more targeted interventions tailored to the specific needs of families.

El Instrumento Abreviado para Evaluación y Clasificación de la Conducta Materna Atípica (AMBIANCE-Abreviado; Madigan, Bronfman, Haltigan y Lyons-Ruth, 2018) se desarrolló para ofrecer a quienes practican en la comunidad una evaluación clínicamente útil y sicométricamente acertada de la conducta de crianza trastornada. Con la anterior evidencia de la confiabilidad y validez de esta herramienta en el marco de los laboratorios (Cooke, Eirich, Racine, Lyons-Ruth y Madigan, 2020), este estudio se propuso determinar si se podría confiar en quienes proveen el servicio como parte de las agencias de servicio a las familias después de un breve entrenamiento. Los proveedores (N = 46) de tres lugares de agencias participaron en un entrenamiento de dos días sobre AMBAIANCE-Abreviado y, al final del entrenamiento, codificaron ocho interacciones madre-niño grabadas en video. Se comparó la forma de codificar de los novatos con el puntaje consenso de los expertos usando correlaciones dentro de clases. El acuerdo entre los evaluadores fue bueno (ICC media = .84, SD = 0.10), con un 89% de los participantes que lograron el estándar de confiabilidad de ICC > .70. En respuesta a preguntas, el 100% de los participantes indicó que ellos recomendarían el entrenamiento de AMBIANCE-Abreviado a sus colegas, 85% reportó que la medida AMBIANCE-Abreviado sería útil o muy útil en su práctica clínica, y 56% creían que los progenitores encontrarían la medida aceptable o muy aceptable para ser integrada en la intervención o el planeamiento de apoyo. En conjunto, estos resultados hablan de la factibilidad de usar AMBIANCE-Abreviado en el marco comunitario.

L'Instrument d'Evaluation et de Classification-Brève du Comportement Maternel Atypique (AMBIANCE-Bref; Madigan, Bronfman, Haltigan, & Lyons-Ruth, 2018) a été développé afin d'offrir une évaluation du comportement de parentage perturbé, cliniquement utile et saine du point de vue psychométrique, pour les acteurs communautaires. Avec des preuves préalables de la fiabilité et de la validité de cet outil en laboratoire (Cooke, Eirich, Racine, Lyons-Ruth, & Madigan, 2020), cette étude s'est donné pour but de déterminer si les prestataires des agences de service à la famille pouvaient devenir fiables pour son utilisation après une formation courte. Des prestataires (N = 46) de trois sites d'agence ont participé à une formation AMBIANCE-Bref de deux jours et à la fin de la formation ont codé huit interactions mère-enfant filmées. Le codage du participant débutant a été comparé aux évaluations par consensus d'expertes en utilisant des corrélations intraclasses. Le coefficient d'objectivité était bon (moyenne des coefficient de corrélation intraclasse [ICC] = 84, SD = 0,10), avec 89% des participants remplissant les standards de fiabilité d'ICC ICC ³,70. En répondant aux questions, 100% des participants ont indiqué qu'ils ou elles recommanderaient la formation AMBIANCE-bref à leurs collègues, 85% ont indiqué que la mesure AMBIANCE-bref serait utile ou très utile pour leur pratique clinique, et 56% ont déclaré qu'ils ou elles croyaient que les parents trouveraient cette mesure acceptable ou très acceptable pour une intégration à une intervention ou le plan de soutien. Au total, ces résultats parlent de la viabilité de l'utilisation de l'AMBIANCE-bref dans des contextes communautaires.

"Honorable Toward Your Whole Self": Experiences of the Body in Fatigued Breast Cancer Survivors.

INTRODUCTION: Cancer Related Fatigue (CRF) is one of the most common and detrimental side effects of cancer treatment. Despite its increasing prevalence and severity CRF remains dismissed by the majority of clinicians. One reason for the apparent gap between clinical need and clinical undertaking is the penchant toward reductionist accounts of the disorder: a tendency to discount the interface between the lived experience of sufferers and the multi-dimensional etiology of CRF as it manifests adversely on a day-to-day basis. METHODS: In order to better understand the interplay between social, bodily, and emotional components of the disorder we undertook semi-structured interviews with thirteen Breast Cancer survivors suffering from CRF, and then subsequently analyzed their responses using Team Based Qualitative Analysis. RESULTS: Our analysis revealed multiple dimensions of the social and bodily underpinnings of fatigue. Most relevantly we found a consistent change in the level and quality of attention to bodily signals. This shift in awareness appeared to be directly connected to the experience of CRF and a newfound, "respect," for the needs of the body. Furthermore, we found that many of the practices that were described as helpful in alleviating fatigue were oriented around eliciting a sense of embodied awareness, examples being: dance, yoga, and shamanic ritual. This relationship with bodily sensations existed in conjunction with the anxiety and trauma that arose as a result of cancer treatment. CONCLUSION: Our analysis suggests that the quality of awareness and relationship to bodily experience in CRF is a functionally relevant component of the disorder and should be considered as an experiential target moving forward.

Distinct Insular Functional Connectivity Changes Related to Mood and Fatigue Improvements in Major Depressive Disorder Following Tai Chi Training: A Pilot Study.

Objective: Tai chi (TC), a contemplative practice combining slow movements and deep breathing, has been shown to be clinically effective in alleviating depressive symptoms. Feelings of fatigue or low vitality often accompany major depressive disorder (MDD) though they are commonly overlooked and not well understood neurologically. By using resting state functional connectivity (rs-FC) using the insula as the seed, this study examines the relationship between mood and vitality symptoms in MDD and how they are impacted by TC training. Methods: Patients (N = 16) with MDD participated in a 10-week TC intervention. Self-report scores of vitality (using the SF-36 scale) and depressed mood (using the Beck Depression Inventory) as well as rs-fMRI were collected pre- and post-intervention. A seed-to-voxel approach was used to test whether changes in insular rs-FC were related to therapeutic improvement in MDD-related symptoms resulting from TC practice. Results: We found decreased self-reported depressed mood and increased vitality following the TC intervention. Furthermore, decreases in depressed mood were associated with increased rs-FC between the right anterior insula (AIC) and superior temporal gyrus and caudate (cluster-corrected p < 0.05). Increased vitality was associated with increased rs-FC between the right posterior insula (PIC) and regions associated with sensorimotor processes (cluster-corrected p < 0.05). Conclusion: These results provide support for differential changes in insula connectivity as neural correlates of symptom improvement in MDD.

The impact of PARPs and ADP-ribosylation on inflammation and host-pathogen interactions.

Poly-adenosine diphosphate-ribose polymerases (PARPs) promote ADP-ribosylation, a highly conserved, fundamental posttranslational modification (PTM). PARP catalytic domains transfer the ADP-ribose moiety from NAD+ to amino acid residues of target proteins, leading to mono- or poly-ADP-ribosylation (MARylation or PARylation). This PTM regulates various key biological and pathological processes. In this review, we focus on the roles of the PARP family members in inflammation and host-pathogen interactions. Here we give an overview the current understanding of the mechanisms by which PARPs promote or suppress proinflammatory activation of macrophages, and various roles PARPs play in virus infections. We also demonstrate how innovative technologies, such as proteomics and systems biology, help to advance this research field and describe unanswered questions.

Can Adults with Mild Cognitive Impairment Build Cognitive Reserve and Learn Mindfulness Meditation? Qualitative Theme Analyses from a Small Pilot Study.

BACKGROUND/OBJECTIVE: High levels of chronic stress negatively impact the hippocampus and are associated with increased incidence of mild cognitive impairment (MCI) and Alzheimer's disease. While mindfulness meditation may mitigate the effects of chronic stress, it is uncertain if adults with MCI have the capacity to learn mindfulness meditation. METHODS: 14 adults with MCI were randomized 2:1 to Mindfulness Based Stress Reduction (MBSR) or a wait-list control group. We conducted qualitative interviews with those who completed MBSR. Transcribed interviews were: a) coded using an emergent themes inductive approach informed by grounded theory; b) rated 0-10, with higher scores reflecting greater perceived benefit from, and understanding of, mindfulness meditation. Ratings were correlated with daily home practice times and baseline level of cognitive function. RESULTS: Seven themes emerged from the interviews: positive perceptions of class; development of mindfulness skills, including meta-cognition; importance of the group experience; enhanced well-being; shift in MCI perspective; decreased stress reactivity and increased relaxation; improvement in interpersonal skills. Ratings of perceived benefit and understanding ranged from 2-10 (mean = 7) and of 0-9.5 (mean = 6), respectively. Many participants experienced substantial benefit/understanding, some had moderate, and a few had minimal benefit/understanding. Understanding the key concepts of mindfulness was highly positively correlated with ≥20 minutes/day of home practice (r = 0.90) but not with baseline cognitive function (r = 0.13). CONCLUSIONS: Most adults with MCI were able to learn mindfulness meditation and had improved MCI acceptance, self-efficacy, and social engagement. Cognitive reserve may be enhanced through a mindfulness meditation program even in patients with MCI.