Genetic disruption of the bacterial raiA motif noncoding RNA causes defects in sporulation and aggregation.

Several structured noncoding RNAs in bacteria are essential contributors to fundamental cellular processes. Thus, discoveries of additional ncRNA classes provide opportunities to uncover and explore biochemical mechanisms relevant to other major and potentially ancient processes. A candidate structured ncRNA named the "raiA motif" has been found via bioinformatic analyses in over 2,500 bacterial species. The gene coding for the RNA typically resides between the raiA and comFC genes of many species of Bacillota and Actinomycetota. Structural probing of the raiA motif RNA from the Gram-positive anaerobe Clostridium acetobutylicum confirms key features of its sophisticated secondary structure model. Expression analysis of raiA motif RNA reveals that the RNA is constitutively produced but reaches peak abundance during the transition from exponential growth to stationary phase. The raiA motif RNA becomes the fourth most abundant RNA in C. acetobutylicum, excluding ribosomal RNAs and transfer RNAs. Genetic disruption of the raiA motif RNA causes cells to exhibit substantially decreased spore formation and diminished ability to aggregate. Restoration of normal cellular function in this knock-out strain is achieved by expression of a raiA motif gene from a plasmid. These results demonstrate that raiA motif RNAs normally participate in major cell differentiation processes by operating as a trans-acting factor.

8-oxoguanine riboswitches in bacteria detect and respond to oxidative DNA damage.

Riboswitches rely on structured aptamer domains to selectively sense their target ligands and regulate gene expression. However, some riboswitch aptamers in bacteria carry mutations in their otherwise strictly conserved binding pockets that change ligand specificities. The aptamer domain of a riboswitch class originally found to selectively sense guanine forms a three-stem junction that has since been observed to exploit numerous alterations in its ligand-binding pocket. These rare variants have modified their ligand specificities to sense other purines or purine derivatives, including adenine, 2'-deoxyguanosine (three classes), and xanthine. Herein, we report the characteristics of a rare variant that is narrowly distributed in the Paenibacillaceae family of bacteria. Known representatives are always associated with genes encoding 8-oxoguanine deaminase. As predicted from this gene association, these variant riboswitches tightly bind 8-oxoguanine (8-oxoG), strongly discriminate against other purine derivatives, and function as genetic "ON" switches. Following exposure of cells to certain oxidative stresses, a representative 8-oxoG riboswitch activates gene expression, likely caused by the accumulation of 8-oxoG due to oxidative damage to G nucleobases in DNA, RNA, and the nucleotide pool. Furthermore, an engineered version of the variant aptamer was prepared that exhibits specificity for 8-oxoadenine, further demonstrating that RNA aptamers can acquire mutations that expand their ability to detect and respond to oxidative damage.

Roles and interplay of reinforcement-based and error-based processes during reaching and gait in neurotypical adults and individuals with Parkinson's disease.

From a game of darts to neurorehabilitation, the ability to explore and fine tune our movements is critical for success. Past work has shown that exploratory motor behaviour in response to reinforcement (reward) feedback is closely linked with the basal ganglia, while movement corrections in response to error feedback is commonly attributed to the cerebellum. While our past work has shown these processes are dissociable during adaptation, it is unknown how they uniquely impact exploratory behaviour. Moreover, converging neuroanatomical evidence shows direct and indirect connections between the basal ganglia and cerebellum, suggesting that there is an interaction between reinforcement-based and error-based neural processes. Here we examine the unique roles and interaction between reinforcement-based and error-based processes on sensorimotor exploration in a neurotypical population. We also recruited individuals with Parkinson's disease to gain mechanistic insight into the role of the basal ganglia and associated reinforcement pathways in sensorimotor exploration. Across three reaching experiments, participants were given either reinforcement feedback, error feedback, or simultaneously both reinforcement & error feedback during a sensorimotor task that encouraged exploration. Our reaching results, a re-analysis of a previous gait experiment, and our model suggests that in isolation, reinforcement-based and error-based processes respectively boost and suppress exploration. When acting in concert, we found that reinforcement-based and error-based processes interact by mutually opposing one another. Finally, we found that those with Parkinson's disease had decreased exploration when receiving reinforcement feedback, supporting the notion that compromised reinforcement-based processes reduces the ability to explore new motor actions. Understanding the unique and interacting roles of reinforcement-based and error-based processes may help to inform neurorehabilitation paradigms where it is important to discover new and successful motor actions.

Variants of the guanine riboswitch class exhibit altered ligand specificities for xanthine, guanine, or 2'-deoxyguanosine.

The aptamer portions of previously reported riboswitch classes that sense guanine, adenine, or 2'-deoxyguanosine are formed by a highly similar three-stem junction with distinct nucleotide sequences in the regions joining the stems. The nucleotides in these joining regions form the major features of the selective ligand-binding pocket for each aptamer. Previously, we reported the existence of additional, rare variants of the predominant guanine-sensing riboswitch class that carry nucleotide differences in the ligand-binding pocket, suggesting that these RNAs have further diversified their structures and functions. Herein, we report the discovery and analysis of three naturally occurring variants of guanine riboswitches that are narrowly distributed across Firmicutes. These RNAs were identified using comparative sequence analysis methods, which also revealed that some of the gene associations for these variants are atypical for guanine riboswitches or their previously known natural variants. Binding assays demonstrate that the newfound variant riboswitch representatives recognize xanthine, guanine, or 2'-deoxyguanosine, with the guanine class exhibiting greater discrimination against related purines than the more common guanine riboswitch class reported previously. These three additional variant classes, together with the four previously discovered riboswitch classes that employ the same three-stem junction architecture, reveal how a simple structural framework can be diversified to expand the range of purine-based ligands sensed by RNA.

The structural and functional diversity of metabolite-binding riboswitches.

The cellular concentrations of certain metabolites are assiduously monitored to achieve appropriate levels of gene expression. Although proteins have long been known to act as sensors in this capacity, metabolite-binding RNAs, or riboswitches, also play an important role. More than 20 distinct classes of riboswitches have been identified to date, and insights to the molecular recognition strategies of a significant subset of these have been provided by detailed structural studies. This diverse set of metabolite-sensing RNAs is found to exploit a variety of distinct mechanisms to regulate genes that are fundamental to metabolism.

The sensorimotor system modulates muscular co-contraction relative to visuomotor feedback responses to regulate movement variability.

The naturally occurring variability in our movements often poses a significant challenge when attempting to produce precise and accurate actions, which is readily evident when playing a game of darts. Two differing, yet potentially complementary, control strategies that the sensorimotor system may use to regulate movement variability are impedance control and feedback control. Greater muscular co-contraction leads to greater impedance that acts to stabilize the hand, while visuomotor feedback responses can be used to rapidly correct for unexpected deviations when reaching toward a target. Here, we examined the independent roles and potential interplay of impedance control and visuomotor feedback control when regulating movement variability. Participants were instructed to perform a precise reaching task by moving a cursor through a narrow visual channel. We manipulated cursor feedback by visually amplifying movement variability and/or delaying the visual feedback of the cursor. We found that participants decreased movement variability by increasing muscular co-contraction, aligned with an impedance control strategy. Participants displayed visuomotor feedback responses during the task but, unexpectedly, there was no modulation between conditions. However, we did find a relationship between muscular co-contraction and visuomotor feedback responses, suggesting that participants modulated impedance control relative to feedback control. Taken together, our results highlight that the sensorimotor system modulates muscular co-contraction, relative to visuomotor feedback responses, to regulate movement variability and produce accurate actions.NEW & NOTEWORTHY The sensorimotor system has the constant challenge of dealing with the naturally occurring variability in our movements. Here, we investigated the potential roles of muscular co-contraction and visuomotor feedback responses to regulate movement variability. When we visually amplified movements, we found that the sensorimotor system primarily uses muscular co-contraction to regulate movement variability. Interestingly, we found that muscular co-contraction was modulated relative to inherent visuomotor feedback responses, suggesting an interplay between impedance and feedback control.

Visual accuracy dominates over haptic speed for state estimation of a partner during collaborative sensorimotor interactions.

We routinely have physical interactions with others, whether it be handing someone a glass of water or jointly moving a heavy object together. These sensorimotor interactions between humans typically rely on visual feedback and haptic feedback. Recent single-participant studies have highlighted that the unique noise and time delays of each sense must be considered to estimate the state, such as the position and velocity, of one's own movement. However, we know little about how visual feedback and haptic feedback are used to estimate the state of another person. Here, we tested how humans utilize visual feedback and haptic feedback to estimate the state of their partner during a collaborative sensorimotor task. Across two experiments, we show that visual feedback dominated haptic feedback during collaboration. Specifically, we found that visual feedback led to comparatively lower task-relevant movement variability, smoother collaborative movements, and faster trial completion times. We also developed an optimal feedback controller that considered the noise and time delays of both visual feedback and haptic feedback to estimate the state of a partner. This model was able to capture both lower task-relevant movement variability and smoother collaborative movements. Taken together, our empirical and modeling results support the idea that visual accuracy is more important than haptic speed to perform state estimation of a partner during collaboration.NEW & NOTEWORTHY Physical collaboration between two or more individuals involves both visual and haptic feedback. Here, we investigated how visual and haptic feedback is used to estimate the movements of a partner during a collaboration task. Our experimental and computational modeling results parsimoniously support the notion that greater visual accuracy is more important than faster yet noisier haptic feedback when estimating the state of a partner.

HPV Vaccination and the Risk of Invasive Cervical Cancer.

BACKGROUND: The efficacy and effectiveness of the quadrivalent human papillomavirus (HPV) vaccine in preventing high-grade cervical lesions have been shown. However, data to inform the relationship between quadrivalent HPV vaccination and the subsequent risk of invasive cervical cancer are lacking. METHODS: We used nationwide Swedish demographic and health registers to follow an open population of 1,672,983 girls and women who were 10 to 30 years of age from 2006 through 2017. We assessed the association between HPV vaccination and the risk of invasive cervical cancer, controlling for age at follow-up, calendar year, county of residence, and parental characteristics, including education, household income, mother's country of birth, and maternal disease history. RESULTS: During the study period, we evaluated girls and women for cervical cancer until their 31st birthday. Cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. The cumulative incidence of cervical cancer was 47 cases per 100,000 persons among women who had been vaccinated and 94 cases per 100,000 persons among those who had not been vaccinated. After adjustment for age at follow-up, the incidence rate ratio for the comparison of the vaccinated population with the unvaccinated population was 0.51 (95% confidence interval [CI], 0.32 to 0.82). After additional adjustment for other covariates, the incidence rate ratio was 0.37 (95% CI, 0.21 to 0.57). After adjustment for all covariates, the incidence rate ratio was 0.12 (95% CI, 0.00 to 0.34) among women who had been vaccinated before the age of 17 years and 0.47 (95% CI, 0.27 to 0.75) among women who had been vaccinated at the age of 17 to 30 years. CONCLUSIONS: Among Swedish girls and women 10 to 30 years old, quadrivalent HPV vaccination was associated with a substantially reduced risk of invasive cervical cancer at the population level. (Funded by the Swedish Foundation for Strategic Research and others.).

Reinforcement-based processes actively regulate motor exploration along redundant solution manifolds.

From a baby's babbling to a songbird practising a new tune, exploration is critical to motor learning. A hallmark of exploration is the emergence of random walk behaviour along solution manifolds, where successive motor actions are not independent but rather become serially dependent. Such exploratory random walk behaviour is ubiquitous across species' neural firing, gait patterns and reaching behaviour. The past work has suggested that exploratory random walk behaviour arises from an accumulation of movement variability and a lack of error-based corrections. Here, we test a fundamentally different idea-that reinforcement-based processes regulate random walk behaviour to promote continual motor exploration to maximize success. Across three human reaching experiments, we manipulated the size of both the visually displayed target and an unseen reward zone, as well as the probability of reinforcement feedback. Our empirical and modelling results parsimoniously support the notion that exploratory random walk behaviour emerges by utilizing knowledge of movement variability to update intended reach aim towards recently reinforced motor actions. This mechanism leads to active and continuous exploration of the solution manifold, currently thought by prominent theories to arise passively. The ability to continually explore muscle, joint and task redundant solution manifolds is beneficial while acting in uncertain environments, during motor development or when recovering from a neurological disorder to discover and learn new motor actions.

Association of fractional exhaled nitric oxide with asthma morbidity in urban minority children.

OBJECTIVE: Fractional exhaled nitric oxide (FeNO) is a well-established measure of allergic airway inflammation and possible useful adjunct disease management tool. We investigated the association of baseline and follow-up FeNO measurements with disease burden in minority children with persistent asthma. METHODS: A retrospective chart review was conducted on 352 African American and Hispanic children seen at an urban Asthma Center in Bronx, NY. Demographic, clinical characteristics, and pulmonary function tests (PFTs) were compared between children with low, intermediate, and high baseline FeNO levels. Among 95 children with subsequent follow up visits, associations of change in FeNO with demographics, clinical characteristics, and PFTs were examined using mixed effects linear regression models. RESULTS: A higher proportion of children with intermediate (54%) and high FeNO (58%) levels had lower airways obstruction compared to those with low FeNO levels (33%). Children with intermediate FeNO levels had more annual hospitalizations (2.8 ± 6.2) compared to those with low and high FeNO levels (1.3 ± 2.8 and 1.3 ± 2.5). These associations did not differ between ethnicities. An increase in FeNO over time was associated with higher BMI z-scores (ß = 6.2, 95% CI: 1.0 to 11.4) and two or more hospitalizations in the past year (ß = 16.1, 95% CI: 1.5 to 30.8). CONCLUSIONS: Intermediate and high FeNO levels are associated with lower airways obstruction and hospitalizations. Initial and serial FeNO measurements can be a useful adjunctive tool in identifying asthma-related morbidity in urban African American and Hispanic children.

Parental views and the key role of nurses for high vaccine acceptance in Sweden - a focus group study.

BACKGROUND: In Sweden, vaccine uptake is exceptionally high due to an efficient child immunization program. More than 97% of Swedish children were vaccinated at child health care centers (CHCs) according to the schedule at 2 years of age in 2021. From the age of 6 years, vaccinations are given within the school health care. Maintaining high vaccination coverage over time is one of the central motives to explore and understand drivers for vaccine acceptance. The current study aimed to assess parental vaccine acceptance concerning the national immunization program and explore factors contributing to the high vaccine acceptance in Sweden. METHODS: Parents of children aged 1-2 years and 8-12 years were recruited through purposive sampling and asked to participate in focus groups held in three cities in Sweden, in February and March 2019. In total, 47 parents participated in two focus groups per city, one session for parents of younger (1-2 years) and older (8-12 years) children respectively. The focus group discussions were analyzed using qualitative content analysis. RESULTS: Parents of children aged 1-2 years expressed the themes; strong compliance to and protection of the value of vaccinations; parents feel safe with an attentive relationship with their nurse; the spectrum of communication needs is essential to meet. For parents to children aged 8-12 years, the themes expressed were; vaccinate to do good for the individual and society; a foundation of trust is built at CHCs for decisions later on; decisions for vaccination become more complex as children get older; communication changes as children get older and need to be explicit and tailored to the situation. CONCLUSION: Both individual and societal perspectives were shown to influence the vaccination decision for childhood immunizations, as manifested in parental reflections and experiences. As nurses have a key role, it is important to provide them with continued support and tools to facilitate their support for parents in making informed decisions. Continuous work for supporting driving factors for vaccination over time is needed to maintain high vaccine acceptance in Sweden.

Random sampling of alters from networks: A promising direction in egocentric network research.

The social network perspective has great potential for advancing knowledge of social mechanisms in many fields. However, collecting egocentric (i.e., personal) network data is costly and places a heavy burden on respondents. This is especially true of the task used to elicit information on ties between network members (i.e., alter-alter ties or density matrix), which grows exponentially in length as network size increases. While most existing national surveys circumvent this problem by capping the number of network members that can be named, this strategy has major limitations. Here, we apply random sampling of network members to reduce cost, respondent burden, and error in network studies. We examine the effectiveness and reliability of random sampling in simulated and real-world egocentric network data. We find that in estimating sample/population means of network measures, randomly selecting a small number of network members produces only minor errors, regardless of true network size. For studies that use network measures in regressions, randomly selecting the mean number of network members (e.g., randomly selecting 10 alters when mean network size is 10) is enough to recover estimates of network measures that correlate close to 1 with those of the full sample. We conclude with recommendations for best practices that will make this versatile but resource intensive methodology accessible to a wider group of researchers without sacrificing data quality.

Social enrichment on the job: Complex work with people improves episodic memory, promotes brain reserve, and reduces the risk of dementia.

Individuals with more complex jobs experience better cognitive function in old age and a lower risk of dementia, yet complexity has multiple dimensions. Drawing on the Social Networks in Alzheimer Disease study, we examine the association between occupational complexity and cognition in a sample of older adults (N = 355). A standard deviation (SD) increase in complex work with people is associated with a 9% to 12% reduction in the probability of mild cognitive impairment or dementia, a 0.14-0.19 SD increase in episodic memory, and a 0.18-0.25 SD increase in brain reserve, defined as the gap (residual) between global cognitive function and magnetic resonance imaging (MRI) indicators of brain atrophy. In contrast, complexity with data or things is rarely associated with cognitive outcomes. We discuss the clinical and methodological implications of these findings, including the need to complement data-centered activities (e.g., Sudoku puzzles) with person-centered interventions that increase social complexity.

What kinds of social networks protect older adults' health during a pandemic? The tradeoff between preventing infection and promoting mental health.

When the coronavirus emerged in early 2020, older adults were at heightened risk of contracting the virus, and of suffering mental health consequences from the pandemic and from the precautions designed to mitigate it. In this paper, we examine how social networks prior to the pandemic helped to shape health beliefs, behaviors, and outcomes among older adults during its onset, focusing on (1) perceived risk of COVID-19, (2) preventative health behaviors, and (3) mental health, including loneliness, perceived stress, depression, and anxiety. Drawing on the longitudinal Social Networks in Alzheimer Disease study, we find that networks high in bridging social capital predict greater perceived risk and more precautions taken, but worse mental health. In contrast, networks high in bonding social capital predict less perceived risk and fewer precautions taken, but better mental health. We discuss this apparent tradeoff between physical and mental health.

Why the cognitive "fountain of youth" may be upstream: Pathways to dementia risk and resilience through social connectedness.

Research suggests social connectedness may help older adults with dementia maintain cognitive functionality and quality of life. However, little is known about its specific social and biological mechanisms. This paper proposes two pathways through social bridging (i.e., cognitive enrichment through expansive social networks) and bonding (i.e., neuroendocrine benefits of integration in cohesive social networks). We provide preliminary evidence for these pathways using neuroimaging, cognitive, and egocentric social network data from the Social Networks and Alzheimer's Disease (SNAD) study (N = 280). We found that network size, density, and presence of weak ties (i.e., social bridging) moderated the association between brain atrophy and cognitive function, while marriage/cohabitation (i.e., social bonding) moderated the association between perceived stress and cognitive function. We argue that social connectedness may have downstream implications for multiple pathophysiological processes in cognitive aging, even negating existing structural damage to the brain, making it a strong candidate for clinical or policy intervention.

Personal networks and mortality in later life: racial and ethnic differences.

BACKGROUND: Social network characteristics are associated with health outcomes in later life, including mortality. Moreover, there are well-established mortality disparities across race and ethnicity. Although previous studies have documented these associations separately, limited research considers the two in tandem. The present study addressed how the associations between social network characteristics and mortality differ across race and ethnicity in later life. METHODS: Data were from the National Social Life, Health, and Aging Project. At baseline, 3005 respondents were interviewed with regards to their health and social networks. Five years later, 430 respondents had died. Logistic regression models were used to estimate the odds of all-cause mortality over the study period. RESULTS: Network size and kin composition were negatively associated with mortality, whereas density was positively associated with mortality. There was a stronger negative association between the kin composition and mortality for Hispanic respondents compared with white and Black respondents. CONCLUSION: The present study contributes to the large literature documenting the link between social networks and health by highlighting the importance of analyzing networks through a sociocultural lens.

Network recall among older adults with cognitive impairments.

Although it is widely accepted that personal networks influence health and illness, network recall remains a major concern. This concern is heightened when studying a population that is vulnerable to cognitive decline. Given these issues, we use data from the Social Network in Alzheimer Disease project to explore similarities and discrepancies between the network perceptions of focal participants and study partners. By leveraging data on a sample of older adults with normal cognition, mild cognitive impairment, and early stage dementia, we explore how cognitive impairment influences older adults' perceptions of their personal networks. We find that the average individual is more likely to omit weaker, peripheral ties from their self-reported networks than stronger, central ties. Despite observing only moderate levels of focal-partner corroboration across our sample, we find minimal evidence of perceptual differences across diagnostic groups. We offer two broad conclusions. First, self-reported network data, though imperfect, offer a reasonable account of the core people in one's life. Second, our findings assuage concerns that cognitively impaired older adults have skewed perceptions of their personal networks.

An outbreak investigation of Legionella non-pneumophila Legionnaires' disease in Sweden, April to August 2018: Gardening and use of commercial bagged soil associated with infections.

In early June 2018, an increase in non-travel-related cases of Legionella non-pneumophila Legionnaires' disease (LD) was observed in Sweden and a national outbreak investigation was started. Outbreak cases were defined as notified confirmed or probable cases of L. non-pneumophila LD, with symptom onset after 1 April 2018. From April to August 2018, 41 cases were reported, 30 of whom were identified as L. longbeachae. We conducted a case-control study with 27 cases and 182 matched controls. Results from the case-control study indicated that gardening and handling commercial bagged soil, especially dusty dry soil, were associated with disease. L. longbeachae was isolated in soils from cases' homes or gardens, but joint analysis of soil and human specimens did not identify any genetic clonality. Substantial polyclonality was noted between and within soil samples, which made finding a genetic match between soil and human specimens unlikely. Therefore, whole genome sequencing may be of limited use to confirm a specific soil as a vehicle of transmission for L. longbeachae. Handling soil for residential gardening was associated with disease and the isolation of L. longbeachae in different soils provided further evidence for Legionella non-pneumophila infection from soil.

Biochemical Validation of a Fourth Guanidine Riboswitch Class in Bacteria.

An intriguing consequence of ongoing riboswitch discovery efforts is the occasional identification of metabolic or toxicity response pathways for unusual ligands. Recently, we reported the experimental validation of three distinct bacterial riboswitch classes that regulate gene expression in response to the selective binding of a guanidinium ion. These riboswitch classes, called guanidine-I, -II, and -III, regulate numerous genes whose protein products include previously misannotated guanidine exporters and enzymes that degrade guanidine via an initial carboxylation reaction. Guanidine is now recognized as the primal substrate of many multidrug efflux pumps that are important for bacterial resistance to certain antibiotics. Guanidine carboxylase enzymes had long been annotated as urea carboxylase enzymes but are now understood to participate in guanidine degradation. Herein, we report the existence of a fourth riboswitch class for this ligand, called guanidine-IV. Members of this class use a novel aptamer to selectively bind guanidine and use an unusual expression platform arrangement that is predicted to activate gene expression when ligand is present. The wide distribution of this abundant riboswitch class, coupled with the striking diversity of other guanidine-sensing RNAs, demonstrates that many bacterial species maintain sophisticated sensory and genetic mechanisms to avoid guanidine toxicity. This finding further highlights the mystery regarding the natural source of this nitrogen-rich chemical moiety.