Methionine and one carbon metabolism as a regulator of bone remodeling with fasting.

Caloric restriction improves metabolic health, but is often complicated by bone loss. We studied bone parameters in humans during a 10-day fast and identified candidate metabolic regulators of bone turnover. P1NP, a bone formation marker, decreased within 3 days of fasting. Whereas dual-energy X-ray absorptiometry measures of bone mineral density were unchanged after 10 days of fasting, high-resolution peripheral quantitative CT demonstrated remodeling of bone microarchitecture. Pathway analysis of longitudinal metabolomics data identified one-carbon metabolism as fasting-dependent. In cultured osteoblasts, we tested the functional significance of one-carbon metabolites modulated by fasting, finding that methionine - which surged after 3 days of fasting - impacted markers of osteoblast cell state in a concentration dependent manner, in some instances exhibiting a U-shaped response with both low and high concentrations driving putative anti-bone responses. Administration of methionine to mice for 5 days recapitulated some fasting effects on bone, including a reduction in serum P1NP. In conclusion, a 10-day fast in humans led to remodeling of bone microarchitecture, potentially mediated by a surge in circulating methionine. These data support an emerging model that points to a window of optimal methionine exposure for bone health.

Impact of the COVID-19 Pandemic on the Personal Networks and Neurological Outcomes of People With Multiple Sclerosis: Cross-Sectional and Longitudinal Case-Control Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has negatively affected the social fabric. OBJECTIVE: We evaluated the associations between personal social networks and neurological function in people with multiple sclerosis (pwMS) and controls in the prepandemic and pandemic periods. METHODS: During the early pandemic (March-December 2020), 8 cohorts of pwMS and controls completed a questionnaire quantifying the structure and composition of their personal social networks, including the health behaviors of network members. Participants from 3 of the 8 cohorts had additionally completed the questionnaire before the pandemic (2017-2019). We assessed neurological function using 3 interrelated patient-reported outcomes: Patient Determined Disease Steps (PDDS), Multiple Sclerosis Rating Scale-Revised (MSRS-R), and Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function. We identified the network features associated with neurological function using paired 2-tailed t tests and covariate-adjusted regressions. RESULTS: In the cross-sectional analysis of the pandemic data from 1130 pwMS and 1250 controls during the pandemic, having a higher percentage of network members with a perceived negative health influence was associated with worse disability in pwMS (MSRS-R: ß=2.181, 95% CI 1.082-3.279; P<.001) and poor physical function in controls (PROMIS Physical Function: ß=-5.707, 95% CI -7.405 to -4.010; P<.001). In the longitudinal analysis of 230 pwMS and 136 controls, the networks of all participants contracted, given an increase in constraint (pwMS-prepandemic: mean 52.24, SD 15.81; pwMS-pandemic: mean 56.77, SD 18.91; P=.006. Controls-prepandemic: mean 48.07, SD 13.36; controls-pandemic: mean 53.99, SD 16.31; P=.001) and a decrease in network size (pwMS-prepandemic: mean 8.02, SD 5.70; pwMS-pandemic: mean 6.63, SD 4.16; P=.003. Controls-prepandemic: mean 8.18, SD 4.05; controls-pandemic: mean 6.44, SD 3.92; P<.001), effective size (pwMS-prepandemic: mean 3.30, SD 1.59; pwMS-pandemic: mean 2.90, SD 1.50; P=.007. Controls-prepandemic: mean 3.85, SD 1.56; controls-pandemic: mean 3.40, SD 1.55; P=.01), and maximum degree (pwMS-prepandemic: mean 4.78, SD 1.86; pwMS-pandemic: mean 4.32, SD 1.92; P=.01. Controls-prepandemic: mean 5.38, SD 1.94; controls-pandemic: mean 4.55, SD 2.06; P<.001). These network changes were not associated with worsening function. The percentage of kin in the networks of pwMS increased (mean 46.06%, SD 29.34% to mean 54.36%, SD 30.16%; P=.003) during the pandemic, a change that was not seen in controls. CONCLUSIONS: Our findings suggest that high perceived negative health influence in the network was associated with worse function in all participants during the pandemic. The networks of all participants became tighter knit, and the percentage of kin in the networks of pwMS increased during the pandemic. Despite these perturbations in social connections, network changes from the prepandemic to the pandemic period were not associated with worsening function in all participants, suggesting possible resilience.

Readmission-related outcomes of surgical versus transcatheter aortic valve replacement in patients aged 65 or older with bicuspid aortic valve.

BACKGROUND: There continues to be debate regarding the superiority of transcatheter (TAVR) over surgical aortic valve replacement (SAVR) in patients with bicuspid aortic valves (BAV). We aimed to compare outcomes during readmissions in elderly patients with BAV who underwent SAVR or TAVR. METHODS: Patients 65 years or older with BAV who underwent TAVR or isolated SAVR were identified using the National Readmission Database from 2012 through 2018. We compared outcomes during readmissions within 90 days after discharge from the index surgery. Propensity score matching was performed to adjust the baseline differences. RESULTS: During the study period, 8555 and 1081 elderly patients with BAV underwent SAVR and TAVR, respectively. The number of patients who underwent TAVR went up by 179 % from 2012 to 2018. Propensity score matching yielded 573 patients in each group. A total of 111 (19.4 %) in the SAVR group and 125 (21.8 %) in the TAVR group were readmitted within 90 days after the index surgery (p = .31). The mortality during the readmissions within 90 days was equivalent between the two groups (0.9 % in the SAVR group vs. 3.2 % in the TAVR group, p = .22). However, the median hospital cost was approximately doubled in the TAVR group during the readmission (18,250 dollars vs. 9310 dollars in the SAVR group, p < .001). CONCLUSIONS: Readmission within 90 days was common in both groups. While the mortality during the readmissions after the surgery was equivalent between the two groups, hospital cost was significantly more expensive in the TAVR group.

Evidence for conservation of primordial ~12-hour ultradian gene programs in humans under free-living conditions.

While circadian rhythms are entrained to the once daily light-dark cycle of the sun, many marine organisms exhibit ~12h ultradian rhythms corresponding to the twice daily movement of the tides. Although human ancestors emerged from circatidal environment millions of years ago, direct evidence of ~12h ultradian rhythms in humans is lacking. Here, we performed prospective, temporal transcriptome profiling of peripheral white blood cells and identified robust ~12h transcriptional rhythms from three healthy participants. Pathway analysis implicated ~12h rhythms in RNA and protein metabolism, with strong homology to the circatidal gene programs previously identified in Cnidarian marine species. We further observed ~12h rhythms of intron retention events of genes involved in MHC class I antigen presentation, synchronized to expression of mRNA splicing genes in all three participants. Gene regulatory network inference revealed XBP1, and GABP and KLF transcription factor family members as potential transcriptional regulators of human ~12h rhythms. These results suggest that human ~12h biological rhythms have a primordial evolutionary origin with important implications for human health and disease.

Acute Coronary Syndrome After Transcatheter Aortic Valve Implantation (Results from Over 40,000 Patients).

Acute coronary syndrome (ACS) encompasses a broad category of presentations from unstable angina to ST-elevation myocardial infarctions. Most patients undergo coronary angiography upon presentation for diagnosis and treatment. However, the ACS management strategy after transcatheter aortic valve implantation (TAVI) may be complicated because of challenging coronary access. The National Readmission Database was reviewed to identify all patients who were readmitted with ACS within 90 days after TAVI between 2012 and 2018. Their outcomes were described between patients who were readmitted with ACS (ACS group) and without (non-ACS group). A total of 44,653 patients were readmitted within 90 days after TAVI. Among them, 1,416 patients (3.2%) were readmitted with ACS. The ACS group had a higher prevalence of men, diabetes, hypertension, congestive heart failure, peripheral vascular disease, and a history of percutaneous coronary intervention (PCI). In the ACS group, 101 patients (7.1%) developed cardiogenic shock, whereas 120 patients (8.5%) developed ventricular arrhythmias. Overall, 141 patients (9.9%) in the ACS group died during readmissions (vs 3.0% in the non-ACS group, p <0.001). Among the ACS group, PCI was performed in 33 (5.9%), whereas coronary bypass grafting was performed in 12 (0.82%). The factors associated with ACS readmission included a history of diabetes, congestive heart failure, chronic kidney disease, and PCI, and nonelective TAVI. Coronary artery bypass grafting was an independent factor related to in-hospital mortality during ACS readmission (odds ratio 11.9, 95% confidence interval 2.18 to 65.4, p = 0.004), whereas PCI was not (odds ratio 0.19, 95% confidence interval 0.03 to 1.44, p = 0.11). In conclusion, patients readmitted with ACS have significantly higher mortality compared with those readmitted without ACS. History of PCI is an independent factor associated with ACS after TAVI.

Impact of the COVID-19 Pandemic on Personal Networks and Neurological Outcomes of People with Multiple Sclerosis: A Case-Control Cross-sectional and Longitudinal Analysis.

Background: The COVID-19 pandemic has negatively impacted the social fabric of people with multiple sclerosis (pwMS). Objective: To evaluate the associations between personal social network environment and neurological function in pwMS and controls during the COVID-19 pandemic and compare with the pre-pandemic baseline. Methods: We first analyzed data collected from 8 cohorts of pwMS and control participants during the COVID-19 pandemic (March-December 2020). We then leveraged data collected between 2017-2019 in 3 of the 8 cohorts for longitudinal comparison. Participants completed a questionnaire that quantified the structure and composition of their personal social network, including the health behaviors of network members. We assessed neurological disability using three interrelated patient-reported outcomes: Patient Determined Disease Steps (PDDS), Multiple Sclerosis Rating Scale â€" Revised (MSRS-R), and Patient Reported Outcomes Measurement Information System (PROMIS)-Physical Function. We identified the network features associated with neurologic disability using paired t-tests and covariate-adjusted regressions. Results: In the cross-sectional analysis of the pandemic data from 1130 pwMS and 1250 control participants, higher percent of network members with a perceived negative health influence was associated with greater neurological symptom burden in pwMS (MSRS-R: Beta[95% CI]=2.181[1.082, 3.279], p<.001) and worse physical function in controls (PROMIS-Physical Function: Beta[95% CI]=-5.707[-7.405, -4.010], p<.001). In the longitudinal analysis of 230 pwMS and 136 control participants, the networks of both pwMS and controls experienced an increase in constraint (pwMS p=.006, control p=.001) as well as a decrease in network size (pwMS p=.003, control p<.001), effective size (pwMS p=.007, control p=.013), maximum degree (pwMS p=.01, control p<.001), and percent contacted weekly or less (pwMS p<.001, control p<.001), suggesting overall network contraction during the COVID-19 pandemic. There was also an increase in percentage of kin (p=.003) in the networks of pwMS but not controls during the COVID-19 pandemic when compared to the pre-pandemic baseline. These changes in personal social network due to the pandemic were not associated with worsening neurological disability during the pandemic. Conclusions: Our findings suggest that perceived negative health influences in personal social networks are associated with worse disability in all participants during the COVID-19 pandemic. Despite the perturbation in social environment and connections during the pandemic, the stability in neurological function among pwMS suggests potential resilience.

Proximate causes and consequences of intergenerational influences of salient sensory experience.

Salient sensory environments experienced by a parental generation can exert intergenerational influences on offspring. While these data provide an exciting new perspective on biological inheritance, questions remain about causes and consequences of intergenerational influences of salient sensory experience. We previously showed that exposing male mice to a salient olfactory experience, like olfactory fear conditioning, resulted in offspring demonstrating a sensitivity to the odor used to condition the paternal generation and possessing enhanced neuroanatomical representation for that odor. In this study, we first injected RNA extracted from sperm of male mice that underwent olfactory fear conditioning into naïve single-cell zygotes and found that adults that developed from these embryos had increased sensitivity and enhanced neuroanatomical representation for the odor (Odor A) with which the paternal male had been conditioned. Next, we found that female, but not male offspring sired by males conditioned with Odor A show enhanced consolidation of a weak single-trial Odor A + shock fear conditioning protocol. Our data provide evidence that RNA found in the paternal germline after exposure to salient sensory experiences can contribute to intergenerational influences of such experiences, and that such intergenerational influences confer an element of adaptation to the offspring. In so doing, our study of intergenerational influences of parental sensory experience adds to existing literature on intergenerational influences of parental exposures to stress and dietary manipulations and suggests that some causes (sperm RNA) and consequences (behavioral flexibility) of intergenerational influences of parental experiences may be conserved across a variety of parental experiences.

Reversing Behavioral, Neuroanatomical, and Germline Influences of Intergenerational Stress.

BACKGROUND: Stressors affect populations exposed to them as well as offspring. Strategies preventing the intergenerational propagation of effects of stress would benefit public health. Olfactory cue-based fear conditioning provides a framework to address this issue. METHODS: We 1) exposed adult male mice to an odor, acetophenone (Ace) or Lyral (parental generation [F0]-Exposed), 2) trained mice to associate these odors with mild foot shocks (F0-Trained), and 3) trained mice to associate these odors with mild foot shocks and then extinguished their fear toward these odors with odor-only presentations (F0-Extinguished). We then examined sensitivity of future generation (F1) offspring to these odors, expression of M71 odorant (Ace-responsive) and MOR23 odorant (Lyral-responsive) receptor-expressing cell populations in F1 offspring, and DNA methylation at genes encoding the Ace- (Olfr151, Olfr160) and Lyral- (Olfr16) responsive receptors in F0 sperm. RESULTS: Extinguishing fear toward Ace or Lyral of F0 male mice (F0-Extinguished) that had been fear conditioned with Ace or Lyral, respectively, results in F1-Extinguished offspring that do not demonstrate behavioral sensitivity to Ace or Lyral, respectively, and do not have enhanced representation for M71 or MOR23 odorant receptors in the olfactory system, as is observed in F1-Trained-Ace or F1-Trained-Lyral cohorts, respectively. The promoters of genes encoding Olfr151 and Olfr160 receptors are less methylated in F0-Trained-Ace sperm compared with F0-Exposed-Ace sperm. The Olfr16 promoter is less methylated in F0-Trained-Lyral sperm compared with F0-Exposed-Lyral sperm, and F0-Extinguished-Lyral sperm have methylation levels comparable to F0-Exposed-Lyral sperm. CONCLUSIONS: Our study demonstrates the potential of using extinction-based behavioral strategies to reverse influences of parental stress in offspring and in the parental germline.

Perineuronal Nets in the Adult Sensory Cortex Are Necessary for Fear Learning.

Lattice-like structures known as perineuronal nets (PNNs) are key components of the extracellular matrix (ECM). Once fully crystallized by adulthood, they are largely stable throughout life. Contrary to previous reports that PNNs inhibit processes involving plasticity, here we report that the dynamic regulation of PNN expression in the adult auditory cortex is vital for fear learning and consolidation in response to pure tones. Specifically, after first confirming the necessity of auditory cortical activity for fear learning and consolidation, we observed that mRNA levels of key proteoglycan components of PNNs were enhanced 4 hr after fear conditioning but were no longer different from the control groups 24 hr later. A similar pattern of regulation was observed in numbers of cells surrounded by PNNs and area occupied by them in the auditory cortex. Finally, the removal of auditory cortex PNNs resulted in a deficit in fear learning and consolidation.