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This paper investigates the impact of two non-technical speech feedback perturbations outside the auditory modality: topical application of commercially-available benzocaine to reduce somatosensory feedback from speakers’ lips and tongue tip, and the presence of a mirror to provide fully-detailed visual self-feedback. In experiment 1, speakers were recorded under normal quiet conditions (i.e., baseline), then again with benzocaine application plus auditory degradation, and finally with the addition of mirror feedback. Speech produced under normal and both feedback-altered conditions was assessed via naïve listeners’ intelligibility discrimination judgments. Listeners judged speech produced under bisensory degradation to be less intelligible than speech from the un-degraded baseline, and with a greater degree of difference than previously observed with auditory-only degradation. The introduction of mirror feedback, however, did not result in relative improvements in intelligibility. Experiment 2, therefore, assessed the effect of a mirror on speech intelligibility in isolation with no other sensory feedback manipulations. Speech was recorded at baseline and then again in front of a mirror, and relative intelligibility was discriminated by naïve listeners. Speech produced with mirror feedback was judged as less intelligible than baseline tokens, indicating a negative impact of visual self-feedback in the absence of other sensory manipulations. The results of both experiments demonstrate that relatively accessible manipulations of non-auditory sensory feedback can produce speech-relevant effects, and that those effects are perceptible to naïve listeners.

Almond skins are known for their antioxidative and anti-inflammatory properties, which are mainly due to the presence of polyphenols. The aim of the present study was to evaluate the antioxidant and anti-inflammatory effects of almond skin extract (ASE) obtained from the Sicilian cultivar “Fascionello” and to evaluate the possible mechanisms of action using an in vitro model of human monocytic U937 cells as well as an in vivo model of carrageenan (CAR)-induced paw edema. The in vitro studies demonstrated that pretreatment with ASE inhibited the formation of ROS and apoptosis. The in vivo studies showed that ASE restored the CAR-induced tissue changes; restored the activity of endogenous antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione; and decreased neutrophil infiltration, lipid peroxidation, and the release of proinflammatory mediators. The anti-inflammatory and antioxidant effects of ASE could be associated with the inhibition of the pro-inflammatory nuclear NF-κB and the activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) antioxidant pathways. In conclusion, almond skin could reduce the levels of inflammation and oxidative stress and could be beneficial in the treatment of several disorders.

Motor skill learning relies on the plasticity of the primary motor cortex as task acquisition drives cortical motor network remodeling. Large-scale cortical remodeling of evoked motor outputs occurs during the learning of corticospinal-dependent prehension behavior, but not simple, non-dexterous tasks. Here we determine the response of corticospinal neurons to two distinct motor training paradigms and assess the role of corticospinal neurons in the execution of a task requiring precise modulation of forelimb movement and one that does not. In vivo calcium imaging in mice revealed temporal coding of corticospinal activity coincident with the development of precise prehension movements, but not more simplistic movement patterns. Transection of the corticospinal tract and optogenetic regulation of corticospinal activity show the necessity for patterned corticospinal network activity in the execution of precise movements but not simplistic ones. Our findings reveal a critical role for corticospinal network modulation in the learning and execution of precise motor movements. Corticospinal activity is temporally coded with precise movements in mice. Here the authors investigate the role of corticospinal neuron activity in motor cortex during the learning of either a precise or imprecise task.

Background Very Low-Calorie Ketogenic Diet (VLCKD) is currently a promising approach for the treatment of obesity. However, little is known about the side effects since most of the studies reporting them were carried out in normal weight subjects following Ketogenic Diet for other purposes than obesity. Thus, the aims of the study were: (1) to investigate the safety of VLCKD in subjects with obesity; (2) if VLCKD-related side effects could have an impact on its efficacy. Methods In this prospective study we consecutively enrolled 106 subjects with obesity (12 males and 94 females, BMI 34.98 ± 5.43 kg/m 2 ) that underwent to VLCKD. In all subjects we recorded side effects at the end of ketogenic phase and assessed anthropometric parameters at the baseline and at the end of ketogenic phase. In a subgroup of 25 subjects, we also assessed biochemical parameters. Results No serious side effects occurred in our population and those that did occur were clinically mild and did not lead to discontinuation of the dietary protocol as they could be easily managed by healthcare professionals or often resolved spontaneously. Nine (8.5%) subjects stopped VLCKD before the end of the protocol for the following reasons: 2 (1.9%) due to palatability and 7 (6.1%) due to excessive costs. Finally, there were no differences in terms of weight loss percentage (13.5 ± 10.9% vs 18.2 ± 8.9%; p = 0.318) in subjects that developed side effects and subjects that did not developed side effects. Conclusion Our study demonstrated that VLCKD is a promising, safe and effective therapeutic tool for people with obesity. Despite common misgivings, side effects are mild, transient and can be prevented and managed by adhering to the appropriate indications and contraindications for VLCKD, following well-organized and standardized protocols and performing adequate clinical and laboratory monitoring.

Objective The growth in gray divorce raises new questions about the marital dissolution process experienced by older adults. Our goal was to assess patterns of reconciliation among couples following marital separation, treating forming a union with a new partner as a competing risk. Background Repartnering after a gray divorce is common, particularly among men. However, the extent to which older adults reconcile with their spouses is unknown. In line with the few prior studies on marital reconciliation among younger people, we anticipated that spouses with fewer resources and more marital‐specific capital would be more likely to reconcile. Method Using the 1998–2018 Health and Retirement Study, we tracked women and men who experienced a marital separation after age 50 to evaluate their propensities to reconcile with their spouse versus form a coresidential union (i.e., cohabitation or remarriage) with a new partner relative to remaining separated. Results Roughly 7% of women and 11% of men reconciled with their spouses, whereas 12% of women and 26% of men instead formed unions with a new partner within 10 years of marital separation. We expected that having fewer resources and greater relationship‐specific investments would encourage reconciliation, but results were mixed for women and men alike. Resources did tend to be positively associated with repartnering, particularly for men. Conclusion Our study contributes to the emerging research on repartnering after late‐life divorce as well as the limited literature on marital reconciliation by underscoring the utility of examining both reconciliation and repartnering as potential outcomes following marital separation.

The cytotoxic effects of topoisomerase I inhibitors such as camptothecin can be modulated by replication fork reversal, in a process that requires Poly(ADP-ribose) polymerase (PARP) activity. Here human RECQ1 helicase is shown to restore such regressed replication forks, whereas PARP1 activity restrains this RECQ1 function. Topoisomerase I (TOP1) inhibitors are an important class of anticancer drugs. The cytotoxicity of TOP1 inhibitors can be modulated by replication fork reversal through a process that requires poly(ADP-ribose) polymerase (PARP) activity. Whether regressed forks can efficiently restart and what factors are required to restart fork progression after fork reversal are still unknown. We have combined biochemical and EM approaches with single-molecule DNA fiber analysis to identify a key role for human RECQ1 helicase in replication fork restart after TOP1 inhibition that is not shared by other human RecQ proteins. We show that the poly(ADP-ribosyl)ation activity of PARP1 stabilizes forks in the regressed state by limiting their restart by RECQ1. These studies provide new mechanistic insights into the roles of RECQ1 and PARP in DNA replication and offer molecular perspectives to potentiate chemotherapeutic regimens based on TOP1 inhibition.

Purpose The purpose of this paper is to investigate the use of trade credit in a sample of small and medium enterprises in Europe, before and after the outbreak of the subprime financial crisis and the sovereign debt crisis (2006-2013). This study aims to verify whether trade credit is an alternative source of funding compared to other sources of financing. In addition, it tests whether firms that grant extended payment terms to their customers demand delayed accounts payable terms from their suppliers. Design/methodology/approach The empirical analysis is conducted on a sample of European SMEs that were observed over the period immediately before and after the outbreak of the subprime crisis (2008) and the sovereign debt crisis (2010-2011). A panel data analysis is conducted using the generalized method of moment. Findings The results suggest that SMEs with a high probability of insolvency use trade credit more extensively. Distressed and weaker SMEs are less able to match accounts receivable to accounts payable. Finally, the evidence suggests that during the financial crises, the substitution hypothesis is weakened and liquidity shocks are propagated through trade credit channels. Originality/value This study contributes to the extant literature as very few studies have analyzed intercompany financing for European SMEs during periods of financial crisis. The results suggest that supporting trade credit channels, through timely injections of liquidity to companies, could reduce the impact of both financial and intercompany credit crunch on SMEs.

Low physical activity (PA) measured by accelerometers and low heart rate variability (HRV) measured from short-term ECG recordings are associated with worse cognitive function. Wearable long-term ECG monitors are now widely used, and some devices also include an accelerometer. The objective of this study was to evaluate whether PA or HRV measured from long-term ECG monitors was associated with cognitive function among older adults. A total of 1590 ARIC participants had free-living PA and HRV measured over 14 days using the Zio® XT Patch [aged 72–94 years, 58% female, 32% Black]. Cognitive function was measured by cognitive factor scores and adjudicated dementia or mild cognitive impairment (MCI) status. Adjusted linear or multinomial regression models examined whether higher PA or higher HRV was cross-sectionally associated with higher factor scores or lower odds of MCI/dementia. Each 1-unit increase in the total amount of PA was associated with higher global cognition (β = 0.30, 95% CI: 0.16–0.44) and executive function scores (β = 0.38, 95% CI: 0.22–0.53) and lower odds of MCI (OR = 0.38, 95% CI: 0.22–0.67) or dementia (OR = 0.25, 95% CI: 0.08–0.74). HRV (i.e., SDNN and rMSSD) was not associated with cognitive function. More research is needed to define the role of wearable ECG monitors as a tool for digital phenotyping of dementia.

From July 2022, a novel Echovirus 11 (E11) variant has been associated with severe neonatal infections and liver failure. Currently, there are no vaccines or antiviral options for the targeted treatment of non-polio enterovirus (EV) infections; therefore, anti-EV drugs are urgently needed. In this study, the putative anti-E11 activity of two isoxzoline-carbocyclic monophosphate nucleotides (4a and 4b) was evaluated in vitro by cytopathic effect (CPE) reduction in VERO 76 cells and qRT-PCR. Treatment with nucleotide 4a at 25 and 50 μM successfully diminished the CPE caused by E11 by 90% and 75%, respectively, and induced a reduction in viral RNA in the supernatant by 72% and 89%. In contrast, the treatment with 25 and 50 μM of 4b caused a minor inhibition of CPE (58 and 38%), and no significant E11 RNA level changes were observed. A time course viral progeny production assay was performed to assess the inhibitory effect of nucleotide 4a on E11 infection progression. Compared to the control, the treated group showed a significant drop in viral RNA levels, with reductions of 43% at 10 h, 65% at 24 h, and 96% at 48 h post-infection. The results showed the extensive antiviral properties of the monophosphate nucleotide 4a in vitro. Moreover, a retrospective molecular docking study strongly supports that nucleotide 4a is an RdRp inhibitor capable of decreasing E11 genome replication and virus particle formation in VERO 76 cells.

INTRODUCTION Evidence is needed to evaluate whether low vitamin B12 from mid‐ to late life, either alone or in the presence of elevated folate, is associated with cognitive decline. METHODS Participants from the Framingham Heart Study without baseline dementia who had ≥ 2 measures of a three‐component vitamin B12 indicator (3cB12) and neuropsychological factor scores were included (n = 1994; mean age: 60 years). Adjusted linear mixed effects models estimated annual changes in each factor score between 3cB12 quartiles. Interaction by folate status was also evaluated. RESULTS Participants in the highest 3cB12 quartile had slower declines in memory, executive function, and language compared to the lowest quartile (memory: β = 0.0071, 95% confidence interval [CI] = 0.003–0.01; executive function: β = 0.0056, 95% CI = 0.0009–0.01; and language: β = 0.0090, 95% CI = 0.004–0.01). Findings were largely robust by folate status (elevated: ≥ 20 ng/mL; non‐elevated: 6–19 ng/mL). DISCUSSION Improving B12 status in dementia‐free older adults may help mitigate cognitive decline into later life. Highlights Higher vitamin B12 status is associated with slower annual cognitive decline. Higher B12 was linked with 0.05 to 0.09 standard deviation less cognitive decline over 10 years. B12 and memory findings are robust for elevated, not non‐elevated, folate status.