A photoredox-catalyzed procedure for the iodoperfluoroalkylation of styrenes and phenylacetylenes using readily available copper phenanthroline catalyst is reported. In contrast to commonly employed ...Ru(bpy)3Cl2, Ru(phen)3Cl2 or fac-Ir(ppy)3, Cu(dap)2Cl is capable to convert styrenes to the corresponding perfluoroalkyl tagged ethylbenzenes, pointing toward an additional role of the copper catalyst beyond photoinduced electron transfer. An inner sphere catalytic cycle involving Cu(III) intermediates or ligand abstraction from a CuI+ intermediate is proposed.
Eukaryotic cells express transcription factor (TF) paralogues that bind to nearly identical DNA sequences in vitro but bind at different genomic loci and perform different functions in vivo. ...Predicting how 2 paralogous TFs bind in vivo using DNA sequence alone is an important open problem. Here, we analyzed 2 yeast bHLH TFs, Cbf1p and Tye7p, which have highly similar binding preferences in vitro, yet bind at almost completely nonoverlapping target loci in vivo. We dissected the determinants of specificity for these 2 proteins by making a number of chimeric TFs in which we swapped different domains of Cbf1p and Tye7p and determined the effects on in vivo binding and cellular function. From these experiments, we learned that the Cbf1p dimer achieves its specificity by binding cooperatively with other Cbf1p dimers bound nearby. In contrast, we found that Tye7p achieves its specificity by binding cooperatively with 3 other DNA-binding proteins, Gcr1p, Gcr2p, and Rap1p. Remarkably, most promoters (63%) that are bound by Tye7p do not contain a consensus Tye7p binding site. Using this information, we were able to build simple models to accurately discriminate bound and unbound genomic loci for both Cbf1p and Tye7p. We then successfully reprogrammed the human bHLH NPAS2 to bind Cbf1p in vivo targets and a Tye7p target intergenic region to be bound by Cbf1p. These results demonstrate that the genome-wide binding targets of paralogous TFs can be discriminated using sequence information, and provide lessons about TF specificity that can be applied across the phylogenetic tree.
Objectives
Patients with olfactory dysfunction (OD) frequently report symptoms of depression. The objective of this study was to determine how clinical characteristics and olfactory‐related quality ...of life (QoL) measures associate with the likelihood for major depressive disorders (MDDs).
Methods
A total of 192 OD patients were included. Olfactory function was measured using all three subtests of the Sniffn' Sticks test. Olfactory‐related quality of life (QoL) was evaluated using the Questionnaires of Olfactory Dysfunction (QOD)‐negative (NS) and ‐positive statement (PS). The likelihood for MDD was assessed using the Patients Health Questionnaire‐2 (PHQ‐2). Demographics and disease‐specific variables (etiology and duration of OD) were collected. Univariate and multivariable analyses were used to associate disease‐specific variables and the QOD with the outcome of the PHQ‐2. Additionally, the predictive ability of the QOD‐NS to predict depressive symptoms was calculated.
Results
In univariate analysis, COVID‐19 related smell loss, the QOD‐NS, and the QOD‐PS were significantly associated with the PHQ‐2. In multivariable analyses adjusting for QoL measures, the QOD‐NS (ß = 0.532, p < 0.001) and sinonasal OD (compared with postinfectious OD) were significantly associated with the PHQ‐2 (ß = 0.146, p = 0.047). When omitting QoL measures from multivariable analyses, only COVID‐19 related OD (compared with postinfectious OD) was significantly associated with the PHQ‐2 (ß = 0.287, p = 0.009). A QOD‐NS score > 20.5 had 70.13% sensitivity and 76.32% specificity for detecting symptoms of depression.
Conclusion
Our results suggest that COVID‐19 related OD might be associated with a higher likelihood for MDD. Furthermore, we showed that the QOD‐NS score might be helpful to predict symptoms of depression in OD patients.
Level of Evidence
4 Laryngoscope, 132:1829–1834, 2022
•We investigated effects of temporal predictability and auditory-motor synchronization (AMS) on the P300 in PD patients.•RAS facilitates attentional processing in PD patients.•The effect of AMS on ...temporal predictability is absent in PD patients.
Rhythmic auditory stimulation (RAS) may compensate dysfunctions of the basal ganglia (BG), involved with intrinsic evaluation of temporal intervals and action initiation or continuation. In the cognitive domain, RAS containing periodically presented tones facilitates young healthy participants’ attention allocation to anticipated time points, indicated by better performance and larger P300 amplitudes to periodic compared to random stimuli. Additionally, active auditory-motor synchronization (AMS) leads to a more precise temporal encoding of stimuli via embodied timing encoding than stimulus presentation adapted to the participants’ actual movements.
Here we investigated the effect of RAS and AMS in Parkinson’s disease (PD). 23 PD patients and 23 healthy age-matched controls underwent an auditory oddball task. We manipulated the timing (periodic/random/adaptive) and setting (pedaling/sitting still) of stimulation. While patients elicited a general timing effect, i.e., larger P300 amplitudes for periodic versus random tones for both, sitting and pedaling conditions, controls showed a timing effect only for the sitting but not for the pedaling condition. However, a correlation between P300 amplitudes and motor variability in the periodic pedaling condition was obtained in control participants only. We conclude that RAS facilitates attentional processing of temporally predictable external events in PD patients as well as healthy controls, but embodied timing encoding via body movement does not affect stimulus processing due to BG impairment in patients. Moreover, even with intact embodied timing encoding, such as healthy elderly, the effect of AMS depends on the degree of movement synchronization performance, which is very low in the current study.
Cells employ a variety of strategies to maintain proteome homeostasis. Beginning during protein biogenesis, the translation machinery and a number of molecular chaperones promote correct de novo ...folding of nascent proteins even before synthesis is complete. Another set of molecular chaperones helps to maintain proteins in their functional, native state. Polypeptides that are no longer needed or pose a threat to the cell, such as misfolded proteins and aggregates, are removed in an efficient and timely fashion by ATP-dependent proteases. In this review, we describe how applications of single-molecule manipulation methods, in particular optical tweezers, are shedding new light on the molecular mechanisms of quality control during the life cycles of proteins.
Age is a well‐known risk factor in trauma patients. The aim of the present study was to define the age‐dependent cut‐off for increasing mortality in multiple injured patients. Pre‐existing medical ...conditions in older age and impaired age‐dependent physiologic reserve contributing to a worse outcome in multiple injured elderly patients are discussed as reasons for increased mortality. A retrospective clinical study of a statewide trauma data set from 1993 through 2000 included 5375 patients with an Injury Severity Score (ISS) ≥ 16 who were stratified by age. The ISS and Abbreviated Injury Score (AIS) quantified the injury severity. Outcome measures were mortality, shock, multiple organ failure, and severe head injury. Mortality in this series increased beginning at age 56 years, and that increase was independent of the ISS. The mortality rate increased from 7.3% (patients 46–55 years of age) to 13.0% (patients ages 56–65 years) in patients with ISS 16–24; from 23.8% to 32.1% in those with ISS 25–50; and from 62.2% to 82.1% in those with ISS 51–75 (P ≤ 0.05). Severe traumatic brain injury (sTBI) was the most frequent cause of death, with a significant peak in patients older than 75 years. The incidence of lethal multiple organ failure increased significantly beginning at age 56 years (P ≤ 0.05), but it showed no further increase in patients aged 76 years or older. In contrast, the incidence of lethal shock showed a significant increase from age 76 years (P ≤ 0.05), but not at age 56 years. However, from age 56 years, mortality increased significantly in patients who sustained multiple trauma—an increase that was independent of trauma severity.
Background
The objective of this study was to determine how clinical characteristics and validated quality of life (QoL)-measures are associated with eating behavior in patients with olfactory ...dysfunction (OD).
Methods
For this cross-sectional study, 150 OD patients of different causes were retrospectively recruited. Olfactory function was measured using the Sniffin’ Sticks (TDI), while olfactory-related QoL was evaluated with the Questionnaire of OD negative and positive statements (QOD-NS and QOD-PS). The importance of olfaction was measured using the Importance of Olfaction Questionnaire (IOQ). The Dutch Eating Behavior Questionnaire (DEBQ) assessed eating behavior based on emotional, external, and restrained eating. Associations were sought between eating behavior metrics (as dependent variables) with clinical characteristics and olfactory-related outcome measures.
Results
Emotional, external, and restrained eating behavior deviating from normative standards were reported in 54%, 71.3%, and 68% of patients, respectively. Multivariate regression modeling revealed that emotional eating was associated with age (ß = –0.227,
p
= 0.032), the body mass index (BMI, ß = 0.253,
p
= 0.005), the TDI (ß = 0.190,
p
= 0.046), and the QOD-NS (ß = 0.203,
p
= 0.049). External eating was associated with OD duration (ß = 0.291,
p
= 0.005), the TDI (ß = 0.225,
p
= 0.018), the QOD-PS (ß = –0.282,
p
= 0.008), and the IOQ (ß = 0.277,
p
= 0.004). Restrained eating was associated with age (ß = 0.216,
p
= 0.033), the BMI (ß = 0.257,
p
= 0.003), male gender (ß = –0.263,
p
= 0.002), and the IOQ (ß = 0.332,
p
< 0.001).
Conclusion
Clinical characteristics and olfactory outcome measures differentially impact eating styles in OD patients. Our study’s results highlight the importance of considering unfavorable changes in eating behavior during clinical counseling.
Previous studies have shown that the effect of temporal predictability of presented stimuli on attention allocation is enhanced by auditory-motor synchronization (AMS). The present P300 event-related ...potential study (N=20) investigated whether this enhancement depends on the process of actively synchronizing one's motor output with the acoustic input or whether a passive state of auditory-motor synchrony elicits the same effect. Participants silently counted frequency deviants in sequences of pure tones either during a physically inactive control condition or while pedaling on a cycling ergometer. Tones were presented either at fixed or variable intervals. In addition to the pedaling conditions with fixed or variable stimulation, there was a third condition in which stimuli were adaptively presented in sync with the participants' spontaneous pedaling. We replicated the P300 enhancement for fixed versus variable stimulation and the amplification of this effect by AMS. Synchronization performance correlated positively with P300 amplitude in the fixed stimulation condition. Most interestingly, P300 amplitude was significantly reduced for the passive synchronization condition by adaptive stimulus presentation as compared to the fixed stimulation condition. For the first time we thus provide evidence that it is not the passive state of (even perfect) auditory-motor synchrony that facilitates attention allocation during AMS but rather the active process of synchronizing one's movements with external stimuli.
Standard guidelines recommend selective serotonin reuptake inhibitors as first-line antidepressants for adults with major depressive disorder, but success is limited and patients who fail to benefit ...are often switched to non–selective serotonin reuptake inhibitor agents. This study investigated whether brain- and behavior-based markers of reward processing might be associated with response to bupropion after sertraline nonresponse.
In a two-stage, double-blinded clinical trial, 296 participants were randomized to receive 8 weeks of sertraline or placebo in stage 1. Individuals who responded continued on another 8-week course of the same intervention in stage 2, while sertraline and placebo nonresponders crossed over to bupropion and sertraline, respectively. Data from 241 participants were analyzed. The stage 2 sample comprised 87 patients with major depressive disorder who switched medication and 38 healthy control subjects. A total of 116 participants with major depressive disorder treated with sertraline in stage 1 served as an independent replication sample. The probabilistic reward task and resting-state functional magnetic resonance imaging were administered at baseline.
Greater pretreatment reward sensitivity and higher resting-state functional connectivity between bilateral nucleus accumbens and rostral anterior cingulate cortex were associated with positive response to bupropion but not sertraline. Null findings for sertraline were replicated in the stage 1 sample.
Pretreatment reward sensitivity and frontostriatal connectivity may identify patients likely to benefit from bupropion following selective serotonin reuptake inhibitor failures. Results call for a prospective replication based on these biomarkers to advance clinical care.
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