When designing and analyzing genetic circuits, researchers are often interested in the probability of the system reaching a given state within a certain amount of time. Usually, this involves ...simulating the system to produce some time series data and analyzing this data to discern the state probabilities. However, as the complexity of models of genetic circuits grow, it becomes more difficult for researchers to reason about the different states by looking only at time series simulation results of the models. To address this problem, this paper employs the use of stochastic model checking, a method for determining the likelihood that certain events occur in a system, with continuous stochastic logic (CSL) properties to obtain similar results. This goal is accomplished by the introduction of a methodology for converting a genetic circuit model (GCM) into a continuous-time Markov chain (CTMC). This CTMC is analyzed using transient Markov chain analysis to determine the likelihood that the circuit satisfies a given CSL property in a finite amount of time. This paper illustrates a use of this methodology to determine the likelihood of failure in a genetic toggle switch and compares these results to stochastic simulation-based analysis of this same circuit. Our results show that this method results in a substantial speedup as compared with conventional simulation-based approaches.
Genetic design automation Myers, Chris J.; Barker, Nathan; Kuwahara, Hiroyuki ...
2009 IEEE/ACM International Conference on Computer-Aided Design - Digest of Technical Papers,
11/2009
Conference Proceeding
Electronic design automation (EDA) tools have facilitated the design of ever more complex integrated circuits each year. Synthetic biology would also benefit from the development of genetic design ...automation (GDA) tools. Existing GDA tools require biologists to design genetic circuits at the molecular level, roughly equivalent to designing electronic circuits at the layout level. Analysis of these circuits is also performed at this very low level. This paper presents the background and issues involved in the development of such a GDA tool for modeling, analysis, and design.
The 2010 cholera epidemic in Haiti was thought to have ended in 2019, and the Prime Minister of Haiti declared the country cholera-free in February 2022. On September 25, 2022, cholera cases were ...again identified in Port-au-Prince. We compared genomic data from 42 clinical Vibrio cholerae strains from 2022 with data from 327 other strains from Haiti and 1,824 strains collected worldwide. The 2022 isolates were homogeneous and closely related to clinical and environmental strains circulating in Haiti during 2012–2019. Bayesian hypothesis testing indicated that the 2022 clinical isolates shared their most recent common ancestor with an environmental lineage circulating in Haiti in July 2018. Our findings strongly suggest that toxigenic V. cholerae O1 can persist for years in aquatic environmental reservoirs and ignite new outbreaks. These results highlight the urgent need for improved public health infrastructure and possible periodic vaccination campaigns to maintain population immunity against V. cholerae.
Purpose
Speech is characterized by dynamic acoustic cues that must be encoded by the auditory periphery, auditory nerve, and brainstem before they can be represented in the auditory cortex. The ...fidelity of these cues in the brainstem can be assessed with the frequency-following response (FFR). Data obtained from older adults—with normal or impaired hearing—were compared with previous results obtained from normal-hearing younger adults to evaluate the effects of age and hearing loss on the fidelity of FFRs to tone glides.
Method
A signal detection approach was used to model a threshold criterion to distinguish the FFR from baseline neural activity. The response strength and temporal coherence of the FFR to tone glides varying in direction (rising or falling) and extent (
1
3
,
2
3
, or 1 octave) were assessed by signal-to-noise ratio (SNR) and stimulus–response correlation coefficient (SRCC) in older adults with normal hearing and with hearing loss.
Results
Significant group mean differences in both SNR and SRCC were noted—with poorer responses more frequently observed with increased age and hearing loss—but with considerable response variability among individuals within each group and substantial overlap among group distributions.
Conclusion
The overall distribution of FFRs across listeners and stimulus conditions suggests that observed group differences associated with age and hearing loss are influenced by a decreased likelihood of older and hearing-impaired individuals having a detectable FFR response and by lower average FFR fidelity among those older and hearing-impaired individuals who do have a detectable response.
Following traumatic brain injury (TBI), reactive oxygen species (ROS) are released in excess, causing oxidative stress, carbonyl stress, and cell death, which induce the additional release of ROS. ...The limited accumulation and retention of small molecule antioxidants commonly used in clinical trials likely limit the target engagement and therapeutic effect in reducing secondary injury. Small molecule drugs also need to be administered every several hours to maintain bioavailability in the brain. Therefore, there is a need for a burst and sustained release system with high accumulation and retention in the injured brain. Here, we utilized Pro-NP™ with a size of 200 nm, which was designed to have a burst and sustained release of encapsulated antioxidants, Cu/Zn superoxide dismutase (SOD1) and catalase (CAT), to scavenge ROS for >24 h post-injection. Here, we utilized a controlled cortical impact (CCI) mouse model of TBI and found the accumulation of Pro-NP™ in the brain lesion was highest when injected immediately after injury, with a reduction in the accumulation with delayed administration of 1 h or more post-injury. Pro-NP™ treatment with 9000 U/kg SOD1 and 9800 U/kg CAT gave the highest reduction in ROS in both male and female mice. We found that Pro-NP™ treatment was effective in reducing carbonyl stress and necrosis at 1 d post-injury in the contralateral hemisphere in male mice, which showed a similar trend to untreated female mice. Although we found that male and female mice similarly benefit from Pro-NP™ treatment in reducing ROS levels 4 h post-injury, Pro-NP™ treatment did not significantly affect markers of post-traumatic oxidative stress in female CCI mice as compared to male CCI mice. These findings of protection by Pro-NP™ in male mice did not extend to 7 d post-injury, which suggests subsequent treatments with Pro-NP™ may be needed to afford protection into the chronic phase of injury. Overall, these different treatment effects of Pro-NP™ between male and female mice suggest important sex-based differences in response to antioxidant nanoparticle delivery and that there may exist a maximal benefit from local antioxidant activity in injured brain.
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•Pro-NP™ is a nanoparticle comprising antioxidant enzymes with burst and sustained release.•Pro-NP™ showed higher accumulation in the brain lesion when injected immediately after injury.•Pro-NP™ scavenged ROS following injury in a controlled cortical impact mouse model of TBI.•Pro-NP™ reduced carbonyl stress in the subacute, but not chronic, phase of injury.•Pro-NP™ delayed the spread of necrosis into the contralateral hemisphere in males but not females.
ObjectiveTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). We report the largest integrated safety analysis of tofacitinib, as of March 2017, using ...data from phase I, II, III, IIIb/IV and long-term extension studies in adult patients with RA.MethodsData were pooled for patients with RA who received ≥1 tofacitinib dose. Incidence rates (IRs; patients with events/100 patient-years PY; 95% CIs) of first-time occurrences were obtained for adverse events (AEs) of interest.Results7061 patients received tofacitinib (total exposure: 22 875 PY; median range exposure: 3.1 0 to 9.6 years). IRs (95% CI) for serious AEs, serious infections, herpes zoster (all), opportunistic infections (excluding tuberculosis TB) and TB were 9.0 (8.6 to 9.4), 2.5 (2.3 to 2.7), 3.6 (3.4 to 3.9), 0.4 (0.3 to 0.5) and 0.2 (0.1 to 0.2), respectively. IRs (95% CI) for malignancies (excluding non-melanoma skin cancer NMSC), NMSC and lymphomas were 0.8 (0.7 to 0.9), 0.6 (0.5 to 0.7) and 0.1 (0.0 to 0.1), respectively. IRs (95% CI) for gastrointestinal perforations, deep vein thrombosis, pulmonary embolism, venous thromboembolism, arterial thromboembolism and major adverse cardiovascular events were 0.1 (0.1 to 0.2), 0.2 (0.1 to 0.2), 0.1 (0.1 to 0.2), 0.3 (0.2 to 0.3), 0.4 (0.3 to 0.5) and 0.4 (0.3 to 0.5), respectively. IR (95% CI) for mortality was 0.3 (0.2 to 0.3). IRs generally remained consistent across 6-month intervals to >78 months.ConclusionThis represents the largest clinical dataset for a JAK inhibitor in RA to date. IRs remained consistent with previous reports from the tofacitinib RA clinical development programme, and stable over time.Trial registration numbersNCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01164579; NCT00976599; NCT01059864; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661.For summary of phase I, phase II, phase III, phase IIIb/IV and LTE studies included in the integrated safety analysis, see online supplemental table 1.
•Temporal coherence of brainstem coding of glimpses is less precise in older adults than younger adults.•Magnitude of the brainstem responses is lower in adults with poorer hearing sensitivity than ...those with better hearing sensitivity.•Shorter duration glimpses are coded less robustly than longer glimpses.•Glimpses are coded less robustly when interrupted by noise than by silence.
Difficulty understanding speech in fluctuating backgrounds is common among older adults. Whereas younger adults are adept at interpreting speech based on brief moments when the signal-to-noise ratio is favorable, older adults use these glimpses of speech less effectively. Age-related declines in auditory brainstem function may degrade the fidelity of speech cues in fluctuating noise for older adults, such that brief glimpses of speech interrupted by noise segments are not faithfully represented in the neural code that reaches the cortex. This hypothesis was tested using electrophysiological recordings of the envelope following response (EFR) elicited by glimpses of speech-like stimuli varying in duration (42, 70, 210 ms) and interrupted by silence or intervening noise. Responses from adults aged 23–73 years indicated that both age and hearing sensitivity were associated with EFR temporal coherence and response magnitude. Age was better than hearing sensitivity for predicting temporal coherence, whereas hearing sensitivity was better than age for predicting response magnitude. Poorer-fidelity EFRs were observed with shorter glimpses and with the addition of intervening noise. However, losses of fidelity with glimpse duration and noise were not associated with participant age or hearing sensitivity. These results suggest that the EFR is sensitive to factors commonly associated with glimpsing but do not entirely account for age-related changes in speech recognition in fluctuating backgrounds.
Understanding speech in background noise is often more difficult for individuals who are older and have hearing impairment than for younger, normal-hearing individuals. In fact, speech-understanding ...abilities among older individuals with hearing impairment varies greatly. Researchers have hypothesized that some of that variability can be explained by how the brain encodes speech signals in the presence of noise, and that brain measures may be useful for predicting behavioral performance in difficult-to-test patients. In a series of experiments, we have explored the effects of age and hearing impairment in both brain and behavioral domains with the goal of using brain measures to improve our understanding of speech-in-noise difficulties. The behavioral measures examined showed effect sizes for hearing impairment that were 6–10 dB larger than the effects of age when tested in steady-state noise, whereas electrophysiological age effects were similar in magnitude to those of hearing impairment. Both age and hearing status influence neural responses to speech as well as speech understanding in background noise. These effects can in turn be modulated by other factors, such as the characteristics of the background noise itself. Finally, the use of electrophysiology to predict performance on receptive speech-in-noise tasks holds promise, demonstrating root-mean-square prediction errors as small as 1–2 dB. An important next step in this field of inquiry is to sample the aging and hearing impairment variables continuously (rather than categorically) – across the whole lifespan and audiogram – to improve effect estimates.
•Listening in noise is unavoidable; common real-world SNRs fall between 0 and 15 dB.•Speech understanding in noise (SNR50) varies widely for hearing-impaired individuals.•Age effects on SNR50 range from 2 to 4 dB; hearing impairment effects range from 2 to 12 dB.•Age and hearing-impairment effects on cortical auditory evoked potentials (CAEPs) are complex.•CAEP-based predictions of behavior within 2 dB of measured SNR50s.
Tofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine ...pharmacovigilance of an ongoing, open-label, blinded-endpoint, tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ≥50 years and with ≥1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within.
This post-hoc analysis used data from separate tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years' exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed.
12 410 tofacitinib-treated patients from the development programmes (RA: n=7964; PsO: n=3663; PsA: n=783) were included. IRs (95% CI) of thromboembolic events among the
average tofacitinib 5 mg and 10 mg twice daily treated patients for RA, respectively, were: DVT (0.17 (0.09-0.27) and 0.15 (0.09-0.22)); PE (0.12 (0.06-0.22) and 0.13 (0.08-0.21)); ATE (0.32 (0.22-0.46) and 0.38 (0.28-0.49)). Among PsO patients, IRs were: DVT (0.06 (0.00-0.36) and 0.06 (0.02-0.15)); PE (0.13 (0.02-0.47) and 0.09 (0.04-0.19)); ATE (0.52 (0.22-1.02) and 0.22 (0.13-0.35)). Among PsA patients, IRs were: DVT (0.00 (0.00-0.28) and 0.13 (0.00-0.70)); PE (0.08 (0.00-0.43) and 0.00 (0.00-0.46)); ATE (0.31 (0.08-0.79) and 0.38 (0.08-1.11)). IRs were similar between tofacitinib doses and generally higher in patients with baseline cardiovascular or VTE risk factors. IRs from the overall Corrona populations and in Corrona RA patients (including tofacitinib-naïve/biologic disease-modifying antirheumatic drug-treated and tofacitinib-treated) with baseline cardiovascular risk factors were similar to IRs observed among the corresponding patients in the tofacitinib development programme. No signals of disproportionate reporting of DVT, PE or ATE with tofacitinib were identified in the FAERS database.
DVT, PE and ATE IRs in the tofacitinib RA, PsO and PsA programmes were similar across tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32-0.87)), versus patients with baseline cardiovascular risk factors treated with tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13-0.41)).
•Complex multi-token oddball paradigms (up to 160 distinct syllables) evoke the auditory P3 waveform.•Increasing complexity resulted in smaller/later P3 peaks and poorer perception.•Presence of ...acoustic background noise resulted in smaller/later N1 and P2 peaks.
We developed and tested a series of novel and increasingly complex multi-token electrophysiology paradigms for evoking the auditory P3 response. The primary goal was to evaluate the degree to which more complex discrimination tasks and listening environments – which are more likely to engage the types of neural processing used in real-world speech-in-noise situations – could still evoke a robust P3 response. If so, this opens the possibility of such a paradigm making up part of the toolkit for a brain-behavioral approach to improve understanding of speech processing. Fourteen normal-hearing adults were tested using four different auditory paradigms consisting of 5 tokens, 20 tokens, 160 tokens, or 160 tokens with background babble. Stimuli were naturally produced consonant-vowel tokens varying in consonant (/d/, /b/, /g/, /v/, and /ð/; all conditions), vowel (/ɑ/, /u/, /i/, and /ɜr/; 20- and 160-token conditions), and talker (4 female, 4 male; 160-token conditions only). All four conditions evoked robust neural responses, and all peaks had visible differences across conditions. However, the more exogenous auditory evoked potentials (N1 and P2) were primarily affected not by overall complexity but by the presence of background noise specifically, the presence of which was associated with longer latencies and smaller amplitudes. The more endogenous P3 peak, as well as the paradigm behavioral measures, revealed a more graded effect of overall paradigm complexity, rather than the background noise dominating the other factors. Our conclusion was that all four complex auditory paradigms, including the most complex (160 distinct consonant-vowel tokens presented in background babble), are viable means of stimulating N1-P2 and N2b-P3 auditory evoked responses and may therefore be useful in brain-behavioral approaches to understanding speech perception in noise.
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