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Development can proceed in “fits and starts”, with rapid transitions between cell states involving concerted transcriptome-wide changes in gene expression. However, it is not clear how these transitions are regulated in complex cell populations, in which cells receive multiple inputs. It is also not clear to what extent these rapid transitions represent developmental commitment. Here we address these issues usingDictyosteliumcells undergoing development in their physiological niche. A continuous single cell transcriptomics time series reveals a sharp “jump” in global gene expression marking functionally different cell states. By simultaneously live imaging the physiological dynamics of transcription and signalling over millimetre length scales, we show that the jump coincides with the onset of collective oscillations of cAMP, the positive feedback signal for multicellular development. Different jump genes respond to distinct dynamic features of signalling. The late gene expression changes of the jump are almost completely dependent on cAMP. In contrast, transcript changes at the onset of the jump require additional input. The spatial boundary marking the jump divides cells separated by only a few minutes of developmental time, with cells missing a jump then waiting several hours for the onset of the next wave of cAMP oscillations. This timing variability contrasts the prevailing developmental paradigm of a timed synchronous process and is associated with substantial pre-jump transcriptome variability. The coupling of collective signalling with gene expression is a potentially powerful strategy to drive robust cell state transitions in heterogeneous signalling environments. Based on the context of the jump, we also conclude that sharp gene expression transitions may not be sufficient for commitment.

Cannabis is the most used illicit drug in the United States. With many states passing legislation to permit its recreational use, there is concern that cannabis use among adolescents could increase dramatically in the coming years. Historically, it has been difficult to model real-world cannabis use to investigate the causal relationship between cannabis use in adolescence and behavioral and neurobiological effects in adulthood. To this end, we used a novel volitional vapor administration model to investigate long-term effects of cannabis use during adolescence on the medial prefrontal cortex (mPFC) and mPFC-dependent behaviors in male and female rats. Adolescent (35-55 day old) female rats had significantly higher rates of responding for vaporized Δ9-tetrahydrocannabinol (THC)-dominant cannabis extract (CANTHC) compared to adolescent males. In adulthood (70-110 day old), female, but not male, CANTHCrats also took more trials to reach criterion and made more regressive errors in an automated attentional set-shifting task compared to vehicle rats. Similar set-shifting deficits were observed in males when they were exposed to a non-contingent CANTHCvapor dosing regimen that approximated CANTHCself-administration rates in females. No differences were observed in effort-based decision making in either sex. In the mPFC, female (but not male) CANTHCrats displayed more reactive microglia with no significant changes in myelin basic protein expression or dendritic spine density. Together, these data reveal important sex differences in rates of cannabis vapor self-administration in adolescence that confer enduring alterations to mPFC structure and function. Importantly, female-specific deficits in behavioral flexibility appear to be driven by elevated rates of CANTHCself-administration as opposed to a sex difference in the effects of CANTHCvaporper se.

Nonminimum carbonic acid clusters provide excitation energies and oscillator strengths in line with observed ice-phase UV absorptions better than traditional optimized minima. This equation-of-motion coupled cluster quantum chemical analysis on carbonic acid monomers and dimers shows that shifts to the dihedral angle for the internal heavy atoms in the monomer produce UV electronic excitations close to 200 nm with oscillator strengths that would produce observable features. This τ(OCOO) dihedral is actually a relatively floppy motion unlike what is often expected for sp

The recent detection of ethynyl-functionalized cyclopropenylidene (c-C3HC2H) has initiated the search for other functional forms of cyclopropenylidene (c-C3H2) in space. There is existing gas-phase rotational spectroscopic data for cyano-cyclopropenylidene (c-C3HCN), but the present work provides the first anharmonic vibrational spectral data for that molecule, as well as the first full set of both rotational and vibrational spectroscopic data for fluoro- and chloro-cyclopropenylidenes (c-C3HF and c-C3HCl). All three molecules have fundamental vibrational frequencies with substantial infrared intensities. Namely, c-C3HCN has a moderately intense fundamental frequency at 1244.4 cm-1, while c-C3HF has two large intensity modes at 1765.4 and 1125.3 cm-1 and c-C3HCl again has two large intensity modes at 1692.0 and 1062.5 cm-1. All of these frequencies are well within the spectral range covered by the high-resolution EXES instrument on NASA's Stratospheric Observatory for Infrared Astronomy (SOFIA). Further, all three molecules have dipole moments of around 3.0 D in line with c-C3H2, enabling them to be observed by pure rotational spectroscopy, as well. Thus, the rovibrational spectral data presented herein should assist with future laboratory studies of functionalized cyclopropenylidenes and may lead to their interstellar or circumstellar detection.

Background and aim Mortality of alcohol-related liver disease (ArLD) is increasing, and liver fibrosis stage is the best mortality predictor. Non-invasive tests (NITs) are increasingly used to detect fibrosis, but their value as prognostic tests in chronic liver disease, and in particular in ArLD, is less well recognized. We aimed to describe the prognostic performance of four widely used NITs (Fibrosis 4 test [FIB4], Enhanced Liver Fibrosis [ELF] test, FibroScan, and FibroTest) in ArLD. Methods Applying systematic review methodology, we searched four databases from inception to May 2020. Inclusion/exclusion criteria were applied to search using Medical Subject Heading terms and keywords. The first and second reviewers independently screened results, extracted data, and performed risk-of-bias assessment using Quality in Prognosis Studies tool. Results Searches produced 25 088 articles. After initial screening, 1020 articles were reviewed independently by both reviewers. Eleven articles remained after screening for eligibility: one on ELF, four on FibroScan, four on FIB4, one on FIB4 + FibroScan, and one on FibroTest + FIB4. Area under the receiver operating characteristic curves for outcome prediction ranged from 0.65 to 0.76 for FibroScan, 0.64 to 0.83 for FIB4, 0.69 to 0.79 for FibroTest, and 0.72 to 0.85 for ELF. Studies scored low-moderate risk of bias for most domains but high risk in confounding/statistical reporting domains. The results were heterogeneous for outcomes and reporting, making pooling of data unfeasible. Conclusions This systematic review returned 11 papers, six of which were conference abstracts and one unpublished manuscript. While the heterogeneity of studies precluded direct comparisons of NITs, each NIT performed well in individual studies in predicting prognosis in ArLD (area under the receiver operating characteristic curves >0.7 in each NIT category) and may add value to prognostication in clinical practice.

Aims. The detection of c-C3HC2H and possible future detection of c-C3HCN provide new molecules for reaction chemistry in the dense interstellar medium (ISM) where R-C2H and R-CN species are prevalent. Determination of chemically viable c-C3HC2H and c-C3HCN derivatives and their prominent spectral features can accelerate potential astrophysical detection of this chemical family. This work characterizes three such derivatives: c-C3(C2H)2, c-C3(CN)2, and c-C3(C2H)(CN). Methods. Interstellar reaction pathways of small carbonaceous species are well replicated through quantum chemical means. Highly accurate cc-pVXZ-F12/CCSD(T)-F12 (X = D,T) calculations generate the energetics of chemical formation pathways as well as the basis for quartic force field and second-order vibrational perturbation theory rovibrational analysis of the vibrational frequencies and rotational constants of the molecules under study. Results. The formation of c-C3(C2H)2 is as thermodynamically and, likely, as stepwise favorable as the formation of c-C3HC2H, rendering its detectability to be mostly dependent on the concentrations of the reactants. Both c-C3(C2H)2 and c-C3(C2H)(CN) will be detectable through radioastronomical observation with large dipole moments of 2.84 D and 4.26 D, respectively, while c-C3(CN)2 has an exceedingly small and likely unobservable dipole moment of 0.08 D. The most intense frequency for c-C3(C2H)2 is v2 at 3316.9 cm–1 (3.01 μm), with an intensity of 140 km mol–1. The mixed-substituent molecule c-C3(C2H)(CN) has one frequency with a large intensity, v1, at 3321.0 cm–1 (3.01 μm), with an intensity of 82 km mol–1. The molecule c-C3(CN)2 lacks intense vibrational frequencies within the range that current instrumentation can readily observe. Conclusions. Both c-C3(C2H)2 and c-C3(C2H)(CN) are viable candidates for astrophysical observation, with favorable reaction profiles and spectral data produced herein, but c-C3(CN)2 will not be directly observable through any currently available remote sensing means, even if it forms in large abundances.

From an ongoing multicenter effort toward differentiation of Parkinsonian spectrum disorders (PSD) from other types of neurodegenerative disorders, the sleep biomarker non-rapid-eye-movement sleep with hypertonia (NRH) emerged.This study included in the PSD group patients with dementia with Lewy bodies/Parkinson disease dementia (DLB/PDD = 16), Parkinson disease (PD = 16), and progressive supranuclear palsy (PSP = 13). The non-PSD group included patients with Alzheimer disease dementia (AD = 24), mild cognitive impairment (MCI = 35), and a control group with normal cognition (CG = 61). In-home, multi-night Sleep Profiler studies were conducted in all participants. Automated algorithms detected NRH, characterized by elevated frontopolar electromyographic power. Between-group differences in NRH were evaluated using Logistic regression, Mann-Whitney U and Chi-squared tests.NRH was greater in the PSD group compared to non-PSD (13.9 ± 11.0% vs. 3.1 ± 4.7%, P 0.0001). The threshold NRH≥5% provided the optimal between-group differentiation (AUC = 0.78, P 0.001). NRH was independently associated with the PSD group after controlling for age, sex, and SSRI/SNRI use (P 0.0001). The frequencies of abnormal NRH by subgroup were PSP = 92%, DLB/PDD = 81%, PD = 56%, MCI = 26%, AD = 17%, and CG = 16%. The odds of abnormal NRH in each PSD subgroup ranged from 3.7 to 61.2 compared to each non-PSD subgroup. The night-to-night and test-retest intraclass correlations were excellent (0.78 and 0.84, both P 0.0001).In this pilot study, NRH appeared to be a novel candidate sleep biomarker for PSD-related neurodegeneration. Future studies in larger cohorts are needed to confirm these findings, understand the etiology of NRH magnitude/duration, and determine whether it is an independent prodromal marker for specific neurodegenerative pathologies.

The low-frequency vibrational fundamentals of D2h inorganic oxides are readily modeled by heuristic scaling factors at fractions of the computational cost compared to explicit anharmonic frequency computations. Oxygen and the other elements in the present study are abundant in geochemical environments and have the potential to aggregate into minerals in planet-forming regions or in the remnants of supernovae. Explicit quartic force field computations at the CCSD(T)-F12b/cc-pVTZ-F12 level of theory generate scaling factors that accurately predict the anharmonic frequencies with an average error of less than 1.0 cm-1 for both the metal-oxygen stretching frequencies and the torsion and antisymmetric stretching frequencies. Inclusion of hydrogen motions is less absolutely accurate but is similarly relatively predictive. The fundamental vibrational frequencies for the seven tetra-atomic inorganic oxides examined presently fall below 876 cm-1 and most of the hydrogenated species do as well. Additionally, ν6 for the SiO dimer is shown to have an intensity of 562 km mol-1, with each of the other molecules having one or more frequencies with intensities greater than 80 km mol-1, again with most in the low-frequency infrared range. These intensities and the frequencies computed in the present study should assist in laboratory characterization and potential interstellar or circumstellar observation.

Survival rates for patients following liver transplantation exceed 90% at 12 months and approach 70% at 10 years. Part 1 of this guideline has dealt with all aspects of liver transplantation up to the point of placement on the waiting list. Part 2 explains the organ allocation process, organ donation and organ type and how this influences the choice of recipient. After organ allocation, the transplant surgery and the critical early post-operative period are, of necessity, confined to the liver transplant unit. However, patients will eventually return to their referring secondary care centre with a requirement for ongoing supervision. Part 2 of this guideline concerns three key areas of post liver transplantation care for the non-transplant specialist: (1) overseeing immunosuppression, including interactions and adherence; (2) the transplanted organ and how to initiate investigation of organ dysfunction; and (3) careful oversight of other organ systems, including optimising renal function, cardiovascular health and the psychosocial impact. The crucial significance of this holistic approach becomes more obvious as time passes from the transplant, when patients should expect the responsibility for managing the increasing number of non-liver consequences to lie with primary and secondary care.

Liver transplantation is a highly successful treatment for all types of liver failure, some non-liver failure indications and liver cancer. Most referrals come from secondary care. This first part of a two-part guideline outlines who to refer, and how that referral should be made, including patient details and additional issues such as those relevant to alcohol and drug misuse. The process of liver transplant assessment involves the confirmation of the diagnosis and non-reversibility, an evaluation of comorbidities and exclusion of contraindications. Finally, those making it onto the waiting list require monitoring and optimising. Underpinning this process is a need for good communication between patient, their carers, secondary care and the liver transplant service, synchronised by the transplant coordinator. Managing expectation and balancing the uncertainty of organ availability against the inevitable progression of underlying liver disease requires sensitivity and honesty from all healthcare providers and the assessment of palliative care needs is an integral part of this process.

The recent detection of ethynyl-functionalized cyclopropenylidene (c-C

Reparameterized semi-empirical methods can reproduce gas-phase experimental vibrational frequencies to within 24 cm−1 or better for a 100-fold decrease in computational cost in the anharmonic fundamental vibrational frequencies. To achieve such accuracy and efficiency, the default parameters in the PM6 semi-empirical model are herein optimized to reproduce the experimental and high-level theoretical vibrational spectra of three small hydrocarbon molecules, C2H2, c-C3H2, and C2H4, with the hope that these same parameters will be applicable to large polycyclic aromatic hydrocarbons (PAHs). This massive cost reduction allows for the computation of explicit anharmonic frequencies and the inclusion of resonance corrections that have been shown to be essential for accurate predictions of anharmonic frequencies. Such accurate predictions are necessary to help to disentangle the heretofore unidentified infrared spectral features observed around diverse astronomical bodies and hypothesized to be caused by PAHs, especially with the upcoming influx of observational data from the James Webb Space Telescope. The optimized PM6 parameters presented herein represent a substantial step in this direction with those obtained for ethylene (C2H4) yielding a 37% reduction in the mean absolute error of the fundamental frequencies compared to the default PM6 parameters.

This work provides the first full set of vibrational and rotational spectral data needed to aid in the detection of AlH$_3$OH$_2$, SiH$_3$OH, and SiH$_3$NH$_2$ in astrophysical or simulated laboratory environments through the use of quantum chemical computations at the CCSD(T)-F12b level of theory employing quartic force fields for the three molecules of interest. Previous work has shown that SiH$_3$OH and SiH$_3$NH$_2$ contain some of the strongest bonds of the most abundant elements in space. AlH$_3$OH$_2$ also contains highly abundant atoms and represents an intermediate along the reaction pathway from H$_2$O and AlH$_3$ to AlH$_2$OH. All three of these molecules are also polar with AlH$_3$OH$_2$ having the largest dipole of 4.58 D and the other two having dipole moments in the 1.10-1.30 D range, large enough to allow for the detection of these molecules in space through rotational spectroscopy. The molecules also have substantial infrared intensities with many of the frequencies being over 90 km mol$^{-1}$ and falling within the currently uncertain 12-17 $\mu$m region of the spectrum. The most intense frequency for AlH$_3$OH$_2$ is $\nu_9$ which has an intensity of 412 km mol$^{-1}$ at 777.0 cm$^{-1}$ (12.87 $\mu$m). SiH$-3$OH has an intensity of 183 km mol$^{-1}$ at 1007.8 cm$^{-1}$ (9.92 $\mu$m) for $\nu_5$, and SiH$_3$NH$_2$ has an intensity of 215 km mol$^{-1}$ at 1000.0 cm$^{-1}$ (10.00 $\mu$m) for $\nu_7$., Comment: 7 pages, 2 figures, accepted in MNRAS