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Enterotoxigenic Escherichia coli (ETEC) is the primary etiologic agent of traveler’s diarrhea and a major cause of diarrheal disease and death worldwide, especially in infants and young children. Despite significant efforts over the past several decades, an affordable vaccine that appreciably decreases mortality and morbidity associated with ETEC infection among children under the age of 5 years remains an unmet aspirational goal. Here, we describe robust, cost-effective biosynthetic routes that leverage glycoengineered strains of non-pathogenic E. coli or their cell-free extracts for producing conjugate vaccine candidates against two of the most prevalent O serogroups of ETEC, O148 and O78. Specifically, we demonstrate site-specific installation of O-antigen polysaccharides (O-PS) corresponding to these serogroups onto licensed carrier proteins using the oligosaccharyltransferase PglB from Campylobacter jejuni. The resulting conjugates stimulate strong O-PS-specific humoral responses in mice and elicit IgG antibodies that possess bactericidal activity against the cognate pathogens. We also show that one of the prototype conjugates decorated with serogroup O148 O-PS reduces ETEC colonization in mice, providing evidence of vaccine-induced mucosal protection. We anticipate that our bacterial cell-based and cell-free platforms will enable creation of multivalent formulations with the potential for broad ETEC serogroup protection and increased access through low-cost biomanufacturing.

Normal aging is associated with a variety of neurologic changes including declines in cognition, memory, and motor activity. These declines correlate with neuronal changes in synaptic structure and function. Degradation of brain network activity and connectivity represents a likely mediator of age-related functional deterioration resulting from these neuronal changes. Human studies have demonstrated both general decreases in spontaneous cortical activity and disruption of cortical networks with aging. Current techniques used to study cerebral network activity are hampered either by limited spatial resolution (e.g. electroencephalography, EEG) or limited temporal resolution (e.g., functional magnetic resonance imaging, fMRI). Here we utilize mesoscale imaging of neuronal activity in Thy1-GCaMP6f mice to characterize neuronal network changes in aging with high spatial resolution across a wide frequency range. We show that while evoked activity is unchanged with aging, spontaneous neuronal activity decreases across a wide frequency range (0.01–4 Hz) involving all regions of the cortex. In contrast to this global reduction in cortical power, we found that aging is associated with functional connectivity (FC) deterioration of select networks including somatomotor, cingulate, and retrosplenial nodes. These changes are corroborated by reductions in homotopic FC and node degree within somatomotor and visual cortices. Finally, we found that whole-cortex delta power and delta band node degree correlate with exploratory activity in young but not aged animals. Together these data suggest that aging is associated with global declines in spontaneous cortical activity and focal deterioration of network connectivity, and that these reductions may be associated with age-related behavioral declines.

BackgroundThe impact of cardiovascular and neurologic complications on infective endocarditis (IE) are well studied, yet the prevalence and significance of pulmonary complications in IE is not defined. To better characterize the multifaceted nature of IE management, we aimed to describe the occurrence and significance of pulmonary complications in IE, including among persons with IE related to drug use.MethodsHospitalizations of adult (≥18 years old) patients diagnosed with IE were identified in the 2016 National Inpatient Sample using ICD-10 codes. Multivariable logistic and linear regression were used to compare IE patient outcomes between those with and without pulmonary complications and to identify predictors of pulmonary complications. Interaction terms were used to assess the impact of drug-use IE (DU-IE) and pulmonary complications on inpatient outcomes.ResultsIn 2016, there were an estimated 88,995 hospitalizations of patients diagnosed with IE. Of these hospitalizations,15,490 (17%) were drug-use related. Drug-use IE (DU-IE) had the highest odds of pulmonary complications (OR 2.97, 95% CI 2.50, 3.45). At least one pulmonary complication was identified in 6,580 (7%) of IE patients. DU-IE hospitalizations were more likely to have a diagnosis of pyothorax (3% vs. 1%, pConclusion and relevanceIE with pulmonary complications is associated with worse outcomes. Patients with DU-IE have a particularly high prevalence of pulmonary complications that may require timely thoracic surgical intervention, likely owing to right-sided valve involvement. More research is needed to determine optimal management strategies for complications to improve patient outcomes.

Die abendländische, klassische wie moderne, Reflexion über das Recht wird durch den Gegensatz zwischen Naturrecht und positivem Recht bestimmt. Das jüdische Verständnis des Gesetzes transzendiert diese Dichotomie durch die Projektion eines zirkulären Modells: Das göttliche Gesetz wird konkret in der Diskussion der rabbinischen Gelehrten entwickelt, und diese Diskussion hat selbst als mündliches Gesetz den Status des gottgegebenen Gesetzes. Die Tora als Grundlage des jüdischen Gesetzes wird also in der rabbinischen Tradition als die Idee eines Gesetzes interpretiert, in dem die konstruktive Interpretation als eine genauere Entdeckung dessen, was wirklich ist, verstanden wird, d.h. in dem Finden und Erfinden des Rechts zusammenfallen. The occidental reflections on Law, classical as modern, is determined by the opposition between natural and positive law. The Jewish understanding of Law transcends this dichotomy by projecting a circular model: The divine Law is developped concretely in the discussion of rabbinical scholars and this discussion has itself, as Oral Law, the status of being god-given. The Torah as the basis of the Jewish law is thus interpreted in the rabbinic tradition as the idea of a law in which the constructive interpretation is understood as a more precise discovery of that what really is, that means an interpretation in which coincides with the invention and exploration of the law.

Cortical malformations are often associated with pharmaco-resistant epilepsy. Alterations in hyperpolarization-activated, cyclic nucleotide-gated, non-specific cation (HCN) channels have been shown to contribute to malformation associated hyperexcitability. We have recently demonstrated that expression of HCN channels and Ih current amplitudes are reduced in layer (L) 5 pyramidal neurons of rats with freeze lesion induced malformations. These changes were associated with an increased EPSP temporal summation. Here, we examine the effects of HCN channel inhibition on synaptic responses in fast spiking, presumptive basket cells and accommodating, presumptive Martinotti, GABAergic interneurons in slices from freeze lesioned animals. In control animals, fast spiking cells showed small sag responses which were reduced by the HCN channel antagonist ZD7288. Fast spiking cells in lesioned animals showed absent or reduced sag responses. The amplitude of single evoked EPSPs in fast spiking cells in the control group was not affected by HCN channel inhibition with ZD7288. EPSP ratios during short stimulus trains at 25 Hz were not significantly different between control and lesion groups. ZD7288 produced an increase in EPSP ratios in the control but not lesion groups. Under voltage clamp conditions, ZD7288 did not affect EPSC ratios. In the control group, accommodating interneurons showed robust sag responses which were significantly reduced by ZD7288. HCN channel inhibition increased EPSP ratios and area in controls but not the lesioned group. The results indicate that HCN channels differentially modulate EPSPs in different classes of GABAergic interneurons and that this control is reduced in malformed rat neocortex.

We demonstrate all-optical division and multiplication of the state order ℓ for data-carrying orbital angular momentum (OAM) beams. We use linear optical transformations between log-polar and Cartesian coordinates to: (i) divide the OAM state order to convert the OAM order from 2ℓ to ℓ (ℓ = −5, −4, …, +4, +5), and (ii) multiply the OAM state order from ℓ to 2ℓ. We analyze the OAM mode purity and the bit-error-rate performance of a classical two-mode OAM multiplexed link for the case of division and multiplication of the OAM state order. The experimental mode purity for halving and doubling OAM state order can reach around 87% and 40%, respectively. We further study the dependence of the OAM mode purity on the displacement of SLMs in simulation. The obtained results show that the transformation for doubling the OAM state order is more sensitive to the increase of the displacement than that for halving the OAM state order. The link bit error rates are below the forward error correction threshold of 3.8 × 10−3 for both channels.

Rett syndrome (RTT) is an X chromosome-linked neurodevelopmental disorder associated with the characteristic neuropathology of dendritic spines common in diseases presenting with mental retardation (MR). Here, we present the first quantitative analyses of dendritic spine density in postmortem brain tissue from female RTT individuals, which revealed that hippocampal CA1 pyramidal neurons have lower spine density than age-matched non-MR female control individuals. The majority of RTT individuals carry mutations in MECP2, the gene coding for a methylated DNA-binding transcriptional regulator. While altered synaptic transmission and plasticity has been demonstrated in Mecp2-deficient mouse models of RTT, observations regarding dendritic spine density and morphology have produced varied results. We investigated the consequences of MeCP2 dysfunction on dendritic spine structure by overexpressing (∼twofold) MeCP2-GFP constructs encoding either the wildtype (WT) protein, or missense mutations commonly found in RTT individuals. Pyramidal neurons within hippocampal slice cultures transfected with either WT or mutant MECP2 (either R106W or T158M) showed a significant reduction in total spine density after 48 h of expression. Interestingly, spine density in neurons expressing WT MECP2 for 96 h was comparable to that in control neurons, while neurons expressing mutant MECP2 continued to have lower spine density than controls after 96 h of expression. Knockdown of endogenous Mecp2 with a specific small hairpin interference RNA (shRNA) also reduced dendritic spine density, but only after 96 h of expression. On the other hand, the consequences of manipulating MeCP2 levels for dendritic complexity in CA3 pyramidal neurons were only minor. Together, these results demonstrate reduced dendritic spine density in hippocampal pyramidal neurons from RTT patients, a distinct dendritic phenotype also found in neurons expressing RTT-associated MECP2 mutations or after shRNA-mediated endogenous Mecp2 knockdown, suggesting that this phenotype represent a cell-autonomous consequence of MeCP2 dysfunction.

We review comprehensive observations of electromagnetic ion cyclotron (EMIC) wave-driven energetic electron precipitation using data collected by the energetic electron detector on the Electron Losses and Fields InvestigatioN (ELFIN) mission, two polar-orbiting low-altitude spinning CubeSats, measuring 50-5000 keV electrons with good pitch-angle and energy resolution. EMIC wave-driven precipitation exhibits a distinct signature in energy-spectrograms of the precipitating-to-trapped flux ratio: peaks at >0.5 MeV which are abrupt (bursty) (lasting ∼17 s, or ΔL∼0.56) with significant substructure (occasionally down to sub-second timescale). We attribute the bursty nature of the precipitation to the spatial extent and structuredness of the wave field at the equator. Multiple ELFIN passes over the same MLT sector allow us to study the spatial and temporal evolution of the EMIC wave - electron interaction region. Case studies employing conjugate ground-based or equatorial observations of the EMIC waves reveal that the energy of moderate and strong precipitation at ELFIN approximately agrees with theoretical expectations for cyclotron resonant interactions in a cold plasma. Using multiple years of ELFIN data uniformly distributed in local time, we assemble a statistical database of ∼50 events of strong EMIC wave-driven precipitation. Most reside at L∼5-7 at dusk, while a smaller subset exists at L∼8-12 at post-midnight. The energies of the peak-precipitation ratio and of the half-peak precipitation ratio (our proxy for the minimum resonance energy) exhibit an L-shell dependence in good agreement with theoretical estimates based on prior statistical observations of EMIC wave power spectra. The precipitation ratio's spectral shape for the most intense events has an exponential falloff away from the peak (i.e., on either side of ∼1.45 MeV). It too agrees well with quasi-linear diffusion theory based on prior statistics of wave spectra. It should be noted though that this diffusive treatment likely includes effects from nonlinear resonant interactions (especially at high energies) and nonresonant effects from sharp wave packet edges (at low energies). Sub-MeV electron precipitation observed concurrently with strong EMIC wave-driven >1 MeV precipitation has a spectral shape that is consistent with efficient pitch-angle scattering down to ∼ 200-300 keV by much less intense higher frequency EMIC waves at dusk (where such waves are most frequent). At ∼100 keV, whistler-mode chorus may be implicated in concurrent precipitation. These results confirm the critical role of EMIC waves in driving relativistic electron losses. Nonlinear effects may abound and require further investigation.

Identifying gaps in care for people with chronic hepatitis C virus (HCV) infection is important to clinicians, public health officials, and federal agencies. The objective of this study was to systematically review the literature to provide estimates of the proportion of chronic HCV-infected persons in the United States (U.S.) completing each step along a proposed HCV treatment cascade: (1) infected with chronic HCV; (2) diagnosed and aware of their infection; (3) with access to outpatient care; (4) HCV RNA confirmed; (5) liver fibrosis staged by biopsy; (6) prescribed HCV treatment; and (7) achieved sustained virologic response (SVR).We searched MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews for articles published between January 2003 and July 2013. Two reviewers independently identified articles addressing each step in the cascade. Studies were excluded if they focused on specific populations, did not present original data, involved only a single site, were conducted outside of the U.S., or only included data collected prior to 2000.9,581 articles were identified, 117 were retrieved for full text review, and 10 were included. Overall, 3.5 million people were estimated to have chronic HCV in the U.S. Fifty percent (95% CI 43-57%) were diagnosed and aware of their infection, 43% (CI 40-47%) had access to outpatient care, 27% (CI 27-28%) had HCV RNA confirmed, 17% (CI 16-17%) underwent liver fibrosis staging, 16% (CI 15-16%) were prescribed treatment, and 9% (CI 9-10%) achieved SVR.Continued efforts are needed to improve HCV care in the U.S. The proposed HCV treatment cascade provides a framework for evaluating the delivery of HCV care over time and within subgroups, and will be useful in monitoring the impact of new screening efforts and advances in antiviral therapy.

The Electron Loss and Fields Investigation with a Spatio-Temporal Ambiguity-Resolving option (ELFIN-STAR, or heretoforth simply: ELFIN) mission comprises two identical 3-Unit (3U) CubeSats on a polar (∼93∘ inclination), nearly circular, low-Earth (∼450 km altitude) orbit. Launched on September 15, 2018, ELFIN is expected to have a >2.5 year lifetime. Its primary science objective is to resolve the mechanism of storm-time relativistic electron precipitation, for which electromagnetic ion cyclotron (EMIC) waves are a prime candidate. From its ionospheric vantage point, ELFIN uses its unique pitch-angle-resolving capability to determine whether measured relativistic electron pitch-angle and energy spectra within the loss cone bear the characteristic signatures of scattering by EMIC waves or whether such scattering may be due to other processes. Pairing identical ELFIN satellites with slowly-variable along-track separation allows disambiguation of spatial and temporal evolution of the precipitation over minutes-to-tens-of-minutes timescales, faster than the orbit period of a single low-altitude satellite (Torbit ∼ 90 min). Each satellite carries an energetic particle detector for electrons (EPDE) that measures 50 keV to 5 MeV electrons with Δ E/E < 40% and a fluxgate magnetometer (FGM) on a ∼72 cm boom that measures magnetic field waves (e.g., EMIC waves) in the range from DC to 5 Hz Nyquist (nominally) with 1 MeV. This broad energy range of precipitation indicates that multiple waves are providing scattering concurrently. Many observed events show significant backscattered fluxes, which in the past were hard to resolve by equatorial spacecraft or non-pitch-angle-resolving ionospheric missions. These observations suggest that the ionosphere plays a significant role in modifying magnetospheric electron fluxes and wave-particle interactions. Routine data captures starting in February 2020 and lasting for at least another year, approximately the remainder of the mission lifetime, are expected to provide a very rich dataset to address questions even beyond the primary mission science objective.

Among a statewide cohort of 1874 patients surviving hospitalization for drug use–associated endocarditis during 2017–2020, the 3-year risk of death or future hospitalization was 38% (16% for death before later infection, 14% for recurrent endocarditis, 14% for soft tissue, 9% for bacteremia, 5% for bone/joint, and 4% for spinal infections). [ABSTRACT FROM AUTHOR]

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