Allosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody

Agonist-induced phosphorylation of G protein-coupled receptors (GPCRs) is a primary determinant of β-arrestin (βarr) recruitment and trafficking. For several GPCRs, such as the vasopressin type II receptor (V2R), which exhibit high affinity for βarrs, agonist-stimulation first drives the translocation of βarrs to the plasma membrane, followed by endosomal trafficking. We previously found that mutation of a single phosphorylation site in V2R (i.e., V2RT360A) results in near-complete loss of βarr translocation to endosomes although βarrs are robustly recruited to the plasma membrane. Here, we show that a synthetic intrabody referred to as intrabody30 (Ib30), which selectively recognizes an active-like βarr1 conformation, rescues endosomal translocation of βarr1 for V2RT360A. In addition, Ib30 also rescues agonist-induced ERK1/2 MAP kinase activation for V2RT360A to levels similar to that of the wild-type V2R. Molecular dynamics simulations reveal that Ib30 binding promotes active-like conformation in βarr1 with respect to the inter-domain rotation. Interestingly, we also observe that Ib30 enhances the interaction of βarr1 with β2-adaptin, which provides a mechanistic basis for the ability of Ib30 to promote endosomal trafficking of βarr1. Taken together, our data provide a novel mechanism to positively modulate the receptor-transducer-effector axis for GPCRs using intrabodies, which can potentially be integrated in the current paradigm of GPCR-targeted drug discovery.

Direct visualization of polaron formation in the thermoelectric SnSe

SnSe is a layered material that currently holds the record for bulk thermoelectric efficiency. The primary determinant of this high efficiency is thought to be the anomalously low thermal conductivity resulting from strong anharmonic coupling within the phonon system. Here we show that the nature of the carrier system in SnSe is also determined by strong coupling to phonons by directly visualizing polaron formation in the material. We employ ultrafast electron diffraction and diffuse scattering to track the response of phonons in both momentum and time to the photodoping of free carriers across the bandgap, observing the bimodal and anisotropic lattice distortions that drive carrier localization. Relatively large (18.7 Å), quasi-one-dimensional (1D) polarons are formed on the 300-fs timescale with smaller (4.2 Å) 3D polarons taking an order of magnitude longer (4 ps) to form. This difference appears to be a consequence of the profoundly anisotropic electron–phonon coupling in SnSe, with strong Fröhlich coupling only to zone-center polar optical phonons. These results demonstrate a high density of polarons in SnSe at optimal doping levels. Strong electron-phonon coupling is critical to the thermoelectric performance of this benchmark material and, potentially, high performance thermoelectrics more generally.

Accounting for the Rising Caesarean Section Rate in Canada: What Are the Roles of Changing Needs, Practices, and Incentives?

In most high-income countries, including Canada, the share of births by Caesarean section (C‑section) has risen over the past decades to far exceed World Health Organization recommendations of the proportion justified on medical grounds (15 percent). Although unnecessary C-sections represent an important cost for health care systems, they are not associated with clear benefits for the mother and the child and can sometimes represent additional risks. Drawing on administrative records of nearly four million births in Canada, as well as macro data from the United States and Australia, we provide a comprehensive account of rising C-section rates. We explicitly consider the contributions of the main factors brought forward in the policy literature, including changing characteristics of mothers, births, and physicians as well as changing financial incentives for C-section deliveries. These factors account for at most one-half of the increase in C-section rates. The majority of the remaining increase in C-sections over the period 1994–2011 occurred in the early 2000s. We suggest that some event or shock in the early 2000s is likely the primary determinant of the recent strong increase in the C-section rate in Canada.

Influence of Environmental Factors on Urban and Architectural Design—Example of a Former Paper Mill in Nanterre

Biophilic design is developed in urban planning concepts for cities—in line with sustainable development. A case study of converting a former paper mill in Nanterre into a university campus showed what factors influence the emergence of the biophilic form. The research informs the planning and design mechanisms and directs attention to the process. As a result, the study demonstrates that biophilic elements from the place-based pattern group are directly related to in-depth environmental analysis—similar to elements from the nature-based and element-based pattern groups. Together they result in a biophilic form. The element of creation is also present in the design process but is not the primary determinant of the choice of a design approach. In part, the form is adapted to the area's environmental characteristics, which result from their interaction with objective determinants. Nevertheless, the implementation is not devoid of compositional, creative, and cultural elements—that is, it assumes the features of biophilic architecture. This fact proves that the environment can influence the creative potential in architecture and urban studies.

Analyses of HIV Proteases Variants at the Threshold of Viability Reveals Relationships Between Processing Efficiency and Fitness

Investigating the relationships between protein function and fitness provides keys for understanding biochemical mechanisms that underly evolution. Mutations with partial fitness defects can delineate the threshold of biochemical function required for viability. We utilized a previous deep mutational scan of HIV-1 protease (PR) to identify variants with 15-45% defects in replication and analyzed the biochemical function of eight variants (L10M, L10S, V32C, V32I, A71V, A71S, Q92I, Q92N). We purified each variant and assessed the efficiency of peptide cleavage for three cut sites (MA-CA, TF-PR, PR-RT) as well as a gel-based analyses of processing of purified Gag. The cutting activity of at least one site was perturbed relative to WT protease for all variants, consistent with cutting activity being a primary determinant of fitness effects. We examined the correlation of fitness defects with cutting activity of different sites. MA-CA showed the weakest correlation (R2=0.02) with fitness, suggesting relatively weak coupling with viral replication. In contrast, cutting of the TF-PR site showed the strongest correlation with fitness (R2=0.53). Cutting at the TF-PR site creates a new PR protein with a free N-terminus that is critical for activity. Our findings indicate that increasing the pool of active PR is rate limiting for viral replication making this an ideal step to target with inhibitors.

Lower Limb Perfusion Asymmetries in Humans at Rest and Following Activity—A Collective View

The significance of lower limb perfusion asymmetries remains unknown in healthy individuals. Our study aims to understand how factors such as posture, sex, age, and body weight relate to perfusion. Data from studies previously published by our group, including experiments using laser Doppler flowmetry as the gold standard for perfusion measurements in baseline, (various) challenge, and recovery phases was assembled from a total of 139 healthy participants. Body position was shown to be a primary determinant of perfusion asymmetry, especially in women. Effects of sex and age were also analyzed. In a supine position, perfusion asymmetries seemed to relate negatively in the aged group of participants, where challenge and recovery seemed to follow different processes. In the upright position, young men and women have shown comparable distributions and asymmetry ratios at baseline and recovery. In the aged group, differences between sexes were observed at baseline, but again, the course of the asymmetry ratios with challenge was essentially similar in men and women. Our analysis suggests that ageing is a critical determinant in our upright study sample, as higher baseline asymmetries and longer recoveries after challenge were linked in older males with higher body mass index (BMI).

Forecasting Foreign Direct Investment Inflow to Egypt and Determinates: Using Machine Learning Algorithms and ARIMA Model

This study aims to determine the primary determination of FDI inflow to Egypt using machine learning algorithms and the ARIMA model and get an accurate prediction of FDI inflow to Egypt during the current decade (2020–2030) and approved that the gradient boosting model is the most accurate algorithms. Also, we find stability in economic indicators in Egypt during the current decade using the ARIMA model. The last step approved that the primary determinant of FDI inflow to Egypt is the Human Development Index, followed by population size, gross domestic product per capita, lending rate, and gross domestic product value.

Analysis of Covid-19 Hospital Admissions in Ivano-Frankivsk, Ukraine

The Covid-19 pandemic has a substantial impact on socioeconomic, political, demographic, and other aspects of life. Effective healthcare is, however, a primary determinant of successful fighting against Covid-19. The analysis of local healthcare indicators serves as a source for estimating pandemic magnitude and the adaptation of healthcare at a national level. In this study, the rates of Covid-19 hospital admissions to the Ivano-Frankivsk City Hospital, Ukraine, from April 2020 to May 2021 were analysed. All cases were grouped by age, sex, and the type of admission; data were analyzed monthly and seasonally. The peaks of hospital admissions were observed in November 2020 and March 2021; however, the highest mortality rates were seen from August to November 2020. The analysis of age- and sex-disaggregated Covid-19 mortality data showed the predominance of elderly males (61.9%, 66.6 ± 3.9 years) over females (38.1%, 71.8 ± 2.3 years). The ratio of hospital admissions was unstable: the percentage of emergency, GP-referred and self-referred admissions was similar from April to May 2020; however, GP-referred admissions prevailed, and the number of self-referral patients decreased twice between March and May 2021. In conclusions, the trends in hospital admissions were similar to those reported in other studies. However, the differences in time frames and socio-demographic characteristics were observed that highlights the importance of considering regional, social and geographic aspects of the population when improving the capacity of healthcare system and establishing effective preventive measures against the pandemic at the local level.

UNEMPLOYMENT CRISIS AMONG FRESH GRADUATES

This paper attempts to explore the topic of the unemployment crisis among fresh graduates. The two main objectives of the study are to examine the influence factors of the unemployment crisis among fresh graduates in Malaysia, and the primary determinant of the unemployment has culminated in many policy implications for higher education. The unemployment rate among fresh graduates increased to 25% in 2020 than the year before, jumping from 13.8%. The null hypothesis is that employer preference, candidate attributes, and economic instability have no significant effect on the unemployment crisis. The information for the paper typically originates from a questionnaire survey method, with one hundred and thirty fresh graduates' participation in this study. The statistical approach is required to analyze numerical data using SPSS applications. Descriptive analyses such as frequency and simple percentages on demographic characteristics were used to analyze data. Inferential statistics such as linear bivariate correlation was used to test the formulated hypothesis. The finding demonstrated a significant association between employer preference, candidate attributes, and economic instability with the unemployment crisis. This finding would shed light on more preparation for fresh graduates' employability who preserve searching for a job by the education ministry. Hopefully, a revision in the academic higher education curriculum is considered to meet the job market's and stakeholders' needs for better graduate employability.