Indoline CD4-mimetic compounds mediate potent and broad HIV-1 inhibition and sensitization to antibody-dependent cellular cytotoxicity.

Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the HIV-1 envelope glycoprotein (Env) trimer [(gp120/gp41)3] that promote virus entry into the cell. CD4-mimetic compounds (CD4mcs) comprise small organic molecules that bind in the highly conserved CD4-binding site of gp120 and prematurely induce inactivating Env conformational changes, including shedding of gp120 from the Env trimer. By inducing more "open," antibody-susceptible Env conformations, CD4mcs also sensitize HIV-1 virions to neutralization by antibodies and infected cells to antibody-dependent cellular cytotoxicity (ADCC). Here, we report the design, synthesis, and evaluation of novel CD4mcs based on an indoline scaffold. Compared with our current lead indane scaffold CD4mc, BNM-III-170, several indoline CD4mcs exhibit increased potency and breadth against HIV-1 variants from different geographic clades. Viruses that were selected for resistance to the lead indane CD4mc, BNM-III-170, are susceptible to inhibition by the indoline CD4mcs. The indoline CD4mcs also potently sensitize HIV-1-infected cells to ADCC mediated by plasma from HIV-1-infected individuals. Crystal structures indicate that the indoline CD4mcs gain potency compared to the indane CD4mcs through more favorable π-π overlap from the indoline pose and by making favorable contacts with the vestibule of the CD4-binding pocket on gp120. The rational design of indoline CD4mcs thus holds promise for further improvements in antiviral activity, potentially contributing to efforts to treat and prevent HIV-1 infection.

The effect of bisimidazolium-based ionic liquids on a bimolecular substitution process. Are two head(group)s better than one?

A homologous series of biscationic ionic liquids based on two imidazolium centres, separated by alkyl chains of varying length, were examined as solvents for a bimolecular substitution reaction across a range of proportions of ionic liquid in the reaction mixture. Their effects on the rate constant of the process were compared to monocationic ionic liquids, with generally a greater rate constant increase observed. Importantly, it was observed that the magnitude of the effect was shown to vary with the length of the linking chain. To investigate the origins of these solvent effects, temperature dependent kinetic studies were performed to obtain activation parameters at high and low mole fractions of ionic liquid. The observed activation parameters showed the rate constant enhancement was due to interaction of the ionic liquid with the starting materials, consistent with previous results. Significantly, however, these data also showed that the balance of enthalpic and entropic effects varied dramatically with the length of the alkyl chain between the cationic centres.

Controlling the outcome of SN2 reactions in ionic liquids: from rational data set design to predictive linear regression models.

Rate constants for a bimolecular nucleophilic substitution (SN2) process in a range of ionic liquids are correlated with calculated parameters associated with the charge localisation on the cation of the ionic liquid (including the molecular electrostatic potential). Simple linear regression models proved effective, though the interdependency of the descriptors needs to be taken into account when considering generality. A series of ionic liquids were then prepared and evaluated as solvents for the same process; this data set was rationally chosen to incorporate homologous series (to evaluate systematic variation) and functionalities not available in the original data set. These new data were used to evaluate and refine the original models, which were expanded to include simple artificial neural networks. Along with showing the importance of an appropriate data set and the perils of overfitting, the work demonstrates that such models can be used to reliably predict ionic liquid solvent effects on an organic process, within the limits of the data set.

High Spatial Resolution Simulation of Sunshine Duration over the Complex Terrain of Ghana.

In this paper, we propose a remote sensing model based on a 1 × 1 km spatial resolution to estimate the spatio-temporal distribution of sunshine percentage (SSP) and sunshine duration (SD), taking into account terrain features and atmospheric factors. To account for the influence of topography and atmospheric conditions in the model, a digital elevation model (DEM) and cloud products from the moderate-resolution imaging spectroradiometer (MODIS) for 2010 were incorporated into the model and subsequently validated against in situ observation data. The annual and monthly average daily total SSP and SD have been estimated based on the proposed model. The error analysis results indicate that the proposed modelled SD is in good agreement with ground-based observations. The model performance is evaluated against two classical interpolation techniques (kriging and inverse distance weighting (IDW)) based on the mean absolute error (MAE), the mean relative error (MRE) and the root-mean-square error (RMSE). The results reveal that the SD obtained from the proposed model performs better than those obtained from the two classical interpolators. This results indicate that the proposed model can reliably reflect the contribution of terrain and cloud cover in SD estimation in Ghana, and the model performance is expected to perform well in similar environmental conditions.

Chiral Ruthenium(II) Complexes as Supramolecular Building Blocks for Heterometallic Self-Assembly.

A series of enantiopure ruthenium(II) polypyridyl complexes are reported that feature pendant pyridyl groups suitable for building larger self-assembled structures. The complexes are characterized in detail in solution using NMR spectroscopy, cyclic voltammetry, and photophysical methods and in the solid state using single-crystal X-ray crystallography. The complexes are luminescent, displaying long excited-state lifetimes that are quenched when the pendant pyridyl groups are protonated. Reaction with cadmium(II) ions results in the formation of a mixed-metal one-dimensional coordination polymer, which was characterized by single-crystal X-ray crystallography.

Thermal Stability of Protic Ionic Liquids.

While protic ionic liquids (ILs) have found great success as solvents for a broad range of applications, little is known about their degradation when exposed to temperatures above ambient for extended periods of time. Here, we report the thermal stability of six protic ILs, namely, ethylammonium nitrate, ethylammonium formate, ethylammonium acetate, ethanolammonium nitrate, ethanolammonium formate, and ethanolammonium acetate. The effect of heating each ionic liquid to 60 °C for 1 h or 1 week (sealed or open to the atmosphere) was evaluated by considering the changes to water content, pH, mass, thermal phase transitions, and molecular structure after each treatment. Heating each of the six ILs when sealed led to measurable shifts in their water content and 10 wt % pH, but there was no significant change in their mass, thermal phase transitions according to differential scanning calorimetry (DSC), or molecular structure using proton nuclear magnetic resonance (1H NMR) spectra, indicating that the samples were largely unchanged. The samples that were heated open to the atmosphere also displayed no significant changes after 1 h but displayed significant changes after 1 week.

Epitope-specific anti-nuclear antibodies are expressed in a mouse model of primary biliary cirrhosis and are cytokine-dependent.

Although the hallmark of primary biliary cirrhosis (PBC) is the presence of anti-mitochondrial antibodies (AMA), a significant number of patients have anti-nuclear antibodies (ANA) directed primarily against two nuclear proteins, gp210 and sp100. In PBC, there are considerable data on the specificity of these anti-nuclear antibodies as well as suggestive evidence that antibodies to gp210 predict a poor outcome. However, a further understanding of the significance of these autoantibodies has been hampered by limitations in accessing human subjects in a preclinical or early asymptomatic stage. To overcome this limitation, we have taken advantage of transgenic mice with abrogated transforming growth factor-ß signalling in T cells (dnTGF-ßRII) that develop histological features of PBC as well as the same AMA specificity. We studied these mice for serum ANA, including specific autoantibodies against gp210 and sp100. We further examined sera from dnTGF-ßRII mice with concurrent deletions of the genes encoding interleukin (IL)-12p35, IL-12p40, IL-23p19, IL-17, IL-6, interferon (IFN)-γ or tumour necrosis factor (TNF)-α. Sera from all the dnTGF-ßRII mouse lines contained antibodies against gp210 and sp100. Of significance, mice with germline deletions of the genes encoding IL-12p40, IL-23p19, IL-17, IL-6 and TNF-α had significantly lower titres of anti-gp210 antibodies. These results provide a platform to dissect the mechanisms of gp210 and sp100 autoantibody production in dnTGF-ßRII mice as well as to study the possible role of ANA in the pathophysiology of PBC.

The Role of Cystine/Glutamate Antiporter SLC7A11/xCT in the Pathophysiology of Cancer.

SLC7A11/xCT is an antiporter that mediates the uptake of extracellular cystine in exchange for glutamate. Cystine is reduced to cysteine, which is a rate-limiting precursor in glutathione synthesis; a process that protects cells from oxidative stress and is, therefore, critical to cell growth, proliferation, and metabolism. SLC7A11 is expressed in different tissues and plays diverse functional roles in the pathophysiology of various diseases, including cancer, by regulating the processes of redox homeostasis, metabolic flexibility/nutrient dependency, immune system function, and ferroptosis. SLC7A11 expression is associated with poor prognosis and drug resistance in cancer and, therefore, represents an important therapeutic target. In this review, we discuss the molecular functions of SLC7A11 in normal versus diseased tissues, with a special focus on how it regulates gastrointestinal cancers. Further, we summarize current therapeutic strategies targeting SLC7A11 as well as novel avenues for treatment.

Projected changes in meteorological drought over East Africa inferred from bias-adjusted CMIP6 models.

The ongoing global warming has caused unprecedented changes in the climate system, leading to an increase in the intensity and frequency of weather and climate extremes. This study uses the sixth phase of Coupled Model Intercomparison Project (CMIP6) data to investigate projected changes in drought events over East Africa (EA) under four Shared Socioeconomic Pathway (SSP) emission scenarios (SSP1-2.6, SSP2-4.5, SSP3-4.0, and SSP5-8.5). The CMIP6 data are bias-corrected using a quantile mapping method, with the Climatic Research Unit's precipitation dataset as reference. Drought is quantified using the standardized precipitation index and different measures of drought are estimated: drought duration, drought frequency, drought severity, and drought intensity. Evaluating the accuracy and reliability of historical data before and after bias correction demonstrates the importance of the approach. The overall distribution after bias correction depicts a close agreement with observation. Moreover, the multi-model ensemble mean demonstrate superiority over individual Global Circulation Models. Projected future changes show enhancement in precipitation over most parts of EA in the far future under different SSP scenarios. However, the arid and semi-arid regions are expected to receive less amount of precipitation, whereas the highlands and lake regions are expected to receive a larger amount of precipitation increase. Furthermore, the dry areas of EA are likely to experience more frequent drought events with longer duration, stronger intensity, and severity in the far future. Overall, this study identifies possible drought hotspots over EA, enabling early preparation for such events. Supplementary Information: The online version contains supplementary material available at 10.1007/s11069-022-05341-8.

Recent Advances in Hydrogels: Ophthalmic Applications in Cell Delivery, Vitreous Substitutes, and Ocular Adhesives.

With the prevalence of eye diseases, such as cataracts, retinal degenerative diseases, and glaucoma, different treatments including lens replacement, vitrectomy, and stem cell transplantation have been developed; however, they are not without their respective shortcomings. For example, current methods to seal corneal incisions induced by cataract surgery, such as suturing and stromal hydration, are less than ideal due to the potential for surgically induced astigmatism or wound leakage. Vitrectomy performed on patients with diabetic retinopathy requires an artificial vitreous substitute, with current offerings having many shortcomings such as retinal toxicity. The use of stem cells has also been investigated in retinal degenerative diseases; however, an optimal delivery system is required for successful transplantation. The incorporation of hydrogels into ocular therapy has been a critical focus in overcoming the limitations of current treatments. Previous reviews have extensively documented the use of hydrogels in drug delivery; thus, the goal of this review is to discuss recent advances in hydrogel technology in surgical applications, including dendrimer and gelatin-based hydrogels for ocular adhesives and a variety of different polymers for vitreous substitutes, as well as recent advances in hydrogel-based retinal pigment epithelium (RPE) and retinal progenitor cell (RPC) delivery to the retina.

Future Changes in Simulated Evapotranspiration across Continental Africa Based on CMIP6 CNRM-CM6.

The main goal of this study was to assess the interannual variations and spatial patterns of projected changes in simulated evapotranspiration (ET) in the 21st century over continental Africa based on the latest Shared Socioeconomic Pathways and the Representative Concentration Pathways (SSP1-2.6, SSP2-4.5, SSP3-7.0, and SSP5-8.5) provided by the France Centre National de Recherches Météorologiques (CNRM-CM) model in the Sixth Phase of Coupled Model Intercomparison Project (CMIP6) framework. The projected spatial and temporal changes were computed for three time slices: 2020-2039 (near future), 2040-2069 (mid-century), and 2080-2099 (end-of-the-century), relative to the baseline period (1995-2014). The results show that the spatial pattern of the projected ET was not uniform and varied across the climate region and under the SSP-RCPs scenarios. Although the trends varied, they were statistically significant for all SSP-RCPs. The SSP5-8.5 and SSP3-7.0 projected higher ET seasonality than SSP1-2.6 and SSP2-4.5. In general, we suggest the need for modelers and forecasters to pay more attention to changes in the simulated ET and their impact on extreme events. The findings provide useful information for water resources managers to develop specific measures to mitigate extreme events in the regions most affected by possible changes in the region's climate. However, readers are advised to treat the results with caution as they are based on a single GCM model. Further research on multi-model ensembles (as more models' outputs become available) and possible key drivers may provide additional information on CMIP6 ET projections in the region.

A Guide to COVID-19: a global pandemic caused by the novel coronavirus SARS-CoV-2.

The emergence of the SARS-CoV-2 strain of the human coronavirus has thrown the world into the midst of a new pandemic. In the human body, the virus causes COVID-19, a disease characterized by shortness of breath, fever, and pneumonia, which can be fatal in vulnerable individuals. SARS-CoV-2 has characteristics of past human coronaviruses, with close genomic similarities to SARS-CoV, the virus that causes the disease SARS. Like these related coronaviruses, SARS-CoV-2 is transmitted through the inhalation of droplets and interaction with contaminated surfaces. Across the world, laboratories are developing candidate vaccines for the virus - with vaccine trials underway in the United States and the United Kingdom - and considering various drugs for possible treatments and prophylaxis. Here, we provide an overview of SARS-CoV-2 by analyzing its virology, epidemiology, and modes of transmission while examining the current progress of testing procedures and possible treatments through drugs and vaccines.

Cloning and sequence analysis of desmosomal glycoproteins 2 and 3 (desmocollins): cadherin-like desmosomal adhesion molecules with heterogeneous cytoplasmic domains.

Desmosomal glycoproteins 2 and 3 (dg2 and 3) or desmocollins have been implicated in desmosome adhesion. We have obtained a 5.0-kb-long clone for dg3 from a bovine nasal epidermal lambda gt11 cDNA library. Sequence analysis of this clone reveals an open reading frame of 2,517 bases encoding a polypeptide of 839 amino acids. The sequence consists of a signal peptide of 28 amino acids, a precursor sequence of 104 amino acids, and a mature protein of 707 amino acids. The latter has the characteristics of a transmembrane glycoprotein with an extracellular domain of 550 amino acids and a cytoplasmic domain of 122 amino acids. The sequence of a partial clone from the same library shows that dg2 has an alternative COOH terminus that is extended by 54 amino acids. Genomic DNA sequence data show that this arises by splicing out of a 46-bp exon that encodes the COOH-terminal 11 amino acids of dg3 and contains an in-frame stop codon. The extracellular domain of dg3 shows 39.4% protein sequence identity with bovine N-cadherin and 28.4% identity with the other major desmosomal glycoprotein, dg1, or desmoglein. The cytoplasmic domain of dg3 and the partial cytoplasmic domain of dg2 show 23 and 24% identity with bovine N-cadherin, respectively. The results support our previous model for the transmembrane organization of dg2 and 3 (Parrish, E.P., J.E. Marston, D.L. Mattey, H.R. Measures, R. Venning, and D.R. Garrod. 1990. J. Cell Sci. 96:239-248; Holton, J.L., T.P. Kenny, P.K. Legan, J.E. Collins, J.N. Keen, R. Sharma, and D.R. Garrod. 1990. J. Cell Sci. 97:239-246). They suggest that these glycoproteins are specialized for calcium-dependent adhesion in their extracellular domains and, cytoplasmically, for the molecular interactions involved in desmosome plaque formation. Moreover this represents the first example of alternative splicing within the cadherin family of cell adhesion molecules.

Birth outcomes and usability of Relaxbirth® for upright positioning intrapartum: A retrospective case control study.

INTRODUCTION: The aim of this study was to pilot Relaxbirth® (Relaxbirth®, Ltd., Helsinki, Finland), an investigational device designed to facilitate upright positioning intrapartum. The objective was to 1) compare birth outcomes with and without the use of Relaxbirth®, and 2) assess device usability. METHODS AND MATERIALS: Study design: prospective product use and retrospective case control study at one perinatal center in Ohio. INCLUSION CRITERIA: ≥18 years old, <300 lbs. women with a low-risk, term gestation of a singleton, vertex fetus, and vaginal birth between January 2013 to June 2016. Participants who used the Relaxbirth® device intrapartum (RB group) were retrospectively case-matched to controls (CON group) according to age, race, insurance, gravida/parity, gestational age and labor type. Birth outcomes (primary outcome) were compared between groups. Providers and women who used Relaxbirth® assessed usability of the device with the Modified System Usability Scale Tool (secondary outcome). RESULTS: Of the n = 60 included in the final analysis, RB women (n = 30) pushed for a shorter average duration compared to CON women (n = 30) [34 min (±48) versus 60 min (±63), p = 0.023]. RB women did not experience more adverse birth outcomes including: longer second stage duration, operative vaginal delivery, malpresentation, perineal laceration/episiotomy, higher blood loss, or low Apgars. Usability survey results were favorable (Total Average Scores: providers 74.1; RB 83.6). CONCLUSION: Clinical experience with the Relaxbirth® device was positive at this pilot site. The device was associated with favorable birth outcomes and usability, suggesting potential as a safe and novel adjunct to promote intrapartum choices, upright positioning and maternal satisfaction.

Developing a risk prediction model for 30-day unplanned hospitalization in patients receiving outpatient parenteral antimicrobial therapy.

OBJECTIVES: Outpatient parenteral antimicrobial therapy (OPAT) is increasingly used to treat a wide range of infections. However, there is risk of hospital readmissions. The study aim was to develop a prediction model for the risk of 30-day unplanned hospitalization in patients receiving OPAT. METHODS: Using a retrospective cohort design, we retrieved data on 1073 patients who received OPAT over 2 years (January 2015 to January 2017) at a large teaching hospital in Sheffield, UK. We developed a multivariable logistic regression model for 30-day unplanned hospitalization, assessed its discrimination and calibration abilities, and internally them validated using bootstrap resampling. RESULTS: The 30-day unplanned hospitalization rate was 11% (123/1073). The main indication for hospitalization was worsening or nonresponse of infection (52/123, 42%). The final regression model consisted of age (adjusted odds ratio (aOR), 1.18 per decade; 95% confidence interval (CI), 1.04-1.34), Charlson comorbidity score (aOR, 1.11 per unit increase; 95% CI, 1.00-1.23), prior hospitalizations in past 12 months (aOR, 1.30 per admission; 95% CI, 1.17-1.45), concurrent intravenous antimicrobial therapy (aOR, 1.89; 95% CI, 1.03-3.47) and endovascular infection (aOR, 3.51; 95% CI, 1.49-8.28). Mode of OPAT treatment was retained in the model as a confounder. The model had adequate concordance (c-statistic 0.72; 95% CI 0.67-0.77) and calibration (Hosmer-Lemeshow p 0.546; calibration slope 0.99; 95% CI 0.78-1.21), and low degree of optimism (bootstrap optimism corrected c-statistic, 0.70). CONCLUSIONS: We identified a set of six important predictors of unplanned hospitalization based on readily available data. The prediction model may help improve OPAT outcomes through better identification of high-risk patients and provision of tailored care.

CyBorD-DARA is potent initial induction for MM and enhances ADCP: initial results of the 16-BCNI-001/CTRIAL-IE 16-02 study.

Daratumumab (DARA) has shown impressive activity in combination with other agents for the treatment of multiple myeloma (MM). We conducted a phase 1b study to assess the safety and preliminary efficacy, as well as potential mechanisms of action, of DARA (16 mg/kg) in combination with a weekly schedule of subcutaneous bortezomib (1.3-1.5 mg/m2), cyclophosphamide (150-300 mg/m2), and dexamethasone (40 mg) (CyBorD DARA) as initial induction before autologous stem cell transplantation (ASCT). Eligible patients were ≤70 years of age with untreated MM requiring treatment and who lacked significant comorbidities. A total of 18 patients were enrolled. Their median age was 56 years (range, 32-66 years), and all patients had Eastern Cooperative Oncology Group performance status ≤1. The International Staging System stages were I, II, and III in 78%, 17%, and 6% of patients, respectively; 28% of patients had high-risk genetic features. There was no dose-limiting toxicity, and the incidence of grade 3 or 4 infection or neutropenia was <10%. On an intention-to-treat basis, 94% achieved ≥very good partial response with ≥complete response in 44% of patients. Among 14 of 15 patients who underwent ASCT and were evaluable for response, all 14 achieved at least very good partial response, with 8 (57%) of 14 achieving complete response. After ASCT, 10 (83%) of 12 patients in whom minimal residual disease analysis was possible were negative at a sensitivity of 10-5 (56% on intention-to-treat/whole study population) according to next-generation sequencing. Flow cytometry analysis of patient samples indicated CyBorD DARA induced activation of macrophage-mediated antibody-dependent cellular phagocytosis. This trial was registered at www.clinicaltrials.gov as #NCT02955810.

Development of a modified dry curing process for beef.

The development of a dry curing process using physical treatments to promote the diffusion of the cure ingredients was studied. Vacuum pulsing with and without tumbling, continuous vacuum, and tumbling only treatments were compared with a conventional static dry cure control method on beef M. supraspinatus. Vacuum tumble and tumble only treatments gave highest core salt content after 7 days conditioning (3.3% and 3.1%, respectively). All test treatments resulted in higher colour uniformity and lower % cook loss in comparison to control (P<0.001). The control and vacuum pulsed samples were tougher (P<0.001). Vacuum tumble and tumble only treatments gave higher acceptability (P<0.001). Based on these findings for M. supraspinatus, indicating that the vacuum tumble treatments gave the best results, further testing of this method was conducted using the M. biceps femoris in addition to the M. supraspinatus. Cured beef slices were stored in modified atmosphere packs (MAP) (80%N(2):20%CO(2)) for up to 28 day at 4°C. Redness (a(∗), P<0.001) decreased over storage time in M. biceps femoris. Vacuum tumble treatment increased (P<0.05) redness in M. supraspinatus. Results obtained demonstrate the benefits of vacuum tumbling over the other physical treatments as a method for accelerating the dry curing process, producing dry cured beef products with enhanced organoleptic quality and increased yields.

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis.

By causing mitochondrial DNA (mtDNA) mutations and oxidation of mitochondrial proteins, reactive oxygen species (ROS) leads to perturbations in mitochondrial proteostasis. Several studies have linked mtDNA mutations to metastasis of cancer cells but the nature of the mtDNA species involved remains unclear. Our data suggests that no common mtDNA mutation identifies metastatic cells; rather the metastatic potential of several ROS-generating mutations is largely determined by their mtDNA genomic landscapes, which can act either as an enhancer or repressor of metastasis. However, mtDNA landscapes of all metastatic cells are characterized by activation of the SIRT/FOXO/SOD2 axis of the mitochondrial unfolded protein response (UPRmt). The UPRmt promotes a complex transcription program ultimately increasing mitochondrial integrity and fitness in response to oxidative proteotoxic stress. Using SOD2 as a surrogate marker of the UPRmt, we found that in primary breast cancers, SOD2 is significantly increased in metastatic lesions. We propose that the ability of selected mtDNA species to activate the UPRmt is a process that is exploited by cancer cells to maintain mitochondrial fitness and facilitate metastasis.

Effects of enhancement procedures on whole and re-formed beef forequarter muscles.

Beef Supraspinatus and Triceps brachii muscles were subjected to three enhancement and/or re-forming treatments: (i) injected whole @ 15%w/w with salt-phosphate solution; (ii) injected and re-formed; (iii) injected with added flavouring and re-formed. The treated muscles were compared to whole uninjected controls. All injection treatments reduced shear force values of cooked samples and in most cases these reductions were reflected in sensory panel tenderness and chewiness ratings. For example, shear values for Supraspinatus were 83N/g in control samples and 50 in whole injected samples, while corresponding sensory panel tenderness ratings were 3.6 and 5.2. Enhanced samples did not differ from controls in sliceability or in colour and binding ratings, indicating that enhancement combined with re-forming can give an acceptable roast beef product. There were no differences in drip loss and very few differences in colour L*, a* and b* values for raw samples between any of the treatments. Addition of beef stock did not result in higher flavour ratings by sensory panels. Whole injected samples scored higher for flavour than both control (p<0.01) and injected+re-formed (p<0.05) samples.