This study provides extended seasonal predictions for the Upper Colorado River Basin (UCRB) precipitation in boreal spring using an artificial neural network (ANN) model and a stepwise linear ...regression model, respectively. Sea surface temperature (SST) predictors are developed taking advantage of the correlation between the precipitation and SST over three ocean basins. The extratropical North Pacific has a higher correlation with the UCRB spring precipitation than the tropical Pacific and North Atlantic. For the ANN model, the Pearson correlation coefficient between the observed and predicted precipitation exceeds 0.45 (
p
-value < 0.01) for a lead time of 12 months. The mean absolute percentage error (MAPE) is below 20% and the Heidke skill score (HSS) is above 50%. Such long-lead prediction skill is probably due to the UCRB soil moisture bridging the SST and precipitation. The stepwise linear regression model shows similar prediction skills to those of ANN. Both models show prediction skills superior to those of an autoregression model (correlation < 0.10) that represents the baseline prediction skill and those of three of the North American Multi-Model Ensemble (NMME) forecast models. The three NMME models exhibit different skills in predicting the precipitation, with the best skills of the correlation ~ 0.40, MAPE < 25%, and HSS > 40% for lead times less than 8 months. This study highlights the advantage of oceanic climate signals in extended seasonal predictions for the UCRB spring precipitation and supports the improvement of the UCRB streamflow prediction and related water resource decisions.
A detailed chemical understanding of H
2
interactions with binding sites in the nanoporous crystalline structure of metal-organic frameworks (MOFs) can lay a sound basis for the design of new sorbent ...materials. Computational quantum chemical calculations can aid in this quest. To set the stage, we review general thermodynamic considerations that control the usable storage capacity of a sorbent. We then discuss cluster modeling of H
2
ligation at MOF binding sites using state-of-the-art density functional theory (DFT) calculations, and how the binding can be understood using energy decomposition analysis (EDA). Employing these tools, we illustrate the connections between the character of the MOF binding site and the associated adsorption thermodynamics using four experimentally characterized MOFs, highlighting the role of open metal sites (OMSs) in accessing binding strengths relevant to room temperature storage. The sorbents are MOF-5, with no open metal sites, Ni
2
(
m
-dobdc), containing Lewis acidic Ni(
ii
) sites, Cu(
i
)-MFU-4
l
, containing π basic Cu(
i
) sites and V
2
Cl
2.8
(btdd), also containing π-basic V(
ii
) sites. We next explore the potential for binding multiple H
2
molecules at a single metal site, with thermodynamics useful for storage at ambient temperature; a materials design goal which has not yet been experimentally demonstrated. Computations on Ca
2+
or Mg
2+
bound to catecholate or Ca
2+
bound to porphyrin show the potential for binding up to 4 H
2
; there is precedent for the inclusion of both catecholate and porphyrin motifs in MOFs. Turning to transition metals, we discuss the prediction that two H
2
molecules can bind at V(
ii
)-MFU-4
l
, a material that has been synthesized with solvent coordinated to the V(
ii
) site. Additional calculations demonstrate binding three equivalents of hydrogen per OMS in Sc(
i
) or Ti(
i
)-exchanged MFU-4
l
. Overall, the results suggest promising prospects for experimentally realizing higher capacity hydrogen storage MOFs, if nontrivial synthetic and desolvation challenges can be overcome. Coupled with the unbounded chemical diversity of MOFs, there is ample scope for additional exploration and discovery.
A detailed chemical understanding of H
2
interactions with binding sites in the nanoporous crystalline structure of metal-organic frameworks (MOFs) can lay a sound basis for the design of new sorbent materials.
Delivering highly water soluble drugs across blood-brain barrier (BBB) is a crucial challenge for the formulation scientists. A successful therapeutic intervention by developing a suitable drug ...delivery system may revolutionize treatment across BBB. Efforts were given here to unravel the capability of a newly developed fatty acid combination (stearic acid:oleic acid:palmitic acid = 8.08:4.13:1) (ML) as fundamental component of nanocarrier to deliver highly water soluble zidovudine (AZT) as a model drug into brain across BBB. A comparison was made with an experimentally developed standard phospholipid-based nanocarrier containing AZT. Both the formulations had nanosize spherical unilamellar vesicular structure with highly negative zeta potential along with sustained drug release profiles. Gamma scintigraphic images showed both the radiolabeled formulations successfully crossed BBB, but longer retention in brain was observed for ML-based formulation (MGF) as compared to soya lecithin (SL)-based drug carrier (SYF). Plasma and brain pharmacokinetic data showed less clearance, prolonged residence time, more bioavailability and sustained release of AZT from MGF in rats compared to those data of the rats treated with SYF/AZT suspension. Thus, ML may be utilized to successfully develop drug nanocarrier to deliver drug into brain across BBB, in a sustained manner for a prolong period of time and may provide an effective therapeutic strategy for many diseases of brain. Further, many anti-HIV drugs cannot cross BBB sufficiently. Hence, the developed formulation may be a suitable option to carry those drugs into brain for better therapeutic management of HIV.
Although both COVID-19 and non-COVID-19 ARDS can be accompanied by significantly increased levels of circulating cytokines, the former significantly differs from the latter by its higher ...vasculopathy, characterized by increased oxidative stress and coagulopathy in lung capillaries. This points towards the existence of SARS-CoV2-specific factors and mechanisms that can sensitize the endothelium towards becoming dysfunctional. Although the virus is rarely detected within endothelial cells or in the circulation, the S1 subunit of its spike protein, which contains the receptor binding domain (RBD) for human ACE2 (hACE2), can be detected in plasma from COVID-19 patients and its levels correlate with disease severity. It remains obscure how the SARS-CoV2 RBD exerts its deleterious actions in lung endothelium and whether there are mechanisms to mitigate this.
In this study, we use a combination of
studies in RBD-treated human lung microvascular endothelial cells (HL-MVEC), including electrophysiology, barrier function, oxidative stress and human ACE2 (hACE2) surface protein expression measurements with
studies in transgenic mice globally expressing human ACE2 and injected with RBD.
We show that SARS-CoV2 RBD impairs endothelial ENaC activity, reduces surface hACE2 expression and increases reactive oxygen species (ROS) and tissue factor (TF) generation in monolayers of HL-MVEC, as such promoting barrier dysfunction and coagulopathy. The TNF-derived TIP peptide (a.k.a. solnatide, AP301) -which directly activates ENaC upon binding to its a subunit- can override RBD-induced impairment of ENaC function and hACE2 expression, mitigates ROS and TF generation and restores barrier function in HL-MVEC monolayers. In correlation with the increased mortality observed in COVID-19 patients co-infected with S. pneumoniae, compared to subjects solely infected with SARS-CoV2, we observe that prior intraperitoneal RBD treatment in transgenic mice globally expressing hACE2 significantly increases fibrin deposition and capillary leak upon intratracheal instillation of S. pneumoniae and that this is mitigated by TIP peptide treatment.
Immunoassays based on label-free technologies (label-free immunoassay LFIA) offer an innovative approach to clinical diagnostics and demonstrate great promise for therapeutic drug monitoring (TDM) of ...monoclonal antibody (mAb) drugs. An LFIA measures immunocomplex formation in real time and allows for quantification on initial binding rate, which facilitates fast measurement within a few minutes.
Based on thin-film interferometry (TFI) technology, open-access LFIAs were developed for the quantification of the mAb drugs adalimumab (ADL) and infliximab (IFX) and for the detection of the antidrug antibodies (ADAs) to the mAb drugs (ADL-ADAs and IFX-ADAs).
The LFIAs for active mAb drugs (ADL and IFX) and for ADAs (ADL-ADAs and IFX-ADAs) were validated. The analytical measurement range (AMR) for both ADL and IFX was from 2 to 100 μg/mL. The AMR for ADL-ADAs was from 5 to 100 μg/mL and for IFX-ADAs was 10 to 100 μg/mL. In the comparison of LFIAs and reporter gene assays, the correlation coefficient was 0.972 for the quantification of ADL and 0.940 for the quantification of IFX. The concordance rate was 90% for the detection of ADL-ADAs and 76% for the detection of IFX-ADAs.
The LFIAs for active mAb drugs and ADAs were appropriate for the TDM of ADL and IFX. The TFI technology has unique advantages compared with other technologies used for the measurement of mAb drugs. Label-free technologies, especially those allowing for open-access LFIAs, have great potential for clinical diagnostics.
Nonribosomal peptides (NRPs) are a class of secondary metabolites usually produced by microorganisms. They are of paramount importance in different applications, including biocontrol and pharmacy.
...spp. are a rich source of NRPs yet have received little attention. In this study, we characterize four novel bogorol variants (bogorols I to L, cationic linear lipopeptides) and four succilins (succilins I to L, containing a succinyl group that is attached to the Orn
/Lys
in bogorols I to L) from the biocontrol strain
MG64. Further investigation revealed that the bogorol family of peptides employs an adenylation pathway for lipoinitiation, different from the usual pattern, which is based on an external ligase and coenzyme A. Moreover, the formation of valinol was proven to be mediated by a terminal reductase domain and a reductase encoded by the
gene. Furthermore, succinylation, which is a novel type of modification in the family of bogorols, was discovered. Its occurrence requires a high concentration of the substrate (bogorols), but its responsible enzyme remains unknown. Bogorols display potent activity against both Gram-positive and Gram-negative bacteria. Investigation of their mode of action reveals that bogorols form pores in the cell membrane of both Gram-positive and Gram-negative bacteria. The combination of bogorols and relacidines, another class of NRPs produced by
MG64, displays a synergistic effect on different pathogens, suggesting the great potential of both peptides as well as their producer
MG64 for broad applications. Our study provides a further understanding of the bogorol family of peptides as well as their applications.
NRPs form a class of secondary metabolites with biocontrol and pharmaceutical potential. This work describes the identification of novel bogorol variants and succinylated bogorols (namely, succilins) and further investigates their biosynthetic pathway and mode of action. Adenylation domain-mediated lipoinitiation of bogorols represents a novel pathway by which NRPs incorporate fatty acid tails. This pathway provides the possibility to engineer the lipid tail of NRPs without identifying a fatty acid coenzyme ligase, which is usually not present in the biosynthetic gene cluster. The terminal reductase domain (TD) and BogI-mediated valinol formation and their effect on the biological activity of bogorols are revealed. Succinylation, which is rarely reported in NRPs, was discovered in the bogorol family of peptides. We demonstrate that bogorols combat bacterial pathogens by forming pores in the cell membrane. We also report the synergistic effect of two natural products (relacidine B and bogorol K) produced by the same strain, which is relevant for competition for a niche.
•Precipitation δ18Os at the NW Himalaya show different values during monsoon and non-monsoon season.•δ18Os during the WD events show strong correlation with the regional meteorological ...parameters.•This property establishes relation between precipitation δ18O and the meteorological parameters.
The Kashmir Valley represents a critical region for understanding isotopic changes in the atmospheric moisture sources since it is located at the intercept between the influences of mid-latitude westerlies and the southwest monsoon circulation. This study presents the variation in isotopic composition (δ18O and δ2H) of daily precipitation samples collected from the Kashmir Valley, North-Western Himalaya, to quantify the effect of meteorological parameters, separately for the Southwest monsoon (SWM) season and the periods of Western Disturbances (WDs). The results suggest that precipitation isotopic composition is strongly modulated by temperature and relative humidity during the periods of WDs. Still, this dependency is weak in the case of the SWM season. Moisture transport pathways calculated from HYSPLIT back trajectory analysis shows a wide spatial variability during the monsoon season. On the other hand, the origin of moisture during the WD season was mostly restricted from the Mediterranean region, providing an explanation of a strong dependency between the precipitation isotopes and the meteorological parameters during the WD period. Such kind of relation may provide additional diagnostic for the WD events and may help in paleo-monsoon investigations.
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