This paper describes the modification of a simple land snow cover module of the INM RAS climate model. The possible liquid water and refreezing of meltwater in the snow layer are taken into account ...by the proposed parameterization. This is particularly important for modelling the transition season, as this phenomenon is mainly observed during the formation and melting of the snow cover when the surface temperature fluctuates around 0 °C. The snow density evolution simulation is also added. This parameterization is implemented in the INM-CM snow module and verified on observation data using the ESM-SnowMIP-like protocol. As a result, the INM-CM mean climate snow melt periods are refined, particularly in middle and high latitudes. The snow-covered area according to the model is also improved. In the future, a modified version of the land snow module can be used, coupled with a snow albedo model that takes into account snow metamorphism. This module can also be applied to sea ice snow.
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Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), has recently emerged as a prominent biomarker of prostate cancer (PC) and as an ...attractive protein trap for drug targeting. At the present time, several drugs and molecular diagnostic tools conjugated with selective PSMA ligands are actively evaluated in different preclinical and clinical trials. In the current work, we discuss design, synthesis and a preliminary biological evaluation of PSMA-specific small-molecule carrier equipped by Doxorubicin (Dox). We have introduced an unstable azo-linker between Dox and the carrier hence the designed compound does release the active substance inside cancer cells thereby providing a relatively high Dox concentration in nuclei and a relevant cytotoxic effect. In contrast, we have also synthesized a similar conjugate with a stable amide linker and it did not release the drug at all. This compound was predominantly accumulated in cytoplasm and did not cause cell death. Preliminary in vivo evaluation has showed good efficiency for the degradable conjugate against PC3-PIP(PSMA+)-containing xenograft mine. Thus, we have demonstrated that the conjugate can be used as a template to design novel analogues with improved targeting, anticancer activity and lower rate of potential side effects. 3D molecular docking study has also been performed to elucidate the underlying mechanism of binding and to further optimization of the linker area for improving the target affinity.
Non-invasive radionuclide imaging of human epidermal growth factor receptor type 2 (HER2) expression in breast, gastroesophageal, and ovarian cancers may stratify patients for treatment using ...HER2-targeted therapeutics. Designed ankyrin repeat proteins (DARPins) are a promising type of targeting probe for radionuclide imaging. In clinical studies, the DARPin 99mTcTc-(HE)3-G3 labeled using a peptide-based chelator His-Glu-His-Glu-His-Glu ((HE)3), provided clear imaging of HER2 expressing breast cancer 2–4 h after injection. The goal of this study was to evaluate if the use of cysteine-containing peptide-based chelators Glu-Glu-Glu-Cys (E3C), Gly-Gly-Gly-Cys (G3C), and Gly-Gly-Gly-Ser-Cys connected via a (Gly-Gly-Gly-Ser)3-linker (designated as G3-(G3S)3C) would further improve the contrast of imaging using 99mTc-labeled derivatives of G3. The labeling of the new variants of G3 provided a radiochemical yield of over 95%. Labeled G3 variants bound specifically to human HER2-expressing cancer cell lines with affinities in the range of 1.9–5 nM. Biodistribution of 99mTcTc-G3-G3C, 99mTcTc-G3-(G3S)3C, and 99mTcTc-G3-E3C in mice was compared with the biodistribution of 99mTcTc-(HE)3-G3. It was found that the novel variants provide specific accumulation in HER2-expressing human xenografts and enable discrimination between tumors with high and low HER2 expression. However, 99mTcTc-(HE)3-G3 provided better contrast between tumors and the most frequent metastatic sites of HER2-expressing cancers and is therefore more suitable for clinical applications.
MXenes are 2D transition metal carbides, nitrides, and/or carbonitrides that can be intercalated with cations through chemical or electrochemical pathways. While the insertion of alkali and alkaline ...earth cations into Ti3C2T x MXenes is well studied, understanding of the intercalation of redox-active transition metal ions into MXenes and its impact on their electronic and electrochemical properties is lacking. In this work, we investigate the intercalation of Cu ions into Ti3C2T x MXene and its effect on its electronic and electrochemical properties. Using X-ray absorption spectroscopy (XAS) and ab initio molecular dynamics (AIMD), we observe an unusual phenomenon whereby Cu2+ ions undergo partial reduction upon intercalation from the solution into the MXene. Furthermore, using in situ XAS, we reveal changes in the oxidation states of intercalated Cu ions and Ti atoms during charging. We show that the pseudocapacitive response of Cu-MXene originates from the redox of both the Cu intercalant and Ti3C2T x host. Despite highly reducing potentials, Cu ions inside the MXene show an excellent stability against full reduction upon charging. Our findings demonstrate how electronic coupling between Cu ions and Ti3C2T x modifies electrochemical and electronic properties of the latter, providing the framework for the rational design and utilization of transition metal intercalants for tuning the properties of MXenes for various electrochemical systems.
HER2 status determination is a necessary step for the proper choice of therapy and selection of patients for the targeted treatment of cancer. Targeted radiotracers such as radiolabeled DARPins ...provide a noninvasive and effective way for the molecular imaging of HER2 expression. This study aimed to evaluate tumor-targeting properties of three
Tc-labeled DARPin G3 variants containing Gly-Gly-Gly-Cys (G
C), (Gly-Gly-Gly-Ser)
-Cys ((G
S)
C), or Glu-Glu-Glu-Cys (E
C) amino acid linkers at the C-terminus and conjugated to the HYNIC chelating agent, as well as to compare them with the clinically evaluated DARPin G3 labeled with
Tc(CO)
using the (HE)
-tag at the N-terminus. The labeling of DARPin G3-HYNIC variants provided radiochemical yields in the range of 50-80%. Labeled variants bound specifically to human HER2-expressing cancer cell lines with affinities in the range of 0.5-3 nM. There was no substantial influence of the linker and HYNIC chelator on the binding of
Tc-labeled DARPin G3 variants to HER2 in vitro; however,
TcTc-G3-(G
S)
C-HYNIC had the highest affinity. Comparative biodistribution of
TcTc-G3-G
C-HYNIC,
TcTc-G3-(G
S)
C-HYNIC,
TcTc-G3-E
C-HYNIC, and
TcTc-(HE)
-G3 in healthy CD1 mice showed that there was a strong influence of the linkers on uptake in normal tissues.
TcTc-G3-E
C-HYNIC had an increased retention of activity in the liver and the majority of other organs compared to the other conjugates. The tumor uptake of
TcTc-G3-(G
S)
C-HYNIC and
TcTc-(HE)
-G3 in Nu/j mice bearing SKOV-3 xenografts was similar. The specificity of tumor targeting in vivo was demonstrated for both tracers.
TcTc-G3-(G
S)
C-HYNIC provided comparable, although slightly lower tumor-to-lung, tumor-to spleen and tumor-to-liver ratios than
TcTc-(HE)
-G3. Radiolabeling of DARPin G3-HYNIC conjugates with
Tc provided the advantage of a single-step radiolabeling procedure; however, the studied HYNIC conjugates did not improve imaging contrast compared to the
Tc-tricarbonyl-labeled DARPin G3. At this stage,
TcTc-(HE)
-G3 remains the most promising candidate for the clinical imaging of HER2-overexpressing cancers.
HER2 status determination is a necessary step for the proper choice of therapy and selection of patients for the targeted treatment of cancer. Targeted radiotracers such as radiolabeled DARPins ...provide a noninvasive and effective way for the molecular imaging of HER2 expression. This study aimed to evaluate tumor-targeting properties of three 99mTc-labeled DARPin G3 variants containing Gly-Gly-Gly-Cys (G3C), (Gly-Gly-Gly-Ser)3-Cys ((G3S)3C), or Glu-Glu-Glu-Cys (E3C) amino acid linkers at the C-terminus and conjugated to the HYNIC chelating agent, as well as to compare them with the clinically evaluated DARPin G3 labeled with 99mTc(CO)3 using the (HE)3-tag at the N-terminus. The labeling of DARPin G3-HYNIC variants provided radiochemical yields in the range of 50–80%. Labeled variants bound specifically to human HER2-expressing cancer cell lines with affinities in the range of 0.5–3 nM. There was no substantial influence of the linker and HYNIC chelator on the binding of 99mTc-labeled DARPin G3 variants to HER2 in vitro; however, 99mTcTc-G3-(G3S)3C-HYNIC had the highest affinity. Comparative biodistribution of 99mTcTc-G3-G3C-HYNIC, 99mTcTc-G3-(G3S)3C-HYNIC, 99mTcTc-G3-E3C-HYNIC, and 99mTcTc-(HE)3-G3 in healthy CD1 mice showed that there was a strong influence of the linkers on uptake in normal tissues. 99mTcTc-G3-E3C-HYNIC had an increased retention of activity in the liver and the majority of other organs compared to the other conjugates. The tumor uptake of 99mTcTc-G3-(G3S)3C-HYNIC and 99mTcTc-(HE)3-G3 in Nu/j mice bearing SKOV-3 xenografts was similar. The specificity of tumor targeting in vivo was demonstrated for both tracers. 99mTcTc-G3-(G3S)3C-HYNIC provided comparable, although slightly lower tumor-to-lung, tumor-to spleen and tumor-to-liver ratios than 99mTcTc-(HE)3-G3. Radiolabeling of DARPin G3-HYNIC conjugates with 99mTc provided the advantage of a single-step radiolabeling procedure; however, the studied HYNIC conjugates did not improve imaging contrast compared to the 99mTc-tricarbonyl-labeled DARPin G3. At this stage, 99mTcTc-(HE)3-G3 remains the most promising candidate for the clinical imaging of HER2-overexpressing cancers.
A critical parameter during the development of protein therapeutics is to endow them with suitable pharmacokinetic and pharmacodynamic properties. Small protein drugs are quickly eliminated by kidney ...filtration, and in vivo half-life extension is therefore often desired. Here, different half-life extension technologies were studied where PAS polypeptides (PAS300, PAS600), XTEN polypeptides (XTEN288, XTEN576), and an albumin binding domain (ABD) were compared for half-life extension of an anti-human epidermal growth factor receptor 2 (HER2) affibody-drug conjugate. The results showed that extension with the PAS or XTEN polypeptides or the addition of the ABD lowered the affinity for HER2 to some extent but did not negatively affect the cytotoxic potential. The half-lives in mice ranged from 7.3 h for the construct including PAS300 to 11.6 h for the construct including PAS600. The highest absolute tumor uptake was found for the construct including the ABD, which was 60 to 160% higher than the PASylated or XTENylated constructs, even though it did not have the longest half-life (9.0 h). A comparison of the tumor-to-normal-organ ratios showed the best overall performance of the ABD-fused construct. In conclusion, PASylation, XTENylation, and the addition of an ABD are viable strategies for half-life extension of affibody-drug conjugates, with the best performance observed for the construct including the ABD.
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Eutrophication is a major ecological problem and affects and endangers freshwater bodies, making assessment of the trophic status of water bodies crucial for their restoration and sustainable use. ...Lake Baikal is affected by a number of environmental stressors, including coastal eutrophication. Daily measurements of concentrations of nutrients, dissolved oxygen (DO), chlorophyll-a (Chl-a), weekly measurements of algae abundance and biomass in the open water season in June-December 2020, and measurements of concentrations of nutrients at 2–7-day intervals in June-October 2021 were made in the littoral of the South Baikal for the first time. It was shown that nitrate and phosphate concentrations decreased by July-August, their minimum content was maintained until September, concentrations began to increase in October and reached a maximum in December. The maximum abundance and biomass of algae and chlorophyll concentrations were only observed in early July. Storm situations increased the content of nitrogen, phosphorus and DO in water, the duration of their influence was not more than 2 days. A correlation matrix revealed significant positive correlations of NO3−-DO, phosphate (SPR)-NO3−, SRP-DO and biomass-Chl-a and strong negative correlations between water temperature (Tw)-DO, Tw-NO3−, Tw-total nitrogen (TN) and Tw-SRP. Based on SRP and NO3− concentrations and TN:TP ratios, it was concluded that algal development was limited to nitrogen and phosphorus in summer. The trophic status of the Southern Baikal littoral zone was assessed using classifications based on TN, TP, NO3−, SRP, Chl-a content and algal biomass, as well as the Carlson index (TSI) and probabilistic assessment. The results of assessments using different methods of trophic status determination showed that the Baikal littoral zone in the study area belongs to the oligotrophic type with minor elements of mesotrophy. According to the saprobity index, water purity of littoral waters varies within the oligosaprobic and β-mesosaprobic zones and corresponded to quality classes II and III (clean and moderate purity); the system demonstrates a high capacity for self-purification.
Human epidermal growth factor receptor type 3 (HER3) plays a crucial role in the progression of many cancer types. In vivo radionuclide imaging could be a reliable method for repetitive detection of ...HER3-expression in tumors. The main challenge of HER3-imaging is the low expression in tumors together with endogenous receptor expression in normal tissues, particularly the liver. A HER3-targeting affibody molecule labeled with radiocobalt via a NOTA chelator
CoCo-NOTA-Z
has demonstrated the most favorable biodistribution profile with the lowest unspecific hepatic uptake and high activity uptake in tumors. We hypothesized that specific uptake of labeled affibody monomer might be selectively blocked in the liver but not in tumors by a co-injection of non-labeled corresponding trivalent affibody (Z
)
. Biodistribution of
CoCo-NOTA-Z
and
InIn-DOTA-(Z
)
was studied in BxPC-3 xenografted mice.
CoCo-NOTA-Z
was co-injected with unlabeled trivalent affibody DOTA-(Z
)
at different monomer:trimer molar ratios. HER3-expression in xenografts was imaged using
CoCo-NOTA-Z
and
CoCo-NOTA-Z
: DOTA-(Z
)
. Hepatic activity uptake of
CoCo-NOTA-Z
: DOTA-(Z
)
decreased with increasing monomer:trimer molar ratio. The tumor activity uptake and tumor-to-liver ratios were the highest for the 1:3 ratio. SPECT/CT images confirmed the biodistribution data. Imaging of HER3 expression can be improved by co-injection of a radiolabeled monomeric affibody-based imaging probe together with a trivalent affibody.
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