The authors show that the diverse mutations in
CALR
that occur in nonmutated
JAK2
myeloproliferative diseases all introduce frameshift mutations that alter the C-terminal part of the protein and ...affect its distribution within cells.
The myeloproliferative neoplasms are chronic myeloid cancers that are characterized by the overproduction of mature blood cells, and that may evolve into acute myeloid leukemia.
1
,
2
In addition to chronic myeloid leukemia with the
BCR-ABL
fusion gene, the three most common myeloproliferative neoplasms are essential thrombocythemia, polycythemia vera, and myelofibrosis.
Many patients with a
BCR-ABL–
negative myeloproliferative neoplasm carry a Janus kinase 2 (
JAK2
) V617F mutation.
3
–
6
The
JAK2
V617F mutation or
JAK2
exon 12 mutations are found in most patients with polycythemia vera,
7
,
8
whereas the
JAK2
V617F mutation is found in only 50 to 60% of . . .
Most myeloproliferative neoplasm (MPN) patients lacking JAK2 mutations harbour somatic CALR mutations that are thought to activate cytokine signalling although the mechanism is unclear. To identify ...kinases important for survival of CALR-mutant cells, we developed a novel strategy (KISMET) that utilizes the full range of kinase selectivity data available from each inhibitor and thus takes advantage of off-target noise that limits conventional small-interfering RNA or inhibitor screens. KISMET successfully identified known essential kinases in haematopoietic and non-haematopoietic cell lines and identified the mitogen activated protein kinase (MAPK) pathway as required for growth of the CALR-mutated MARIMO cells. Expression of mutant CALR in murine or human haematopoietic cell lines was accompanied by myeloproliferative leukemia protein (MPL)-dependent activation of MAPK signalling, and MPN patients with CALR mutations showed increased MAPK activity in CD34 cells, platelets and megakaryocytes. Although CALR mutations resulted in protein instability and proteosomal degradation, mutant CALR was able to enhance megakaryopoiesis and pro-platelet production from human CD34
progenitors. These data link aberrant MAPK activation to the MPN phenotype and identify it as a potential therapeutic target in CALR-mutant positive MPNs.
In this study, the economic viability of hydrogen production in the Republic of Uzbekistan was evaluated. Specifically, the costs and breakeven prices for hydrogen production were analysed across ...five selected regions within the Republic. The analysis focused on the potential reduction in production costs achievable through investor engagement. Among the regions studied, Tashkent exhibited the lowest production cost at 1.2 USD/kg. In scenarios devoid of investor participation, the levelized cost of hydrogen (LCOH) was estimated to range between 1.25 and 2.00 USD/kg. The inclusion of investors was found to yield an average profit of 0.35 USD/kg across the Republic. The findings suggest that with an average production cost of 1.2 USD/kg, hydrogen production in the Republic of Uzbekistan could be economically viable.
Ni(II) complexes with the composition Ni(L
n
)
A
(
n
= 1-4,
A
= NH
3
, Py) based on the products obtained by the condensation of benzoylacetalaldehyde with hydrazides of aromatic acids (H
2
L
1
–H
...2
L
4
) are synthesized and studied. The obtained crystallographic data for complex NiL
2
·Py are: triclinic crystal system, space group
,
a
= 9.3151(9) Å,
b
= 10.5675(11) Å,
c
= 11.9266(7) Å, α = 112.030(7)°, β = 92.227(6)°, γ = 115.341(10)°,
V
= 955.33(17) Å
3
,
Z
= 2,
R
1
= 0.045, and
wR
2
= 0.106; for complex NiL
4
·NH
3
: monoclinic system, space group
P
2
1
/
c
,
a
= 10.3837(9) Å,
b
= 8.2507(6) Å,
c
= 19.630(2) Å, β = 98.658(11)°,
V
= 1662.5(3) Å
3
,
Z
= 3,
R
1
= 0.0485, and
wR
2
= 0.1305.
Abstract
This article focuses on the study of physical and geographical aspects of toponymy, which involves the naming and renaming of geographical objects based on the natural features of a place. ...The research in this field prioritizes the normalization and standardization of geographical names, compilation of a state register of geographical names, proper use of names, publication of toponymic dictionaries, and transliteration of geographical names. In this regard, the present paper analyzes scientific research on toponyms from various regions worldwide, including Uzbekistan. A classification system of geographical names and physical and geographical features of toponyms specific to the regions of Uzbekistan has been developed and recommended, taking into account the natural characteristics of the place. Additionally, thematic toponymic maps have been developed.
Studies of misfolded protein targeting to endoplasmic reticulum-associated degradation (ERAD) have largely focused on glycoproteins, which include the bulk of the secretory proteins. Mechanisms of ...targeting of nonglycosylated proteins are less clear. Here, we studied three nonglycosylated proteins and analyzed their use of known glycoprotein quality control and ERAD components. Similar to an established glycosylated ERAD substrate, the uncleaved precursor of asialoglycoprotein receptor H2a, its nonglycosylated mutant, makes use of calnexin, EDEM1, and HRD1, but only glycosylated H2a is a substrate for the cytosolic SCFFbs2 E3 ubiquitin ligase with lectin activity. Two nonglycosylated BiP substrates, NS-1κ light chain and truncated Igγ heavy chain, interact with the ERAD complex lectins OS-9 and XTP3-B and require EDEM1 for degradation. EDEM1 associates through a region outside of its mannosidase-like domain with the nonglycosylated proteins. Similar to glycosylated substrates, proteasomal inhibition induced accumulation of the nonglycosylated proteins and ERAD machinery in the endoplasmic reticulum-derived quality control compartment. Our results suggest a shared ERAD pathway for glycosylated and nonglycosylated proteins composed of luminal lectin machinery components also capable of protein-protein interactions.
Background:N-Glycan processing and interactions with lectins regulate the quality control and endoplasmic reticulum-associated degradation (ERAD) of glycoproteins.
Results: Most of the same machinery targets nonglycosylated misfolded proteins.
Conclusion: They share some membrane and luminal ERAD machinery but not all cytosolic components.
Significance: ER glycan-interacting proteins must possess a dual specificity for glycan structure and for exposed misfolded polypeptide domains.
The endoplasmic reticulum (ER) forms an interconnected network of tubules stretching throughout the cell. Understanding how ER functionality relies on its structural organization is crucial for ...elucidating cellular vulnerability to ER perturbations, which have been implicated in several neuronal pathologies. One of the key functions of the ER is enabling CaFormula: see text signaling by storing large quantities of this ion and releasing it into the cytoplasm in a spatiotemporally controlled manner. Through a combination of physical modeling and live-cell imaging, we demonstrate that alterations in ER shape significantly impact its ability to support efficient local CaFormula: see text releases, due to hindered transport of luminal content within the ER. Our model reveals that rapid CaFormula: see text release necessitates mobile luminal buffer proteins with moderate binding strength, moving through a well-connected network of ER tubules. These findings provide insight into the functional advantages of normal ER architecture, emphasizing its importance as a kinetically efficient intracellular CaFormula: see text delivery system.
DnaK/Hsp70 chaperones form oligomers of poorly understood structure and functional significance. Site-specific proteolysis and crosslinking were used to probe the architecture of oligomers formed by ...the endoplasmic reticulum (ER) Hsp70, BiP. These were found to consist of adjacent protomers engaging the interdomain linker of one molecule in the substrate binding site of another, attenuating the chaperone function of oligomeric BiP. Native gel electrophoresis revealed a rapidly-modulated reciprocal relationship between the burden of unfolded proteins and BiP oligomers and slower equilibration between oligomers and inactive, covalently-modified BiP. Lumenal ER calcium depletion caused rapid oligomerization of mammalian BiP and a coincidental diminution in substrate binding, pointing to the relative inertness of the oligomers. Thus, equilibration between inactive oligomers and active monomeric BiP is poised to buffer fluctuations in ER unfolded protein load on a rapid timescale attainable neither by inter-conversion of active and covalently-modified BiP nor by the conventional unfolded protein response.
The endoplasmic reticulum (ER) forms an interconnected network of tubules stretching throughout the cell. Understanding how ER functionality relies on its structural organization is crucial for ...elucidating cellular vulnerability to ER perturbations, which have been implicated in several neuronal pathologies. One of the key functions of the ER is enabling Ca2+ signaling by storing large quantities of this ion and releasing it into the cytoplasm in a spatiotemporally controlled manner. Through a combination of physical modeling and live-cell imaging, we demonstrate that alterations in ER shape significantly impact its ability to support efficient local Ca2+ releases, due to hindered transport of luminal content within the ER. Our model reveals that rapid Ca2+ release necessitates mobile luminal buffer proteins with moderate binding strength, moving through a well-connected network of ER tubules. These findings provide insight into the functional advantages of normal ER architecture, emphasizing its importance as a kinetically efficient intracellular Ca2+ delivery system.
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