A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo

Parkinson’s disease (PD) is the most common age-related movement disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons. To date, PD treatment strategies are mostly based on dopamine replacement medicines, which can alleviate motor symptoms but do not slow down the progression of neurodegeneration. Thus, there is a need for disease-modifying PD therapies. The aim of this work was to evaluate the neuroprotective effects of the novel compound PA96 on dopamine neurons in vivo and in vitro, assess its ability to alleviate motor deficits in MPTP- and haloperidol-based PD models, as well as PK profile and BBB penetration. PA96 was synthesized from (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl) cyclohex-3-ene-1,2-diol (Prottremin) using the original three-step stereoselective procedure. We found that PA96: (1) supported the survival of cultured näive dopamine neurons; (2) supported the survival of MPP+-challenged dopamine neurons in vitro and in vivo; (3) had chemically appropriate properties (synthesis, solubility, etc.); (4) alleviated motor deficits in MPTP- and haloperidol-based models of PD; (5) penetrated the blood–brain barrier in vivo; and (6) was eliminated from the bloodstream relative rapidly. In conclusion, the present article demonstrates the identification of PA96 as a lead compound for the future development of this compound into a clinically used drug

Interdecadal Oscillation of the Ocean Heat Content as a Contribution to Understanding of Physical Aspects of the Present-Day Climate

A Specific feature of the present-day climate dynamics consists in its multidecadal oscillations with a period of about 20–60 years, and intradecadal disturbances with time scales of 2–8 years. The period of 1940–1999 was distinctive due to the two–phase structure in which the initial phase (1940–1974) was substantially dry, and the final one (1975–1999) was relatively humid. The transition of the climate from the dry to the humid phase in the mid-1970s was recognized as a climatic shift. The certain globality and quasisynchronism of multidecadal climate changes occur involving planetary thermodynamic structures in the two most important components of the climate system, namely, the ocean and the atmosphere. The search for the origin of the observed present-day climate variability revealed the World Ocean (WO) active upper layer (AUL) heat content to demonstrate sequential multidecadal phases of heat accumulation and discharge consistent with multidecadal phases of climate disturbances. Thus, the WO AUL heat accumulation phase corresponds to a dry climate, and its thermal discharge corresponds to a relatively humid one. The mechanism of the observed multidecadal phase variability in the present-day climate consists of the planetary intrasystemic redistribution of heat between WO and continental air masses, where the general circulation of the atmosphere plays the role of an intermediary

Interdecadal Oscillation of the Ocean Heat Content as a Contribution to Understanding of Physical Aspects of the Present-Day Climate

A Specific feature of the present-day climate dynamics consists in its multidecadal oscillations with a period of about 20–60 years, and intradecadal disturbances with time scales of 2–8 years. The period of 1940–1999 was distinctive due to the two–phase structure in which the initial phase (1940–1974) was substantially dry, and the final one (1975–1999) was relatively humid. The transition of the climate from the dry to the humid phase in the mid-1970s was recognized as a climatic shift. The certain globality and quasisynchronism of multidecadal climate changes occur involving planetary thermodynamic structures in the two most important components of the climate system, namely, the ocean and the atmosphere. The search for the origin of the observed present-day climate variability revealed the World Ocean (WO) active upper layer (AUL) heat content to demonstrate sequential multidecadal phases of heat accumulation and discharge consistent with multidecadal phases of climate disturbances. Thus, the WO AUL heat accumulation phase corresponds to a dry climate, and its thermal discharge corresponds to a relatively humid one. The mechanism of the observed multidecadal phase variability in the present-day climate consists of the planetary intrasystemic redistribution of heat between WO and continental air masses, where the general circulation of the atmosphere plays the role of an intermediary

A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo

Parkinson's disease (PD) is the most common age-related movement disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons. To date, PD treatment strategies are mostly based on dopamine replacement medicines, which can alleviate motor symptoms but do not slow down the progression of neurodegeneration. Thus, there is a need for disease-modifying PD therapies. The aim of this work was to evaluate the neuroprotective effects of the novel compound PA96 on dopamine neurons in vivo and in vitro, assess its ability to alleviate motor deficits in MPTP- and haloperidol-based PD models, as well as PK profile and BBB penetration. PA96 was synthesized from (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl) cyclohex-3-ene-1,2-diol (Prottremin) using the original three-step stereoselective procedure. We found that PA96: (1) supported the survival of cultured naive dopamine neurons; (2) supported the survival of MPP+-challenged dopamine neurons in vitro and in vivo; (3) had chemically appropriate properties (synthesis, solubility, etc.); (4) alleviated motor deficits in MPTP- and haloperidol-based models of PD; (5) penetrated the blood-brain barrier in vivo; and (6) was eliminated from the bloodstream relative rapidly. In conclusion, the present article demonstrates the identification of PA96 as a lead compound for the future development of this compound into a clinically used drug.Peer reviewe

Supplementary Table S6 from Passenger Gene Coamplifications Create Collateral Therapeutic Vulnerabilities in Cancer

QC sample reporting for Gas chromatography–mass spectrometry (GS-MS)</p

Supplementary Figures S1-S9 from Passenger Gene Coamplifications Create Collateral Therapeutic Vulnerabilities in Cancer

Legends for supplementarytables and supplementary figures. Supplementary Figure S1. Passenger genes are frequently co-amplified with oncogenes in cancers. Supplementary Figure S2. DDX1 is highly expressed when co-amplified with MYCN. Supplementary Figure S3. Neuroblastoma cell lines with DDX1-MYCN co-amplification depend on mTORC1. Supplementary Figure S4. Ectopic DDX1 expression does not alter MYCN-driven tumorigenesis in zebrafish. Supplementary Figure S5.DDX1 expression does not affect tumorigenic properties of cancer cell lines but induces changes in cell size. Supplementary Figure S6. Aberrant DDX1 overexpression results in mTOCR1 pathway activation. Supplementary Figure S7. DDX1 interacts with alpha-KGDH complex members and disruption of the DDX1:DLST interaction reduces mTORC1 pathway activation. Supplementary Figure S8. High DDX1 expression is associated with -KG accumulation and OXPHOS reduction. Supplementary Figure S9. Aberrant DDX1 expression is associated with increased sensitivity to KG and pharmacological mTORC1 inhibition.</p

Supplementary Table S5 from Passenger Gene Coamplifications Create Collateral Therapeutic Vulnerabilities in Cancer

Metabolite levels in cells with DDX1-MYCN co-amplification compared to cell lines without such co-amplification.</p

Figure 3 from Passenger Gene Coamplifications Create Collateral Therapeutic Vulnerabilities in Cancer

A proof-of-principle study identifies a selective mTOR pathway dependency in cells with DDX1-MYCN coamplification. A, Correlation between DDX1 copy-number and dependency scores (CERES) for RAPTOR in neuroblastoma cell lines (Pearson correlation analysis, R = −0.5996, P = 0.0152, N = 13). B, Western immunoblot of RAPTOR and DDX1 in the KELLY cells transduced with the doxycycline-inducible DDX1-mCherry vectors and with two pairs of sgRNAs targeting RAPTOR (sgRAPTOR) or a nontargeting sgRNA (sgNT) as well as Cas9 in the presence and absence of doxycycline (1 μg/mL). Tubulin serves as a loading control. C, Representative images of cell colonies formed by KELLY cells transduced with the doxycycline-inducible DDX1-mCherry vectors and with two pairs of sgRNA targeting RAPTOR (sgRAPTOR) or nontarget sgRNA (sgNT) as well as Cas9 in the presence and absence of doxycycline (1 μg/mL) and stained with crystal violet (left). Quantification of colony numbers (right, mean ± SE. N = 3 biological replicates; Welch t test, P = 0.564, 0.000117, and 0.00131 for sgNT, sgRAPTOR_1, and sgRAPTOR_2, respectively). D, Gene set enrichment analysis (GSEA) based on a set of genes regulated by mTORC1 measured in genes differentially expressed in tumors with high versus low DDX1 expression. E, GSEA based on a set of genes regulated by mTORC1 measured in genes differentially expressed in KELLY cells harboring a MYCN amplification with versus without ectopic DDX1 expression. F, Western blot of the relative protein expression of mTOR ser2448 phosphorylation and P70-S6K Thr389 phosphorylation in KELLY cell after inducible expression of DDX1 (1,000 ng/mL doxycycline treatment for 48 hours).</p