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Data for: Inhibition is a prevalent mode of activity in the neocortex around awake hippocampal ripples in mice

Coordinated peri-ripple activity in the hippocampal-neocortical network is essential for mnemonic information processing in the brain. Hippocampal ripples likely serve different functions in sleep and awake states. Thus, the corresponding neocortical activity patterns may differ in important ways. We addressed this possibility by conducting voltage and glutamate wide-field imaging of the neocortex with concurrent hippocampal electrophysiology in awake mice. Contrary to our previously published sleep results, deactivation and activation were dominant in post-ripple neocortical voltage and glutamate activity, respectively, especially in the agranular retrosplenial cortex (aRSC). Additionally, the spiking activity of aRSC neurons, estimated by two-photon calcium imaging, revealed the existence of two subpopulations of excitatory neurons with opposite peri-ripple modulation patterns: one increases and the other decreases firing rate. These differences in peri-ripple spatiotemporal patterns of neocortical activity in sleep versus awake states might underlie the reported differences in the function of sleep versus awake ripples.

Data for: Inhibition drives habituation of a larval zebrafish visual response

Habituation allows animals to learn to ignore persistent but inconsequential stimuli. Despite being the most basic form of learning, a consensus model on the underlying mechanisms has yet to emerge. To probe relevant mechanisms we took advantage of a visual habituation paradigm in larval zebrafish, where larvae reduce their reactions to abrupt global dimming (a dark flash). Using Ca2+ imaging during repeated dark flashes, we identified 12 functional classes of neurons that differ based on their rate of adaptation, stimulus response shape, and anatomical location. While most classes of neurons depressed their responses to repeated stimuli, we identified populations that did not adapt, or that potentiated their response. To identify molecular players, we used a small molecule-screening approach to search for compounds that alter habituation learning. Among the pathways we identified were Melatonin and Estrogen signaling, as well as GABAergic inhibition. By analyzing which functional classes of neurons are GABAergic, and the result of pharmacological manipulations of the circuit, we propose that GABAergic inhibitory motifs drive habituation, perhaps through the potentiation of GABAergic synapses. Our results have identified multiple molecular pathways and cell types underlying a form of long-term plasticity in a vertebrate brain, and allow us to propose the first iteration of a model for how and where this learning process occurs.

opencc-by-4.0Jan 2023View details →

Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication

Raw data of the paper titled "Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication".

Underwater light attenuation inhibits native submerged plants and facilitates the invasive co-occurring plant Cabomba caroliniana

Decreasing in the diversity and distribution of native submerged plants have been widely observed in recent decades. Global underwater darkening, which is mainly caused by radiation dimming and a decrease in transparency due to e.g. eutrophication, has emerged as a general trend that strongly hampers the growth of submerged plants in lakes by decreasing the light available for photosynthesis. However, few studies have attempted to compare the responses of native and invasive submerged plants to underwater darkening. In this study, we aimed to compare the effects of light attenuation on the growth and photosynthesis traits of native and invasive submerged plants.

A mechanism of uncompetitive inhibition of the serotonin transporter

The serotonin transporter (SERT/SLC6A4) is arguably the most extensively studied solute carrier (SLC). During its eponymous action - i.e., the retrieval of serotonin from the extracellular space - SERT undergoes a conformational cycle. Typical inhibitors (antidepressant drugs and cocaine), partial and full substrates (amphetamines and their derivatives) and atypical inhibitors (ibogaine analogues) bind preferentially to different states in this cycle. This results in competitive or non-competitive transport inhibition. Here, we explored the action of N-formyl-1,3-bis (3,4-methylenedioxyphenyl)-prop-2-yl-amine (ECSI#6) on SERT: inhibition of serotonin uptake by ECSI#6 was enhanced with increasing serotonin concentration. Conversely, the KM for serotonin was lowered by augmenting ECSI#6. ECSI#6 bound with low affinity to the outward-facing state of SERT but with increased affinity to a potassium-bound state. Electrophysiological recordings showed that ECSI#6 preferentially interacted with the inward-facing state. Kinetic modeling recapitulated the experimental data and verified that uncompetitive inhibition arose from preferential binding of ECSI#6 to the K+-bound, inward-facing conformation of SERT. This binding mode predicted a pharmacochaperoning action of ECSI#6, which was confirmed by examining its effect on the folding-deficient mutant SERT-PG601,602AA: pre-incubation of HEK293 cells with ECSI#6 restored export of SERT-PG601,602AA from the endoplasmic reticulum and substrate transport. Similarly, in transgenic flies, administration of ECSI#6 promoted delivery of SERT-PG601,602AA to the presynaptic specialization of serotonergic neurons. To the best of our knowledge, ECSI#6 is the first example of an uncompetitive SLC inhibitor. Pharmacochaperones endowed with the binding mode of ECSI#6 are attractive because they can rescue misfolded transporters at concentrations, which cause modest transport inhibition.

opencc-by-4.0Feb 2023View details →

Metabolomics data: glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes

Malignancies can become reliant on glutamine as an alternative energy source and as a facilitator of aberrant DNA methylation, thus implicating glutaminase (GLS) as a potential therapeutic target. We demonstrate preclinical synergy of Telaglenastat (CB-839), a selective GLS inhibitor, when combined with AZA, in vitro and in vivo, followed by a phase Ib/II study of the combination in patients with advanced MDS. Treatment with Telaglenastat/AZA led to an ORR of 70% with CRs in 66% patients and a median overall survival of 11.6 months. scRNAseq and flow cytometry demonstrated a myeloid differentiation program at the stem cell level in clinical responders. Expression of non-canonical glutamine transporter, SLC38A1, was found to be overexpressed in MDS stem cells and was associated with clinical responses to Telaglenastat/AZA; was predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of a combined metabolic and epigenetic approach in MDS.

opencc-by-4.0Mar 2022View details →

Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling

Molecular dynamics simulations of UCP1 models with and without nucleotides.

opencc-by-4.0Mar 2023View details →

Long-range inhibition synchronizes and updates prefrontal task activity

Trial-by-trial physiology data (synchrony measurements and population activity vectors used to compute population vector similarity) supporting Cho et al., 2023. Any use of this data should cite this DOI as well as the associated publication.

opencc-zeroMar 2023View details →

Data for: HPV upregulates MARCHF8 ubiquitin ligase and inhibits apoptosis by degrading the death receptors in head and neck cancer

The membrane-associated RING-CH-type finger ubiquitin ligase MARCHF8 is a human homolog of the viral ubiquitin ligases Kaposi's sarcoma herpesvirus K3 and K5 that promote host immune evasion. Previous studies have shown that MARCHF8 ubiquitinates several immune receptors, such as the major histocompatibility complex II and CD86. While human papillomavirus (HPV) does not encode any ubiquitin ligase, the viral oncoproteins E6 and E7 are known to regulate host ubiquitin ligases. Here, we report that MARCHF8 expression is upregulated in HPV-positive head and neck cancer (HNC) patients but not in HPV-negative HNC patients compared to normal individuals. The MARCHF8 promoter is highly activated by HPV oncoprotein E6-induced MYC/MAX transcriptional activation. The knockdown of MARCHF8 expression in human HPV-positive HNC cells restores cell surface expression of the tumor necrosis factor receptor superfamily (TNFRSF) death receptors, FAS, TRAIL-R1, and TRAIL-R2, and enhances apoptosis. MARCHF8 protein directly interacts with and ubiquitinates the TNFRSF death receptors. Further, MARCHF8 knockout in mouse oral cancer cells expressing HPV16 E6 and E7 augments cancer cell apoptosis and suppresses tumor growth in vivo. Our findings suggest that HPV inhibits host cell apoptosis by upregulating MARCHF8 and degrading TNFRSF death receptors in HPV-positive HNC cells.

opencc-by-4.0Apr 2023View details →

Parvalbumin interneuron activity drives fast inhibition-induced vasoconstriction followed by slow substance P-mediated vasodilation

Here, we investigated the hemodynamic responses elicited by optogenetic stimulation of parvalbumin (PV) neurons, the largest population of GABAergic interneurons in the neocortex. This dataset corresponds to the following publication: Thanh Tan Vo, Geun Ho Im, Kayoung Han, Minah Suh, Patrick J. Drew, and SG Kim. Parvalbumin interneuron activity drives fast inhibition-induced vasoconstriction followed by slow substance P-mediated vasodilation. Proceedings of the National Academy of Sciences of the United States of America 2023; Accepted.

opencc-zeroApr 2023View details →

Long-term nitrogen deposition inhibits soil priming effects by enhancing phosphorus limitation in a subtropical forest

It is widely accepted that phosphorus (P) limits microbial metabolic processes and thus soil organic carbon (SOC) decomposition in tropical forests. Global change factors like elevated atmospheric nitrogen (N) deposition can enhance P limitation, raising concerns about the fate of SOC. However, how elevated N deposition affects the soil priming effect (PE) (i.e., fresh C inputs induced changes in SOC decomposition) in tropical forests remains unclear. We incubated soils exposed to nine years of experimental N deposition in a subtropical evergreen broadleaved forest with two types of 13C-labeled substrates of contrasting bioavailability (glucose and cellulose) with and without P amendments. We found that N deposition decreased soil total P and microbial biomass P, suggesting enhanced P limitation. In P unamended soils, N deposition significantly inhibited the PE. In contrast, adding P significantly increased the PE under N deposition and by a larger extent for the PE of cellulose (PEcellu) than the PE of glucose (PEglu). Relative to adding glucose or cellulose solely, adding P with glucose alleviated the suppression of soil microbial biomass and C-acquiring enzymes induced by N deposition, whereas adding P with cellulose attenuated the stimulation of acid phosphatase induced by N deposition. Across treatments, the PEglu increased as C-acquiring enzyme activity increased, whereas the PEcellu increased as acid phosphatase activity decreased. This suggests that P limitation, enhanced by N deposition, inhibits the soil PE through varying mechanisms depending on substrate bioavailability; that is, P limitation regulates the PEglu by affecting soil microbial growth and investment in C acquisition, whereas regulates the PEcellu by affecting microbial investment in P acquisition. These findings provide new insights for tropical forests impacted by N loading, suggesting that expected changes in C quality and P limitation can affect the long-term regulation of the soil PE.

opencc-zeroMay 2023View details →

Data for: Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus

To gain a better insight of how Cu ions toxify cells, metabolomic analyses were performed in S. aureus strains that lack the described Cu ion detoxification systems (ΔcopBL ΔcopAZ; cop-). Exposure of the cop- strain to Cu(II) resulted in an increase in the concentrations of metabolites utilized to synthesize phosphoribosyl diphosphate (PRPP). PRPP is created using the enzyme phosphoribosylpyrophosphate synthetase (Prs) which catalyzes the interconversion of ATP and ribose 5-phosphate to PRPP and AMP. Supplementing growth medium with metabolites requiring PRPP for synthesis improved growth in the presence of Cu(II). A suppressor screen revealed that a strain with a lesion in the gene coding adenine phosphoribosyltransferase (apt) was more resistant to Cu. Apt catalyzes the conversion of adenine with PRPP to AMP. The apt mutant had an increased pool of adenine suggesting that the PRPP pool was being redirected. Over-production of apt, or alternate enzymes that utilize PRPP, increased sensitivity to Cu(II). Increasing or decreasing expression of prs resulted in decreased and increased sensitivity to growth in the presence of Cu(II), respectively. We demonstrate that Prs is inhibited by Cu ions in vivo and in vitro and that treatment of cells with Cu(II) results in decreased PRPP levels. Lastly, we establish that S. aureus that lacks the ability to remove Cu ions from the cytosol is defective in colonizing the airway in a murine model of acute pneumonia, as well as the skin. The data presented are consistent with a model wherein Cu ions inhibits pentose phosphate pathway function and are used by the immune system to prevent S. aureus infections.

opencc-by-4.0May 2023View details →

Annona squamosa Leaf Extract Inhibit Migration of Human Cervical Cancer Cells Through MMP-9 Expression

Figure 1. a.Annona squamosa leaf . b.Simplicia powder of Annona squamosa leaves Figure 2. Annona squamosa leaves ethanol    extract. Figure 3. FTIR spectrophotometer results of acetogenin compounds of Annona squamosa leaves extract Figure 4. The cytotoxic test of HeLa cells at 24 hours.  The combination of ASL (Annona squamosa leaf Extract) 12.5 mg/ml + cisplatin was very effective compared with  a single therapy.  *P < 0.05Figure 4. The cytotoxic test of HeLa cells at 24 hours.  The combination of ASL (Annona squamosa leaf Extract) 12.5 mg/ml + cisplatin was very effective compared with  a single therapy.  *P < 0.05 Figure 5. The percentage of living cells of HeLa cells were cultured with different concentrations of Annona squamosa leaf extract. Figure 6. The combination therapy of ASL with cisplatin reduced the expressions of MMP-9 in HeLa cells. a. A significant concentration for cytotoxicity was a concentration of 12.5 mg/mL ASL + 5 μg/mL Cisplatin. b. The number of MMP-9 positive cells. *P< 0.005. Figure 7. The combination therapy of ASL and Cisplatin inhibit cell migration. a. HeLa cells were treated with single cisplatin or in combination with ASL 12.5; 25, 50, and a single dose of ASL 75 mg/mL. b.  Percentage area of cells undergoing migration. *P<0.005.

opencc-by-4.0Jun 2023View details →

Supplementary Figure MiR-497-5p inhibits metastasis in cervical cancer

Supplementary Figure A. Expression of apoptosis-related proteins, cleaved caspase 3 and cleaved caspase 9, was assayed by WB Supplementary Figure B. Cell migration and invasion abilities were assayed through transwell assay (Mann-Whitney test) Supplementary Figure C. Changes in expression of EMT-related proteins were assayed by WB (Mann-Whitney test). *p<0.050 representing statistically significant.

opencc-by-4.0Jun 2023View details →

Molecular dynamics simulations of CD59 and CD59-inhibited Membrane Attack Complex

Coarse-grain (CG) trajectories of CD59-C5b8 (last 1,500 ns): <ul> <li>cd59-c5b8_1500ns_rep1.xtc</li> <li>cd59-c5b8_1500ns_rep2.xtc</li> <li>cd59-c5b8_1500ns_rep3.xtc</li> </ul> PyLipID analysis results from CG CD59-C5b8 simulations: <ul> <li>Interactions_CHOL.csv</li> <li>Interactions_DOPC.csv</li> </ul> Atomistic CD59 simulations in DOPC membrane: <ul> <li>cd59_at_rep1_light.trr</li> <li>cd59_at_rep2_light.trr</li> <li>cd59_at_rep3_light.trr</li> </ul> CD59 Euler angles relative to the membrane:  <ul> <li>rep1.csv</li> <li>rep2.csv</li> <li>rep3.csv</li> </ul> All xtc and trr files were down-sampled (frames removed) to decrease file size.

opencc-by-4.0Feb 2023View details →

dCK inhibition is synthetic lethal with BRCA2 deficiency

BRCA2 is a well-established cancer driver in several human malignancies. While the remarkable success of PARP inhibitors proved the clinical potential of targeting BRCA deficiencies, the emergence of resistance mechanisms underscores the importance of seeking novel Synthetic Lethal (SL) targets for future drug development efforts. In this work, we performed a BRCA2-centric SL screen with a collection of plant-derived compounds from South America. We identified the steroidal alkaloid Solanocapsine as a selective SL inducer, and we were able to substantially increase its potency by deriving multiple analogs. The use of two complementary chemoproteomic approaches led to the identification of the nucleotide salvage pathway enzyme deoxycytidine kinase (dCK) as Solanocapsine’s target responsible for its BRCA2-linked SL induction. Additional confirmatory evidence was obtained by using the highly specific dCK inhibitor (DI-87), which induces SL in multiple BRCA2-deficient and KO contexts. Interestingly, dCK-induced SL is mechanistically different from the one induced by PARP inhibitors. dCK inhibition generates substantially lower levels of DNA damage, and cytotoxic phenotypes are associated exclusively with mitosis, thus suggesting that the fine-tuning of nucleotide supply in mitosis is critical for the survival of BRCA2-deficient cells. Moreover, by using a xenograft model of contralateral tumors, we show that dCK impairment suffices to trigger SL in-vivo. Taken together, our findings unveil dCK as a promising new target for BRCA2-deficient cancers, thus setting the ground for future therapeutic alternatives to PARP inhibitors.

closedIPD-NOFeb 2026View details →

Trial of PDE4 Inhibition With Roflumilast for the Management of Plaque Psoriasis

ClinicalTrials.gov study NCT04211363. IPD Sharing: NO. Countries: 2. Publications: 3.

restrictedIPD-UNDECIDEDFeb 2026View details →

Pharmacogenetics of Warfarin Induction and Inhibition

ClinicalTrials.gov study NCT01447511. IPD Sharing: Not stated. Countries: 1. Publications: 1.

closedIPD-NOFeb 2026View details →

Fibroblast Specific Inhibition of LOXL2 and TGFbeta1 Signaling in Patients With Pulmonary Fibrosis.

ClinicalTrials.gov study NCT03928847. IPD Sharing: NO. Countries: 1. Publications: 2.