Pharmacological aspects of neonatal antidepressant withdrawal

Depression is common in reproductive age women, and continued pharmacologic treatment of depression during pregnancy may be necessary to prevent relapse, which could be harmful for both the fetus and the mother. Although data on drug safety are imperfect and incomplete, the benefits of antidepressant therapy during pregnancy generally outweigh the risks. Neonates who are exposed to antidepressant medications during gestation are at increased risk to have neonatal withdrawal syndrome, although the exact incidence of this complication is unknown because the definition of the syndrome is not clear and withdrawal reactions are probably underreported. Tricyclic antidepressant withdrawal syndrome is most likely related to muscarinergic activity and individual drug half-lives, and selective serotonin reuptake inhibitor withdrawal may be due to a decrease in available synaptic serotonin in the face of down-regulated serotonin receptors, the secondary effects of other neurotransmitters, and biological or cognitive sensitivity. Other factors that influence neonatal toxicity or withdrawal include the normal physiologic changes of pregnancy, the altered activity of CYP450 enzymes during pregnancy, drug-drug transporter (PgP and OCT3) interaction, and the presence of genetic polymorphisms in genes influencing drug metabolism. Further research is necessary

Discovery-2: an interactive resource for the rational selection and comparison of putative drug target proteins in malaria

BACKGROUND: Drug resistance to anti-malarial compounds remains a serious problem, with resistance to newer pharmaceuticals developing at an alarming rate. The development of new anti-malarials remains a priority, and the rational selection of putative targets is a key element of this process. Discovery-2 is an update of the original Discovery in silico resource for the rational selection of putative drug target proteins, enabling researchers to obtain information for a protein which may be useful for the selection of putative drug targets, and to perform advanced filtering of proteins encoded by the malaria genome based on a series of molecular properties. METHODS: An updated in silico resource has been developed where researchers are able to mine information on malaria proteins and predicted ligands, as well as perform comparisons to the human and mosquito host characteristics. Protein properties used include: domains, motifs, EC numbers, GO terms, orthologs, protein-protein interactions, protein-ligand interactions. Newly added features include drugability measures from ChEMBL, automated literature relations and links to clinical trial information. Searching by chemical structure is also available. RESULTS: The updated functionality of the Discovery-2 resource is presented, together with a detailed case study of the Plasmodium falciparum S-adenosyl-L-homocysteine hydrolase (PfSAHH) protein. A short example of a chemical search with pyrimethamine is also illustrated. CONCLUSION: The updated Discovery-2 resource allows researchers to obtain detailed properties of proteins from the malaria genome, which may be of interest in the target selection process, and to perform advanced filtering and selection of proteins based on a relevant range of molecular characteristics

The hibernation-derived compound SUL-138 shifts the mitochondrial proteome towards fatty acid metabolism and prevents cognitive decline and amyloid plaque formation in an Alzheimer’s disease mouse model

Background: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide and remains without effective cure. Increasing evidence is supporting the mitochondrial cascade hypothesis, proposing that loss of mitochondrial fitness and subsequent ROS and ATP imbalance are important contributors to AD pathophysiology. Methods: Here, we tested the effects of SUL-138, a small hibernation-derived molecule that supports mitochondrial bioenergetics via complex I/IV activation, on molecular, physiological, behavioral, and pathological outcomes in APP/PS1 and wildtype mice. Results: SUL-138 treatment rescued long-term potentiation and hippocampal memory impairments and decreased beta-amyloid plaque load in APP/PS1 mice. This was paralleled by a partial rescue of dysregulated protein expression in APP/PS1 mice as assessed by mass spectrometry-based proteomics. In-depth analysis of protein expression revealed a prominent effect of SUL-138 in APP/PS1 mice on mitochondrial protein expression. SUL-138 increased the levels of proteins involved in fatty acid metabolism in both wildtype and APP/PS1 mice. Additionally, in APP/PS1 mice only, SUL-138 increased the levels of proteins involved in glycolysis and amino acid metabolism pathways, indicating that SUL-138 rescues mitochondrial impairments that are typically observed in AD. Conclusion: Our study demonstrates a SUL-138-induced shift in metabolic input towards the electron transport chain in synaptic mitochondria, coinciding with increased synaptic plasticity and memory. In conclusion, targeting mitochondrial bioenergetics might provide a promising new way to treat cognitive impairments in AD and reduce disease progression

Tidal Energy Fish Impact : method development to determine the impact of open water tidal energy converters on fish

The goals of the proposed project are: 1. to develop a robust method and experimental set‐up to determine behaviour of fish in the vicinity of tidal turbines and collision risk in the strong turbid currents of the Marsdiep based on DIDSON technology, 2. to provide a first insight and measure avoidance and collision rate of fish (and although the focus will be on fish, also if marine mammals such as harbour porpoises and seals approach the device this will be determined within the project), 3. to develop data analysis methodology since analysing large DIDSON datasets manually is very labour‐intensive and will enhance the efficiency of future large scale studies using DIDSON

Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease

BACKGROUND: Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. METHODS: We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer's Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. RESULTS: We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood-brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. CONCLUSIONS: CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood-brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles

DUALZ: Deep UNCOVER-ALMA Legacy High-Z Survey

We present the survey design and initial results of the ALMA Cycle 9 program of DUALZ, which aims to establish a joint ALMA and JWST public legacy field targeting the massive galaxy cluster Abell 2744. DUALZ features a contiguous $4'\times6'$ ALMA 30-GHz-wide mosaic in Band 6, covering areas of $\mu>2$ down to a sensitivity of $\sigma=32.7~\mu$Jy. Through a blind search, we identified 69 dust continuum sources at S/N $\gtrsim5.0$ with median redshift and intrinsic 1.2-mm flux of $z=2.30$ and $S_{\rm 1.2mm}^{\rm int}=0.24$~mJy. Of these, 27 have been spectroscopically confirmed, leveraged by the latest NIRSpec observations, while photometric redshift estimates are constrained by the comprehensive HST, NIRCam, and ALMA data for the remaining sources. With priors, we further identify a [CII]158 $\mu$m line emitter at $z=6.3254\pm0.0004$, confirmed by the latest NIRSpec spectroscopy. The NIRCam counterparts of the 1.2-mm continuum exhibit undisturbed morphologies, denoted either by disk or spheroid, implying the triggers for the faint mm emission are less catastrophic than mergers. We have identified 8 HST-dark galaxies (F150W$>$27mag, F150W$-$F444W$>$2.3) and 2 JWST-dark (F444W$>$30mag) galaxy candidates among the ALMA continuum sources. The former includes face-on disk galaxies, hinting that substantial dust obscuration does not always result from inclination. We also detect a marginal dust emission from an X-ray-detected galaxy at $z_{\rm spec}=10.07$, suggesting an active co-evolution of the central black hole and its host. We assess the infrared luminosity function up to $z\sim10$ and find it consistent with predictions from galaxy formation models. To foster diverse scientific outcomes from the community, we publicly release reduced ALMA mosaic maps, cubes, and the source catalog.Comment: 33 pages, 16 figures, and 5 tables. Submitted to ApJS. The ALMA products are fully available from here: https://jwst-uncover.github.io/DR2.html#DUAL

Multidrug resistance-associated protein-1 (MRP1) genetic variants, MRP1 protein levels and severity of COPD

<p>Abstract</p> <p>Background</p> <p>Multidrug resistance-associated protein-1 (MRP1) protects against oxidative stress and toxic compounds generated by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease (COPD). We have previously shown that single nucleotide polymorphisms (SNPs) in <it>MRP1 </it>significantly associate with level of FEV₁in two independent population based cohorts. The aim of our study was to assess the associations of <it>MRP1 </it>SNPs with FEV₁level, MRP1 protein levels and inflammatory markers in bronchial biopsies and sputum of COPD patients.</p> <p>Methods</p> <p>Five SNPs (rs212093, rs4148382, rs504348, rs4781699, rs35621) in <it>MRP1 </it>were genotyped in 110 COPD patients. The effects of <it>MRP1 </it>SNPs were analyzed using linear regression models.</p> <p>Results</p> <p>One SNP, rs212093 was significantly associated with a higher FEV₁level and less airway wall inflammation. Another SNP, rs4148382 was significantly associated with a lower FEV₁level, higher number of inflammatory cells in induced sputum and with a higher MRP1 protein level in bronchial biopsies.</p> <p>Conclusions</p> <p>This is the first study linking <it>MRP1 </it>SNPs with lung function and inflammatory markers in COPD patients, suggesting a role of <it>MRP1 </it>SNPs in the severity of COPD in addition to their association with MRP1 protein level in bronchial biopsies.</p

UNCOVER: A NIRSpec Census of Lensed Galaxies at z=8.50-13.08 Probing a High AGN Fraction and Ionized Bubbles in the Shadow

We present JWST NIRSpec prism spectroscopy of gravitationally lensed galaxies at $z\gtrsim9$ found behind the massive galaxy cluster Abell 2744 in the UNCOVER Cycle 1 Treasury Program. We confirm the source redshift via emission lines and/or the Ly$\alpha$ break feature for ten galaxies at z=8.50-13.08 down to $M_{\rm UV}=-17.3$. We achieve a high confirmation rate of 100\% for $z>9$ candidates reported in Atek et al. (2023). Using six sources with multiple emission line detections, we find that the offset of the redshift estimates between the lines and the Ly$\alpha$ break alone with prism can be as large as $\pm0.2$, raising caution in designing future follow-up spectroscopy for the break-only sources. With spec-$z$ confirmed sources in UNCOVER and the literature, we derive lower limits on the rest-frame ultraviolet (UV) luminosity function (LF) at $z\simeq9$-12 and find these lower limits to be consistent with recent photometric measurements. We identify at least two unambiguous and several possible active galactic nucleus (AGN) systems based on X-ray emission, broad line (BL) H$\beta$, high ionization line (e.g., NIV]1487, CIV1549) detections, and excess in UVLF. This requires the AGN LFs at $z\simeq$ 9-10 to be comparable or even higher than the X-ray AGN LF estimated at $z\sim6$ and indicates a plausible cause of the high abundance of $z>9$ galaxies claimed in recent photometric studies may be AGNs. One UV-luminous source is confirmed at the same redshift as a dusty BL AGN at $z=8.50$ with a physical separation of 380 kpc in the source plane. These two sources show blueward Ly$\alpha$ line or continuum emission, suggesting that they reside in the same ionized bubble with a radius of $7.69\pm0.18$ pMpc. Our results imply that AGNs have a non-negligible contribution to cosmic reionization.Comment: 27 pages, 11 figures, 4 tables, submitted to ApJ (See also arXiv:2308.11610