Aims
The goal of the current study was to assess the risk for major congenital malformations following first‐trimester exposure to amoxicillin, or amoxicillin and clavulanic acid (ACA).
Methods
A ...population‐based retrospective cohort study was conducted, by linking 4 computerized databases: maternal and infant hospitalization records, drug dispensing database of Clalit Health Services in Israel and data concerning pregnancy terminations. Multivariate negative‐binomial regression was used to assess the risk for major malformations following first‐trimester exposure, adjusted for mother's age, ethnicity (Bedouin vs Jewish), parity, diabetes mellitus, lack of perinatal care, and the year of birth.
Results
The study included 101 615 pregnancies, of which 6919 (6.8%) were exposed to amoxicillin: 1045 (1.0%) to amoxicillin only and 6041 (5.9%) to ACA. No significant association was found, in the univariate and multivariate analyses, between first‐trimester exposure to amoxicillin or ACA and major malformations in general (crude relative risk, 1.05 95% confidence interval 0.95–1.16; adjusted relative risk 1.09, 95% confidence interval 0.98–1.20), or for major malformations according to organ systems. No dose–response relationship was found between exposure in terms of the defined daily dose and major malformations.
Conclusion
Exposure to amoxicillin and ACA during the first trimester of pregnancy was not associated with an increased risk of major congenital malformations.
Cytosolic Events in the Biogenesis of Mitochondrial Proteins Bykov, Yury S.; Rapaport, Doron; Herrmann, Johannes M. ...
Trends in biochemical sciences (Amsterdam. Regular ed.),
August 2020, 2020-08-00, 20200801, Letnik:
45, Številka:
8
Journal Article
Recenzirano
Odprti dostop
While targeting of proteins synthesized in the cytosol to any organelle is complex, mitochondria present the most challenging of destinations. First, import of nuclear-encoded proteins needs to be ...balanced with production of mitochondrial-encoded ones. Moreover, as mitochondria are divided into distinct subdomains, their proteins harbor a number of different targeting signals and biophysical properties. While translocation into the mitochondrial membranes has been well studied, the cytosolic steps of protein import remain poorly understood. Here, we review current knowledge on mRNA and protein targeting to mitochondria, as well as recent advances in our understanding of the cellular programs that respond to accumulation of mitochondrial precursor proteins in the cytosol, thus linking defects in targeting-capacity to signaling.
Mitochondrial proteins synthetized in the cytosol can be targeted to mitochondria at different stages of gene expression: as mRNAs, ribosome-nascent chain complexes, or complete precursor proteins.While almost all proteins use the same entry gate to the mitochondria, before and after it they can embark on different targeting and import pathways.Delays in mitochondrial protein import or mistargeting to other organelles affect cellular homeostasis; hence, cells have evolved specific mechanisms to sense and counteract such situations.Cytosolic chaperones promote mitochondrial protein import under normal conditions, as well as play a major role in stress response pathways associated with mitochondrial protein import defects.
Astrocytes respond to neuronal activity and were shown to be necessary for plasticity and memory. To test whether astrocytic activity is also sufficient to generate synaptic potentiation and enhance ...memory, we expressed the Gq-coupled receptor hM3Dq in CA1 astrocytes, allowing their activation by a designer drug. We discovered that astrocytic activation is not only necessary for synaptic plasticity, but also sufficient to induce NMDA-dependent de novo long-term potentiation in the hippocampus that persisted after astrocytic activation ceased. In vivo, astrocytic activation enhanced memory allocation; i.e., it increased neuronal activity in a task-specific way only when coupled with learning, but not in home-caged mice. Furthermore, astrocytic activation using either a chemogenetic or an optogenetic tool during acquisition resulted in memory recall enhancement on the following day. Conversely, directly increasing neuronal activity resulted in dramatic memory impairment. Our findings that astrocytes induce plasticity and enhance memory may have important clinical implications for cognitive augmentation treatments.
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•Astrocytic activation induces de novo NMDA-dependent long-term potentiation in CA1•Chemogenetic activation of astrocytes, but not neurons, enhances memory acquisition•Astrocytic, but not neuronal, activation specifically promotes memory allocation•Optogenetic activation of the Gq-pathway in astrocytes augments memory acquisition
Astrocyte activation in the hippocampus is sufficient to generate synaptic potentiation, enhance memory allocation, and improve cognitive performance beyond what can be achieved by elevating neuronal activity alone.
Chemiexcitation of phenoxy‐1,2‐dioxetane chemiluminescent luminophores is initiated by electron transfer from a meta‐positioned phenolate ion to the peroxide‐dioxetane bond. Here we report the ...development of a unique 1,2‐dioxetane chemiluminescent scaffold with chemiexcitation gated by an OR logic dual‐set of triggering events. This scaffold is composed of meta‐dihydroxyphenyl‐1,2‐dioxetane‐adamantyl molecules, equipped with acrylic acid and chlorine substituents, that chemiexcitation under physiological conditions. A dual‐mode chemiluminescent probe, armed with two different triggering substrates designed for activation by the enzymes β‐galactosidase and alkaline phosphatase, was synthesized. The probe emitted intense light signals in the response to each enzyme, demonstrating its ability to serve as a single‐component chemiluminescent sensor for dual‐analyte detection. We also demonstrated the ability of the probe to detect β‐galactosidase and phosphatase activities in bacteria. This is the first 1,2‐dioxetane scaffold capable of responding to two different chemiexcitation events from two different positions on the same dioxetane molecule. We anticipate that the OR‐gated mode of chemiexcitation, described herein, will find utility in the preparation of chemiluminescent probes with a dual‐analyte detection/imaging mode.
The development of a unique 1,2‐dioxetane chemiluminescent scaffold with chemiexcitation gated by an OR logic set of triggering events is reported. The scaffold was applied to design a chemiluminescent probe that is activated by the enzymes β‐galactosidase and alkaline phosphatase. The ability of the probe to detect the two enzymatic activities in bacteria was successfully demonstrated.
With the COVID-19 pandemic ongoing, accurate assessment of population immunity and the effectiveness of booster and enhancer vaccine doses is critical. We compare COVID-19-related hospitalization ...incidence rates in 2,412,755 individuals across four exposure levels: non-recent vaccine immunity (two BNT162b2 COVID-19 vaccine doses five or more months prior), boosted vaccine immunity (three BNT162b2 doses), infection-induced immunity (previous COVID-19 without a subsequent BNT162b2 dose), and enhanced infection-induced immunity (previous COVID-19 with a subsequent BNT162b2 dose). Rates, adjusted for potential demographic, clinical and health-seeking-behavior confounders, were assessed from July-November 2021 when the Delta variant was predominant. Compared with non-recent vaccine immunity, COVID-19-related hospitalization incidence rates were reduced by 89% (87-91%) for boosted vaccine immunity, 66% (50-77%) for infection-induced immunity and 75% (61-83%) for enhanced infection-induced immunity. We demonstrate that infection-induced immunity (enhanced or not) provides more protection against COVID-19-related hospitalization than non-recent vaccine immunity, but less protection than booster vaccination. Additionally, our results suggest that vaccinating individuals with infection-induced immunity further enhances their protection.
BackgroundThe registration trials of messenger RNA (mRNA) vaccines against SARS-CoV-2 did not address patients with inflammatory rheumatic diseases (IRD).ObjectiveTo assess the humoral response after ...two doses of mRNA vaccine against SARS-CoV-2, in patients with IRD treated with immunomodulating drugs and the impact on IRD activity.MethodsConsecutive patients treated at the rheumatology institute, who received their first SARS-CoV-2 (Pfizer) vaccine, were recruited to the study, at their routine visit. They were reassessed 4–6 weeks after receiving the second dose of vaccine, and blood samples were obtained for serology. IRD activity assessment and the vaccine side effects were documented during both visits. IgG antibodies (Abs) against SARS-CoV-2 were detected using the SARS-CoV-2 IgG II Quant (Abbott) assay.ResultsTwo hundred and sixty-four patients with stable disease, (mean(SD) age 57.6 (13.18) years, disease duration 11.06 (7.42) years), were recruited. The immunomodulatory therapy was not modified before or after the vaccination. After the second vaccination, 227 patients (86%) mounted IgG Ab against SARS-CoV-2 (mean (SD) 5830.8 (8937) AU/mL) and 37 patients (14%) did not, 22/37 were treated with B cell-depleting agents. The reported side effects of the vaccine were minor. The rheumatic disease remained stable in all patients.ConclusionsThe vast majority of patients with IRD developed a significant humoral response following the administration of the second dose of the Pfizer mRNA vaccine against SARS-CoV-2 virus. Only minor side effects were reported and no apparent impact on IRD activity was noted.
The debate around ethics review boards (IRBs) has assumed an increasingly central place in academic practice and discourse. In this article, we summarize a unique workshop (study-group) that convened ...at the University of Haifa, attended by 27 academics from around the globe, representing nine countries in four continents. The participants presented data and points of view, which served as the basis for an open, interdisciplinary discussion. The group developed a set of recommendations, including working toward a transition from a review system to an advisory and validation system; focusing on respectful research approach to participants, rather than “ethical” research; building a procedure that focuses on feedback, rather than the process itself; recognizing that a unified examination need not necessarily be standardized; and constructing a feedback procedure in which researchers can respond to the review of their research.
Temperate viruses can become dormant in their host cells, a process called lysogeny. In every infection, such viruses decide between the lytic and the lysogenic cycles, that is, whether to replicate ...and lyse their host or to lysogenize and keep the host viable. Here we show that viruses (phages) of the SPbeta group use a small-molecule communication system to coordinate lysis-lysogeny decisions. During infection of its Bacillus host cell, the phage produces a six amino-acids-long communication peptide that is released into the medium. In subsequent infections, progeny phages measure the concentration of this peptide and lysogenize if the concentration is sufficiently high. We found that different phages encode different versions of the communication peptide, demonstrating a phage-specific peptide communication code for lysogeny decisions. We term this communication system the 'arbitrium' system, and further show that it is encoded by three phage genes: aimP, which produces the peptide; aimR, the intracellular peptide receptor; and aimX, a negative regulator of lysogeny. The arbitrium system enables a descendant phage to 'communicate' with its predecessors, that is, to estimate the amount of recent previous infections and hence decide whether to employ the lytic or lysogenic cycle.
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