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Background: Alzheimer's disease (AD) is of growing concern worldwide as the demographic changes to a more aged population. Amyloid-β (Aβ deposition is thought to be a key target for treating AD. However, Aβ antibodies have had mixed results, and there is concern over their safety. Studies have shown that the sigma-2 receptor (σ-2R)/TMEM97 is a binding site for Aβ oligomers. Therefore, targeting the receptor may be beneficial in displacing Aβ oligomers from the brain. CT1812 is a σ-2R/TMEM97 antagonist that is effective in preclinical studies of AD and has been entered into clinical trials. Objective: The objective of this study was to systematically review the safety and efficacy of CT1812 for the treatment of AD. Methods: Between June and August 2023, we searched the primary literature (PubMed, Scopus, Google Scholar, etc.) and clinical trials databases (http://www.clinicaltrails.gov). The extracted data is evaluated within this manuscript. Results: CT1812 is relatively safe, with only mild adverse events reported at doses up to 840 mg. CT1812 can displace Aβ in the clinical studies, in line with the preclinical data. Studies have investigated brain connectivity and function in response to CT1812. However, the cognitive data is still lacking, with only one study including cognitive data as a secondary outcome. Conclusions: CT1812 safely works to displace Aβ however, whether this is enough to prevent/slow the cognitive decline seen in AD remains to be seen. Longer clinical trials are needed to assess the efficacy of CT1812; several trials of this nature are currently ongoing. [ABSTRACT FROM AUTHOR]

Integrated modeling of the pharmacokinetic (PK) and target binding, by means of a TMDD model, can provide valuable insights into the expected pharmacodynamic (PD) effects of monoclonal antibodies (mAbs). Optimal characterization of the human PK and target binding for mAbs requires data obtained after intravenous (IV) administration which can be combined with subcutaneous (SC) data to further this characterization. Integration of free and/or total target measurements in a population TMDD model will allow quantification of target engagement which is the first step in the cascade leading to efficacy. However, the assays for determination of free target concentrations are analytically challenging and are inherently biased to overpredict the true concentrations in the presence of mAb:target complexes. For that reason, the objective of the current research was to evaluate the predictive value of free target concentrations in a TMDD model developed using PK and total target observations only. Further, a secondary objective was to demonstrate that prediction of SC data is feasible, based on an existing IV model and typical values of mAb parameters reported for SC absorption. GSK3772847, a human immunoglobulin G2 sigma isotype (IgG2f) mAb that binds to the extracellular domain of the interleukin‐33 receptor (IL‐33R or ST2) and neutralizes IL‐33‐mediated ST2 signaling, was used as a model compound for mAbs in this study. [ABSTRACT FROM AUTHOR]

Here, we describe the characterization of a radioligand selective for GluN2B‐containing NMDA receptors, 3‐[3H] 1‐(azetidin‐1‐yl)‐2‐(6‐(4‐fluoro‐3‐methyl‐phenyl)pyrrolo[3,2‐b]pyridin‐1‐yl)ethanone ([3H]‐JNJ‐ GluN2B‐5). In rat cortical membranes, the compound bound to a single site, and the following kinetic parameters were measured; association rate constant Kon = 0.0066 ± 0.0006 min−1 nM−1, dissociation rate constant Koff = 0.0210 ± 0.0001 min−1 indicating calculated KD = Koff/Kon = 3.3 ± 0.4 nM, (mean ± SEM, n = 3). The equilibrium dissociation constant determined from saturation binding experiments in rat cortex was KD of 2.6 ± 0.3 nM (mean ± SEM, n = 3). In contrast to the widely used GluN2B radioligand [3H]‐Ro 25‐6981, whose affinity Ki for sigma 1 and sigma 2 receptors are 2 and 189 nM, respectively, [3H]‐JNJ‐GluN2B‐5 exhibits no measurable affinity for sigma 1 and sigma 2 receptors (Ki > 10 μM for both) providing distinct selectivity advantages. Anatomical distribution of [3H]‐JNJ‐GluN2B‐5 binding sites in rat, mouse, dog, monkey, and human brain tissue was studied using in vitro autoradiography, which showed high specific binding in the hippocampus and cortex and negligible binding in the cerebellum. Enhanced selectivity for GluN2B‐containing receptors translated to a good signal‐to‐noise ratio in both in vitro radioligand binding and in vitro autoradiography assays. In conclusion, [3H]‐JNJ‐GluN2B‐5 is a high‐affinity GluN2B radioligand with excellent signal‐to‐noise ratio and unprecedented selectivity. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine, 5-HT) is a ubiquitous neurotransmitter in the human body. In the central nervous system, 5-HT affects sleep, pain, mood, appetite, and attention, while in the peripheral nervous system, 5-HT modulates peristalsis, mucus production, and blood vessel dilation. Fourteen membrane receptors mediate 5-HT activity. In agreement with the crucial roles played by 5-HT, many drugs target 5-HT receptors (5-HTRs). Therefore, it is unsurprising that many efforts have been devoted to discovering multitarget-directed ligands (MTDLs) capable of engaging one or more 5-HTRs plus another target phenotypically linked to a particular disease. In this review, we will describe medicinal chemistry efforts in designing MTDLs encompassing activity for one or more 5-HTRs, starting with atypical antipsychotics and moving to dual 5-HT1AR/serotonin transporter ligands, 5-HT6R antagonists/acetyl cholinesterases inhibitors, and 5-HT4R agonists/acetyl cholinesterases inhibitors. We will also provide an outlook on the most recent efforts made in the field. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a major long-lasting side effect of some chemotherapy drugs, which threatens cancer survival rate. CIPN mostly affects sensory neurons and occasionally motor neurons, causing numbness, tingling, discomfort, and burning pain in the upper and lower extremities. The pathophysiology of CIPN is not completely understood; however, it is believed that chemotherapies induce peripheral neuropathy via directly damaging mitochondria, impairing the function of ion channels, triggering immunological mechanisms, and disrupting microtubules. The treatment of CIPN is a medical challenge, and there are no approved pharmacological options. Currently, duloxetine and other antidepressants, antioxidant, anti-inflammatory, and ion-channel targeted therapies are commonly used in clinics to relieve the symptoms of CIPN. Several other types of drugs, such as cannabinoids, sigma−1 receptor antagonists, and nicotinamides ribose, are being evaluated in preclinical and clinical studies. This paper summarizes the information related to the physiology of CIPN and medicines that could be used for treating this condition. [ABSTRACT FROM AUTHOR]

Summary Nanopore ion channels are a promising solution for certain molecular structure analyses. Large arrays of nanopore channels and their associated readout circuits are used in many molecular studies such as DNA sequencing. Readout circuits must meet challenging performance criteria such as low noise operation, low power consumption, in‐channel digitization capability, and high linearity. Previously, sigma–delta modulators have been presented to address these criteria; however, their specifications show drifts with temperature. In this paper, an approach is presented to keep modulator performance constant with temperature variations. For this purpose, the sigma–delta modulator's feedforward and feedback branches are modified so that their gain coefficient remains constant over a certain temperature range. With large sensors arrays, solutions employing high bias currents in the feedback paths are not suitable due to power consumption limitations. Here, the design gives the possibility of switching low current levels in the feedback paths without affecting the ENOB. The proposed temperature compensation solution shows good performance when temperature is swept from 27°C to 100°C. Over the mentioned temperature range, the gain and bandwidth of the modulator show a change of less than 0.4%. It is further shown that for a 10 kHz input current signal with an amplitude of 600 pA, the ENOB and power consumption are 12.9 and 4.6 mW, respectively. [ABSTRACT FROM AUTHOR]

Background: 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is commonly used for diagnosis of dementia because brain glucose metabolism reflects neuronal activity. However, as [18F]FDG is an analogue of glucose, accumulation of tracer in the brain is affected by plasma glucose levels. In contrast, cerebral blood flow (CBF) tracers are theoretically unaffected by plasma glucose levels and are therefore expected to be useful alternatives for the diagnosis of dementia in patients with diabetes. The techniques currently used for CBF imaging using single photon emission computed tomography (SPECT) and [15O]H2O positron emission tomography (PET), but these are limited by their insufficient resolution and sensitivity for regional brain imaging, especially in patients with brain atrophy. N-isopropyl-4-[11C]methylamphetamine ([11C]MMP) is a possible CBF tracer with high resolution and sensitivity that exhibits comparable performance to that of [15O]H2O in conscious monkey brains. We performed process validation of the radiosynthesis and preclinical development of [11C]MMP prior to clinical translation. Results: The decay-corrected yields of [11C]MMP at the end of synthesis were 41.4 ± 6.5%, with 99.7 ± 0.3% radiochemical purity, and 192.3 ± 22.5 MBq/nmol molar activity. All process validation batches complied with the product specifications. The acute toxicity of MMP was evaluated at a dose of 3.55 mg/kg body weight, which is 10,000 times the potential maximum clinical dose of [11C]MMP. The acute toxicity of [11C]MMP injection at 150 or 200 times, to administer a postulated dose of 740 MBq of [11C]MMP, was also evaluated after the decay-out of 11C. No acute toxicity of MMP and [11C]MMP injection was found. No mutagenic activity was observed for MMP. The effective dose calculated according to the Medical Internal Radiation Dose (MIRD) method was 5.4 µSv/MBq, and the maximum absorbed dose to the bladder wall was 57.6 µGy/MBq. MMP, a derivative of phenylalkylamine, showed binding to the sigma receptor, but had approximately 1/100 of the affinity of existing sigma receptor imaging agents. The affinity for other brain neuroreceptors was low. Conclusions: [11C]MMP shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risk associated with [11C]MMP PET imaging is well within the acceptable dose limit. [ABSTRACT FROM AUTHOR]

SigE is one of the main regulators of mycobacterial stress response and is characterized by a complex regulatory network based on two pathways, which have been partially characterized in conditions of surface stress. The first pathway is based on the induction of sigE transcription by the two-component system MprAB, while the second is based on the degradation of SigE antisigma factor RseA by ClpC1P2, a protease whose structural genes are induced by ClgR. We characterized the dynamics of the SigE network activation in conditions of surface stress and low pH in Mycobacterium tuberculosis. Using a series of mutants in which the main regulatory nodes of the network have been inactivated, we could explore their hierarchy, and we determined that MprAB had a key role in the network activation in both stress conditions through the induction of sigE. However, while in conditions of surface stress the absence of MprAB totally abrogated sigE induction, under low pH conditions it only resulted in a small delay of the induction of sigE. In this case, sigE induction was due to SigH, which acted as a MprAB backup system. The ClgR pathway, leading to the degradation of the SigE anti-sigma factor RseA, was shown to be essential for the activation of the SigE network only following surface stress, where it showed an equal hierarchy with the MprAB pathway. [ABSTRACT FROM AUTHOR]

The cell envelope fortifies bacterial cells against antibiotics and other insults. Species in the Mycobacteriales order have a complex envelope that includes an outer layer of mycolic acids called the mycomembrane (MM) and a cell wall composed of peptidoglycan and arabinogalactan. This envelope architecture is unique among bacteria and contributes significantly to the virulence of pathogenic Mycobacteriales like Mycobacterium tuberculosis. Characterization of pathways that govern envelope biogenesis in these organisms is therefore critical in understanding their biology and for identifying new antibiotic targets. To better understand MM biogenesis, we developed a cell sorting-based screen for mutants defective in the surface exposure of a porin normally embedded in the MM of the model organism Corynebacterium glutamicum. The results revealed a requirement for the conserved σD envelope stress response in porin export and identified MarP as the site-1 protease, respectively, that activate the response by cleaving the membrane-embedded anti-sigma factor. A reporter system revealed that the σD pathway responds to defects in mycolic acid and arabinogalactan biosynthesis, suggesting that the stress response has the unusual property of being induced by activating signals that arise from defects in the assembly of two distinct envelope layers. Our results thus provide new insights into how C. glutamicum and related bacteria monitor envelope integrity and suggest a potential role for members of the σD regulon in protein export to the MM. Author summary: Bacteria within the Mycobacteriales order, which includes the pathogen Mycobacterium tuberculosis, have a unique multilayered cell surface architecture. How they sense and respond to defects in the construction of this distinct envelope to maintain homeostasis remains poorly understood. Here, we used the model organism Corynebacterium glutamicum to reveal that the conserved σD envelope stress response pathway responds to two distinct signals resulting from defects in different envelope layers. The results provide new insight into how members of the Mycobacteriales monitor the integrity of their surface and pave the way for the identification of novel vulnerabilities in envelope biogenesis that may be useful for targeting with antibiotics. [ABSTRACT FROM AUTHOR]

Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein, we describe the identification of novel SR ligands, obtained by a chemical hybridization approach. There wereendowed with pan-affinity for both SR subtypes and evaluated their potential anticancer activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach, we identified novel compounds (4d, 4e, 4g, and 4j) with dual affinity for SR1 and SR2 receptors. These compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent cytotoxic effects against both cancer cell lines, with IC50 values comparable to HAL. Interestingly, the cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism of action. The further exploration of their structure-activity relationships and their evaluation in additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the development of novel anticancer agents that target SRs. [ABSTRACT FROM AUTHOR]

Sigma factors are transcriptional regulators that are part of complex regulatory networks for major cellular processes, as well as for growth phase-dependent regulation and stress response. Actinoplanes sp. SE50/110 is the natural producer of acarbose, an α-glucosidase inhibitor that is used in diabetes type 2 treatment. Acarbose biosynthesis is dependent on growth, making sigma factor engineering a promising tool for metabolic engineering. ACSP50_0507 is a homolog of the developmental and osmotic-stress-regulating Streptomyces coelicolor σHSc. Therefore, the protein encoded by ACSP50_0507 was named σHAs. Here, an Actinoplanes sp. SE50/110 expression strain for the alternative sigma factor gene ACSP50_0507 (sigHAs) achieved a two-fold increased acarbose yield with acarbose production extending into the stationary growth phase. Transcriptome sequencing revealed upregulation of acarbose biosynthesis genes during growth and at the late stationary growth phase. Genes that are transcriptionally activated by σHAs frequently code for secreted or membrane-associated proteins. This is also mirrored by the severely affected cell morphology, with hyperbranching, deformed and compartmentalized hyphae. The dehydrated cell morphology and upregulation of further genes point to a putative involvement in osmotic stress response, similar to its S. coelicolor homolog. The DNA-binding motif of σHAs was determined based on transcriptome sequencing data and shows high motif similarity to that of its homolog. The motif was confirmed by in vitro binding of recombinantly expressed σHAs to the upstream sequence of a strongly upregulated gene. Autoregulation of σHAs was observed, and binding to its own gene promoter region was also confirmed. [ABSTRACT FROM AUTHOR]

Psychostimulant use disorders (PSUD) are prevalent; however, no FDA‐approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3‐24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine‐induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8‐091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine‐induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine. [ABSTRACT FROM AUTHOR]

Acetogens can fix carbon (CO or CO2) into acetyl-CoA via the Wood-Ljungdahl pathway (WLP) that also makes them attractive cell factories for the production of fuels and chemicals from waste feedstocks. Although most biochemical details of the WLP are well understood and systems-level characterization of acetogen metabolism has recently improved, key transcriptional features such as promoter motifs and transcriptional regulators are still unknown in acetogens. Here, we use differential RNAsequencing to identify a previously undescribed promoter motif associated with essential genes for autotrophic growth of the model-acetogen Clostridium autoethanogenum. RNA polymerase was shown to bind to the new promoter motif using a DNA-binding protein assay and proteomics enabled the discovery of four candidates to potentially function directly in control of transcription of the WLP and other key genes of C1 fixation metabolism. Next, in vivo experiments showed that a TetR-family transcriptional regulator (CAETHG_0459) and the housekeeping sigma factor (sA) activate expression of a reporter protein (GFP) in-frame with the new promoter motif from a fusion vector in Escherichia coli. Lastly, a protein-protein interaction assay with the RNA polymerase (RNAP) shows that CAETHG_0459 directly binds to the RNAP. Together, the data presented here advance the fundamental understanding of transcriptional regulation of C1 fixation in acetogens and provide a strategy for improving the performance of gas-fermenting bacteria by genetic engineering. [ABSTRACT FROM AUTHOR]

Gray mold, caused by Botrytis cinerea, poses significant threats to various crops, while it can be remarkably inhibited by ε-poly-L-lysine (ε-PL). A previous study found that B. cinerea extracts could stimulate the ε-PL biosynthesis of Streptomyces albulus, while it is unclear whether the impact of the B. cinerea signal on ε-PL biosynthesis is direct or indirect. This study evaluated the role of elevated reactive oxygen species (ROS) in efficient ε-PL biosynthesis after B. cinerea induction, and its underlying mechanism was disclosed with a transcriptome analysis. The microbial call from B. cinerea could arouse ROS elevation in cells, which fall in a proper level that positively influenced the ε-PL biosynthesis. A systematic transcriptional analysis revealed that this proper dose of intracellular ROS could induce a global transcriptional promotion on key pathways in ε-PL biosynthesis, including the embden-meyerhof-parnas pathway, the pentose phosphate pathway, the tricarboxylic acid cycle, the diaminopimelic acid pathway, ε-PL accumulation, cell respiration, and energy synthesis, in which sigma factor HrdD and the transcriptional regulators of TcrA, TetR, FurA, and MerR might be involved. In addition, the intracellular ROS elevation also resulted in a global modification of secondary metabolite biosynthesis, highlighting the secondary signaling role of intracellular ROS in ε-PL production. This work disclosed the transcriptional mechanism of efficient ε-PL production that resulted from an intracellular ROS elevation after B. cinerea elicitors' induction, which was of great significance in industrial ε-PL production as well as the biocontrol of gray mold disease. [ABSTRACT FROM AUTHOR]

We present results of dust continuum and [C  ii ] |$\, 158\, {\rm \mu m}$| emission line observations of a remarkably UV luminous (M UV = −21.6) galaxy at z = 10.603: GN-z11. Using the Northern Extended Millimeter Array (NOEMA), observations have been carried out over multiple observing cycles. We achieved a high sensitivity resulting in a |$\lambda _{\rm rest}=160\, {\rm \mu m}$| continuum |$1\, \sigma$| sensitivity of |$13.0\, \rm {\mu Jy \, beam}^{ -1}$| and a [C  ii ] emission line |$1\, \sigma$| sensitivity of |$31\, \rm {mJy\, beam^{ -1}\, km \, s}^{ -1}$| using |$50\, \rm {km \, s}^{ -1}$| binning with a |$\sim 2\, {\rm arcsec}$| synthesized beam. Neither dust continuum nor [C  ii ] |$\, 158\, {\rm \mu m}$| line emission are detected at the expected frequency of ν[C ii ] |$= 163.791\, \rm {GHz}$| and the sky location of GN-z11. The upper limits show that GN-z11 is neither luminous in L IR nor L [C ii ], with a dust mass |$3\, \sigma$| limit of |${\rm log}\, (M_{\rm dust}/{\rm {\rm M}_{\odot }}) \, \lt\, 6.5-6.9$| and with a [C  ii ] based molecular gas mass |$3\, \sigma$| limit of log (M mol, [C ii ] |$/{\rm {\rm M}_{\odot }}) \, \lt \, 9.3$|⁠. Together with radiative transfer calculations, we also investigated the possible cause of the dust poor nature of the GN-z11 showed by the blue colour in the UV continuum of GN-z11 (βUV = −2.4), and found that ≳3 × deeper observations are crucial to study dust production at very high-redshift. Nevertheless, our observations show the crucial role of deep mm/submm observations of very high-redshift galaxies to constrain multiple phases in the interstellar medium. [ABSTRACT FROM AUTHOR]

Microbial population heterogeneity leads to different stress responses and growth behavior of individual cells in a population. Previously, a point mutation in the rpsU gene (rpsUG50C) encoding ribosomal protein S21 was identified in a Listeria monocytogenes LO28 variant, which leads to increased multistress resistance and a reduced maximum specific growth rate. However, the underlying mechanisms of these phenotypic changes remain unknown. In L. monocytogenes, the alternative sigma factor SigB regulates the general stress response, with its activation controlled by a series of Rsb proteins, including RsbR1 and anti-sigma factor RsbW and its antagonist RsbV. We combined a phenotype and proteomics approach to investigate the acid and heat stress resistance, growth rate, and SigB activation of L. monocytogenes EGDe wild type and the ΔsigB, ΔrsbV, and ΔrsbR1 mutant strains. While the introduction of rpsUG50C in the ΔsigB mutant did not induce a SigB-mediated increase in robustness, the presence of rpsUG50C in the ΔrsbV and the ΔrsbR1 mutants led to SigB activation and concomitant increased robustness, indicating an alternative signaling pathway for the SigB activation in rpsUG50C mutants. Interestingly, all these rpsUG50C mutants exhibited reduced maximum specific growth rates, independent of SigB activation, possibly attributed to compromised ribosomal functioning. In summary, the increased stress resistance in the L. monocytogenes EGDe rpsUG50C mutant results from SigB activation through an unknown mechanism distinct from the classical stressosome and RsbV/RsbW partner switching model. Moreover, the reduced maximum specific growth rate of the EGDe rpsUG50C mutant is likely unrelated to SigB activation and potentially linked to impaired ribosomal function. [ABSTRACT FROM AUTHOR]

Up to approximately 70% of cancer survivors report persistent deficits in memory, attention, speed of information processing, multi-tasking, and mental health functioning, a series of symptoms known as “brain fog.” The severity and duration of such effects can vary depending on age, cancer type, and treatment regimens. In particular, every year, hundreds of thousands of patients worldwide undergo radiotherapy (RT) for primary brain tumors and brain metastases originating from extracranial tumors. Besides its potential benefits in the control of tumor progression, recent studies indicate that RT reprograms the brain tumor microenvironment inducing increased activation of microglia and astrocytes and a consequent general condition of neuroinflammation that in case it becomes chronic could lead to a cognitive decline. Furthermore, radiation can induce endothelium reticulum (ER) stress directly or indirectly by generating reactive oxygen species (ROS) activating compensatory survival signaling pathways in the RT-surviving fraction of healthy neuronal and glial cells. In particular, the anomalous accumulation of misfolding proteins in neuronal cells exposed to radiation as a consequence of excessive activation of unfolded protein response (UPR) could pave the way to neurodegenerative disorders. Moreover, exposure of cells to ionizing radiation was also shown to affect the normal proteasome activity, slowing the degradation rate of misfolded proteins, and further exacerbating ER-stress conditions. This compromises several neuronal functions, with neuronal accumulation of ubiquitinated proteins with a consequent switch from proteasome to immunoproteasome that increases neuroinflammation, a crucial risk factor for neurodegeneration. The etiology of brain fog remains elusive and can arise not only during treatment but can also persist for an extended period after the end of RT. In this review, we will focus on the molecular pathways triggered by radiation therapy affecting cognitive functions and potentially at the origin of so-called “brain fog” symptomatology, with the aim to define novel therapeutic strategies to preserve healthy brain tissue from cognitive decline. [ABSTRACT FROM AUTHOR]

Axonal growth cones mediate axonal guidance and growth regulation. We show that migrating neurons in mice possess a growth cone at the tip of their leading process, similar to that of axons, in terms of the cytoskeletal dynamics and functional responsivity through protein tyrosine phosphatase receptor type sigma (PTPσ). Migrating-neuron growth cones respond to chondroitin sulfate (CS) through PTPσ and collapse, which leads to inhibition of neuronal migration. In the presence of CS, the growth cones can revert to their extended morphology when their leading filopodia interact with heparan sulfate (HS), thus re-enabling neuronal migration. Implantation of an HS-containing biomaterial in the CS-rich injured cortex promotes the extension of the growth cone and improve the migration and regeneration of neurons, thereby enabling functional recovery. Thus, the growth cone of migrating neurons is responsive to extracellular environments and acts as a primary regulator of neuronal migration. Structure and functions of the tip of migratory neurons remain elusive. Here, the authors show that the PTPσ-expressing growth cone senses extracellular matrix changes and drives neuronal migration in the injured brain, leading to the functional recovery. [ABSTRACT FROM AUTHOR]

This correction notice addresses errors in an article about the influence of perinatal exposure to titanium dioxide (TiO2) on the intestinal barrier function and susceptibility to inflammatory bowel diseases (IBD) in mice. The corrected text provides accurate information about the impact of TiO2 exposure on the expression of cytokines and immune cells in the colon, as well as the transfer of TiO2-triggered microbiota dysbiosis to healthy mice. The study suggests that perinatal exposure to TiO2 may increase the risk of developing colitis later in life. The research also examines the effects of TiO2 exposure on the intestinal epithelium and the composition of chemical elements in various organs. [Extracted from the article]

Aim. In light of this dire situation, the primary objective of this study was to devise optimal conditions for the restoration and recovery of hybridoma cells that produced antibodies targeting protein C. By identifying effective restoration protocols, we aimrd to mitigate the impact of compromised storage conditions and ensure the continued utility of these invaluable cell lines for ongoing research and biomedical applications. Methods. For cultivation, a clone of cells producing IV-6A antibody that was frozen in the liquid nitrogen, but was transferred to the freezer –80 °С on 01.03.2022. Cells were cultured in RPMI medium (Sigma) that contained 10% of Fetal Bovine Serum (FBS). Three variants of FBS were used: FBS, sterile-filtrated, suitable for cell culture, suitable for hybridoma (F7524, Sigma), USA; FBS, sterile-filtrated, suitable for cell culture, suitable for hybridoma (F2442, Sigma), USA; Fetal Bovine Serum, One Shot format, Glibco, USA (A5256701,ThermoFisher). Cell viability was monitored using a light microscope (Carl Zeiss Jena, Germany) under magnification ×200. After cultivation and accumulation of antibody in cultural liquid cells were spun-down and antibody was obtained by affinity chromatography on Protein G Sepharose (Sigma). ELISA using recombinant protein C, kindly provided by Dr Olexandr Korchynski, checked the activity of antibody in the culture liquid and purified antibody. HRP-conjugated anti-mouse antibody was purchased from (Sigma). Results. Samples of hybridoma cell lines that were stored in the freezer –80 °С during 6 months were unfrozen according to the standard procedure and cultivated in RPMI medium. Different types of bovine serum were used to select the most appropriate for cells restoration. Discussion. Use of different sources of fetal bovine serum allowed to select the best medium for the restoration of hybridoma cells that were stored at –80 °С during 6 months. We were able to restore the stable cell line and to obtain the monoclonal antibody able to bind protein C. Such antibody is of interest for the development of test-system for quantification of protein C in blood plasma. Conclusions. We managed to grow hybridoma cells capable of producing monoclonal antibodies specific to protein C, despite the fact that the cells were forced to be stored in the wrong conditions for a long time. Antibody that has high specificity and affinity for protein C can be used to develop immunochemical test systems for the detection of this fast-reacting protein for diagnostic purposes. [ABSTRACT FROM AUTHOR]

The tumor microenvironment is a barrier to breast cancer therapy. Cancer-associated fibroblast cells (CAFs) can support tumor proliferation, metastasis, and drug resistance by secreting various cytokines and growth factors. Abnormal angiogenesis provides sufficient nutrients for tumor proliferation. Considering that CAFs express the sigma receptor (which recognizes anisamide, AA), we developed a CAFs and breast cancer cells dual-targeting nano drug delivery system to transport the LightOn gene express system, a spatiotemporal controlled gene expression consisting of a light-sensitive transcription factor and a specific minimal promoter. We adopted RGD (Arg-Gly-Asp) to selectively bind to the αvβ3 integrin on activated vascular endothelial cells and tumor cells. After the LightOn system has reached the tumor site, LightOn gene express system can spatiotemporal controllably express toxic Pseudomonas exotoxin An under blue light irradiation. The LightOn gene express system, combined with multifunctional nanoparticles, achieved high targeting delivery efficiency both in vitro and in vivo. It also displayed strong tumor and CAFs inhibition, anti-angiogenesis ability and anti-metastasis ability, with good safety. Moreover, it improved survival rate, survival time, and lung metastasis rate in a mouse breast cancer model. This study proves the efficacy of combining the LightOn system with targeted multifunctional nanoparticles in tumor and anti-metastatic therapy and provides new insights into tumor microenvironment regulation. [Display omitted] • pPEA@mNP is a multi-functional gene delivery system, with high targetability and sensitive release profile • pPEA@mNP can spatiotemporally inhibits tumor cells, cancer associated fibroblasts and tumor angiogenesis • pPEA@mNP can eliminate breast cancer and regulate tumor microenvironment, providing a novel anti-metastatic therapy strategy [ABSTRACT FROM AUTHOR]

In Mycobacterium smegmatis, the transcriptional activity of the alternative sigma factor SigF is posttranslationally regulated by the partner switching system consisting of SigF, the anti-SigF RsbW1, and three anti-SigF antagonists (RsfA, RsfB, and RsbW3). We previously demonstrated that expression of the SigF regulon is strongly induced in the Δaa3 mutant of M. smegmatis lacking the aa3 cytochrome c oxidase, the major terminal oxidase in the respiratory electron transport chain. Here, we identified and characterized the RsfSR twocomponent system involved in regulating the phosphorylation state of the major anti-SigF antagonist RsfB. RsfS (MSMEG_6130) is a histidine kinase with the cyclase/histidine kinase-associated sensing extracellular 3 domain at its N terminus, and RsfR (MSMEG_6131) is a receiver domain-containing protein phosphatase 2C-type phosphatase that can dephosphorylate phosphorylated RsfB. We demonstrated that phosphorylation of RsfR on Asp74 by RsfS reduces the phosphatase activity of RsfR toward phosphorylated RsfB and that the cellular abundance of the active unphosphorylated RsfB is increased in the Δaa3 mutant relative to the WT strain. We also demonstrated that the RsfSR two-component system is required for induction of the SigF regulon under respirationinhibitory conditions such as inactivation of the cytochrome bcc1 complex and aa3 cytochrome c oxidase, as well as hypoxia, electron donor-limiting, high ionic strength, and low pH conditions. Collectively, our results reveal a key regulatory element involved in regulating the SigF signaling system by monitoring the state of the respiratory electron transport chain. [ABSTRACT FROM AUTHOR]

Cells are unceasingly confronted by oxidative stresses that oxidize proteins on their cysteines. The thioredoxin (Trx) system, which is a ubiquitous system for thiol and protein repair, is composed of a thioredoxin (TrxA) and a thioredoxin reductase (TrxB). TrxAs reduce disulfide bonds of oxidized proteins and are then usually recycled by a single pleiotropic NAD(P)H-dependent TrxB (NTR). In this work, we first analyzed the composition of Trx systems across Bacteria. Most bacteria have only one NTR, but organisms in some Phyla have several TrxBs. In Firmicutes, multiple TrxBs are observed only in Clostridia, with another peculiarity being the existence of ferredoxin-dependent TrxBs. We used Clostridioides difficile, a pathogenic sporulating anaerobic Firmicutes, as a model to investigate the biological relevance of TrxB multiplicity. Three TrxAs and three TrxBs are present in the 630Δerm strain. We showed that two systems are involved in the response to infection-related stresses, allowing the survival of vegetative cells exposed to oxygen, inflammation-related molecules and bile salts. A fourth TrxB copy present in some strains also contributes to the stress-response arsenal. One of the conserved stress-response Trx system was found to be present both in vegetative cells and in the spores and is under a dual transcriptional control by vegetative cell and sporulation sigma factors. This Trx system contributes to spore survival to hypochlorite and ensure proper germination in the presence of oxygen. Finally, we found that the third Trx system contributes to sporulation through the recycling of the glycine-reductase, a Stickland pathway enzyme that allows the consumption of glycine and contributes to sporulation. Altogether, we showed that Trx systems are produced under the control of various regulatory signals and respond to different regulatory networks. The multiplicity of Trx systems and the diversity of TrxBs most likely meet specific needs of Clostridia in adaptation to strong stress exposure, sporulation and Stickland pathways. Author summary: Cells, that are exposed to oxidative stress in their environment, must rapidly adapt and repair their proteins and thiols. The thioredoxin (Trx) system plays a crucial role in the protection of cysteine from oxidation. Despite being ubiquitous, their role in the obligate anaerobic Clostridia, the relevance of the atypical multiplicity of Trx reductases in bacterial physiology and the importance of a clostridial-specific ferredoxin-dependent Trx reductase had remained unexplored. We analyzed the role of the thiol repair Trx systems in the gut enteropathogen Clostridioides difficile, a major cause of antibiotic-associated diarrhea. Two Trx systems are involved in the response to stresses encountered in the gastrointestinal tract during infection. One of these Trx systems is also present in the spore, the form of transmission and persistence in the environment, and protects the spore from hypochlorite, a disinfectant used to eradicate the spores in hospital. The third system is involved in glycine catabolism and contributes to efficient sporulation. This multiplicity of enzymes seems to meet the needs of cell during growth, compartmentation, and differentiation, not only in Clostridia but perhaps in other multiple-Trx reductase organisms such as Cyanobacteria or eukaryotes, which have dedicated Trx systems in mitochondria and chloroplast. [ABSTRACT FROM AUTHOR]

Platinum-based chemotherapy drugs commonly used for cancer treatment can cause peripheral neuropathy, which damages nerves in the peripheral nervous system and affects patients' quality of life. A recent study found that activating the S1P2 receptor can counteract the effects of cisplatin-induced peripheral neuropathy, suggesting that targeting this receptor could be a potential treatment approach. The study used animal models and gene sequencing analysis to investigate the neuroprotective effects of S1P2 activation and found that it restored gene dysregulation associated with nerve growth and mitochondrial functions. These findings indicate that S1P2 activation may be a promising therapeutic target for cisplatin-induced peripheral neuropathy. [Extracted from the article]

Some insertion sequence (IS) elements were actively transposed using oxidative stress conditions, including gamma irradiation and hydrogen peroxide treatment, in Deinococcus geothermalis, a radiation-resistant bacterium. D. geothermalis wild-type (WT), sigma factor gene-disrupted (∆dgeo_0606), and LysR gene-disrupted (∆dgeo_1692) mutants were examined for IS induction that resulted in non-pigmented colonies after gamma irradiation (5 kGy) exposure. The loss of pigmentation occurred because dgeo_0524, which encodes a phytoene desaturase in the carotenoid pathway, was disrupted by the transposition of IS elements. The types and loci of the IS elements were identified as ISDge2 and ISDge6 in the ∆dgeo_0606 mutant and ISDge5 and ISDge7 in the ∆dgeo_1692 mutant, but were not identified in the WT strain. Furthermore, 80 and 100 mM H2O2 treatments induced different transpositions of IS elements in ∆dgeo_0606 (ISDge5, ISDge6, and ISDge7) and WT (ISDge6). However, no IS transposition was observed in the ∆dgeo_1692 mutant. The complementary strain of the ∆dgeo_0606 mutation showed recovery effects in the viability assay; however, the growth-delayed curve did not return because the neighboring gene dgeo_0607 was overexpressed, probably acting as an anti-sigma factor. The expression levels of certain transposases, recognized as pivotal contributors to IS transposition, did not precisely correlate with active transposition in varying oxidation environments. Nevertheless, these findings suggest that specific IS elements integrated into dgeo_0524 in a target-gene-deficient and oxidation-source-dependent manner. [ABSTRACT FROM AUTHOR]

By reducing the 2-nitrophenylhydrazone of cyclohexanone with sodium dithionite, an unexpected yellow compound was obtained instead of the corresponding colorless amino derivative. Many years later, the structure of this compound, namely, cyclohexane-3-spiro-3,4-dihydro-1,2,4-benzotriazine, was demonstrated. From that time, the reduction of 2-nitrophenylhydrazones of different kinds of ketones, followed by air oxidation of the initially formed amino compounds, has represented a general way to synthesize a variety of 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines. Many derivatives have been obtained so far by a single research group, and most of them have demonstrated interesting pharmacological activities, mainly antihypertensive, anti-inflammatory, and diuretic effects and other activities with lower diffusion. Moreover, 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines represent a novel class of ligands for sigma receptors, with nanomolar affinity to the σ1 subtype. This property might promote the development of agents for cardiovascular, neurodegenerative, and proliferative pathologies. The present commentary, by collecting compounds and biological results obtained so far, intends to celebrate the centennial of the discovery of the first member of this class of compounds and to promote further investigation in the field. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is spreading its root disproportionately among the worldwide population. Many genes have been identified as the hallmarks of AD. Based upon the knowledge, many clinical trials have been designed and conducted. Attempts have been made to alleviate the pathology associated with AD by targeting the molecular products of these genes. Irrespective of the understanding on the genetic component of AD, many clinical trials have failed and imposed greater challenges on the path of drug discovery. Therefore, this review aims to identify research and review articles to pinpoint the limitations of drug candidates (thiethylperazine, CT1812, crenezumab, CNP520, and lecanemab), which are under or withdrawn from clinical trials. Thorough analysis of the cross-talk pathways led to the identification of many confounding factors, which could interfere with the success of clinical trials with drug candidates such as thiethylperazine, CT1812, crenezumab, and CNP520. Though these drug candidates were enrolled in clinical trials, yet literature review shows many limitations. These limitations raise many questions on the rationale behind the enrollments of these drug candidates in clinical trials. A meticulous prior assessment of the outcome of clinical studies may stop risky clinical trials at their inceptions. This may save time, money, and resources. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine, 5-HT) is a ubiquitous neurotransmitter in the human body. In the central nervous system, 5-HT affects sleep, pain, mood, appetite, and attention, while in the peripheral nervous system, 5-HT modulates peristalsis, mucus production, and blood vessel dilation. Fourteen membrane receptors mediate 5-HT activity. In agreement with the crucial roles played by 5-HT, many drugs target 5-HT receptors (5-HTRs). Therefore, it is unsurprising that many efforts have been devoted to discovering multitarget-directed ligands (MTDLs) capable of engaging one or more 5-HTRs plus another target phenotypically linked to a particular disease. In this review, we will describe medicinal chemistry efforts in designing MTDLs encompassing activity for one or more 5-HTRs, starting with atypical antipsychotics and moving to dual 5-HT1AR/serotonin transporter ligands, 5-HT6R antagonists/acetyl cholinesterases inhibitors, and 5-HT4R agonists/acetyl cholinesterases inhibitors. We will also provide an outlook on the most recent efforts made in the field.

Up to approximately 70% of cancer survivors report persistent deficits in memory, attention, speed of information processing, multi-tasking, and mental health functioning, a series of symptoms known as “brain fog.” The severity and duration of such effects can vary depending on age, cancer type, and treatment regimens. In particular, every year, hundreds of thousands of patients worldwide undergo radiotherapy (RT) for primary brain tumors and brain metastases originating from extracranial tumors. Besides its potential benefits in the control of tumor progression, recent studies indicate that RT reprograms the brain tumor microenvironment inducing increased activation of microglia and astrocytes and a consequent general condition of neuroinflammation that in case it becomes chronic could lead to a cognitive decline. Furthermore, radiation can induce endothelium reticulum (ER) stress directly or indirectly by generating reactive oxygen species (ROS) activating compensatory survival signaling pathways in the RT-surviving fraction of healthy neuronal and glial cells. In particular, the anomalous accumulation of misfolding proteins in neuronal cells exposed to radiation as a consequence of excessive activation of unfolded protein response (UPR) could pave the way to neurodegenerative disorders. Moreover, exposure of cells to ionizing radiation was also shown to affect the normal proteasome activity, slowing the degradation rate of misfolded proteins, and further exacerbating ER-stress conditions. This compromises several neuronal functions, with neuronal accumulation of ubiquitinated proteins with a consequent switch from proteasome to immunoproteasome that increases neuroinflammation, a crucial risk factor for neurodegeneration. The etiology of brain fog remains elusive and can arise not only during treatment but can also persist for an extended period after the end of RT. In this review, we will focus on the molecular pathways triggered by radiation therapy affecting cognitive functions and potentially at the origin of so-called “brain fog” symptomatology, with the aim to define novel therapeutic strategies to preserve healthy brain tissue from cognitive decline.

The sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal antinociceptive effect is approximately 24 h following dosing. We sought to understand this unique antineuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout mice for Tmem97, we find that a σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce antinociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain. [ABSTRACT FROM AUTHOR]

Anti-sigma factor antagonists SpoIIAA and RsbV from Bacillus subtilis are the archetypes for singledomain STAS proteins in bacteria. The structures and mechanisms of these proteins along with their cognate anti-sigma factors have been well studied. SpoIIAA and RsbV utilize a partnerswitching mechanism to regulate gene expression through protein-protein interactions to control the activity of their downstream anti-sigma factor partners. The Vibrio fischeri STAS domain protein SypA is also proposed to employ a partner-switching mechanism with its partner SypE, a serine kinase/phosphatase that controls SypA's phosphorylation state. However, this regulation appears opposite to the canonical pathway, with SypA being the more downstream component rather than SypE. Here we explore the commonalities and differences between SypA and the canonical single-domain STAS proteins SpoIIAA and RsbV. We use a combination of AlphaFold 2 structure predictions and computational modeling to investigate the SypA-SypE binding interface. We then test a subset of our predictions in V.fischeri by generating and expressing SypA variants. Our findings suggest that, while SypA shares many sequence and structural traits with anti-sigma factor antagonist STAS domain proteins, there are significant differences that may account for SypA's distinct regulatory output. [ABSTRACT FROM AUTHOR]

Simple Summary: Selective estrogen receptor modulators are a major treatment modality for estrogen receptor-positive breast cancers, but the emergence of resistance or a lack of initial responsiveness is a major cause of treatment failures. This study describes TMEM97, also known as sigma 2 receptor, as a novel regulator of estrogen receptor activation. High expression of TMEM97 is found in breast tumor tissues with estrogen receptor positivity. Depletion of TMEM97 expression reduces estrogen receptor activities and breast cancer cell growth. Increased expression of TMEM97 in breast cancer cells stimulates estrogen receptor activities and growth. Further, TMEM97 increases the resistance of breast cancer cells to tamoxifen through elaborating the mTOR/S6K1 signaling. The results suggest an important role for TMEM97 in estrogen receptor activation and resistance to tamoxifen in breast cancer cells. Aberrant estrogen receptor (ER) signaling is a major driver of breast tumor growth and progression. Sigma 2 receptor has long been implicated in breast carcinogenesis based on pharmacological studies, but its molecular identity had been elusive until TMEM97 was identified as the receptor. Herein, we report that the TMEM97/sigma 2 receptor is highly expressed in ER-positive breast tumors and its expression is strongly correlated with ERs and progesterone receptors (PRs) but not with HER2 status. High expression levels of TMEM97 are associated with reduced overall survival of patients. Breast cancer cells with increased expression of TMEM97 had a growth advantage over the control cells under both nutrition-limiting and sufficient conditions, while the knockdown of TMEM97 expression reduced tumor cell proliferations. When compared to their vector control cells, MCF7 and T47D cells with increased TMEM97 expression presented increased resistance to tamoxifen treatment and also grew better under estrogen-depleted conditions. The TMEM97/sigma 2 receptor enhanced the ERα transcriptional activities and increased the expression of genes responsive to estrogen treatment. Increased TMEM97 also stimulated the mTOR/S6K1 signaling pathways in the MCF7 and T47D cells. The increased level of active, phosphorylated ERα, and the enhanced resistance to tamoxifen treatment with increased TMEM97, could be blocked by an mTOR inhibitor. The knockdown of TMEM97 expression reduced the ERα and mTOR/S6K1 signaling activities, rendering the cells with an increased sensitivity to tamoxifen. The observations suggest that the TMEM97/sigma 2 receptor is a novel regulator of ERα activities in breast tumor cell growth. [ABSTRACT FROM AUTHOR]

This paper deals with classical solution of system$ \begin{array}{*{20}{l}}{\begin{eqnarray} { } \left\{ \begin{array}{ll} u_t = \epsilon_1\Delta u-\chi_{1}\nabla\cdot(u\nabla v)-\chi_{2}\nabla\cdot(u\nabla z)+\mu_1 u(1-u-a_1w), &\\ 0 = \Delta v-v+w^{\sigma_1}, &\\ w_t = \epsilon_2\Delta w-\chi_3\nabla\cdot(w\nabla z)-\chi_4\nabla\cdot(w\nabla v)+\mu_2 w(1-w-a_2u), &\\ 0 = \Delta z-z+u^{\sigma_2} & \end{array} \right. \end{eqnarray}}&{\;\;\;\;(1)}\end{array} $and strong $ W^{1, q}(\Omega) $-solution of hyperbolic-elliptic-hyperbolic-elliptic model$ \begin{array}{*{20}{l}}{\begin{eqnarray} { } \left\{ \begin{array}{ll} u_t = -\chi_{1}\nabla\cdot(u\nabla v)-\chi_{2}\nabla\cdot(u\nabla z)+\mu_1 u(1-u-a_1w), &\\ 0 = \Delta v-v+w^{\sigma_1}, &\\ w_t = -\chi_3\nabla\cdot(w\nabla z)-\chi_4\nabla\cdot(w\nabla v)+\mu_2 w(1-w-a_2u), &\\ 0 = \Delta z-z+u^{\sigma_2}, & \end{array} \right. \end{eqnarray}}&{\;\;\;(2)}\end{array} $in a smoothly bounded domain $ \Omega\subset \mathbb{R}^n $. By the viscosity vanishing method and logarithmic Sobolev inequality, we first built the local well-pose of the strong $ W^{1, q}(\Omega) $-solution in the sense that the classical solution of (1) will converge to the strong $ W^{1, q}(\Omega) $-solution of (2) as $ \epsilon_1, \epsilon_2\searrow0 $ and then get a blow-up result with nonradial symmetry setting:● if $ \sigma_1 = \sigma_2 = 1 $, then for suitably larger $ \chi_2, \chi_4 $ and initial data, the strong $ W^{1, q}(\Omega) $-solution $ (u, w) $ blows up in finite time with $ L^q(\Omega)\times L^q(\Omega) $-norm.● if $ \sigma_1 = \sigma_2>1 $, then the suitably larger initial data is enough to ensure the strong $ W^{1, q}(\Omega) $-solution $ (u, w) $ blows up in finite time with $ L^q(\Omega)\times L^q(\Omega) $-norm.The upper bound estimates of blow-up time and rate are obtained. We also hypothesize that if $ \epsilon_1, \epsilon_2 $ are suitably small, the classical solution of (1) can exceed arbitrarily large finite value. [ABSTRACT FROM AUTHOR]

Low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1), also known as receptor associated protein (RAP), is an endoplasmic reticulum (ER) chaperone and inhibitor of LDL receptor related protein 1 (LRP1) and related receptors. These receptors have dozens of physiological ligands and cell functions, but it is not known whether cells release LRPAP1 physiologically at levels that regulate these receptors and cell functions. We used mouse BV-2 and human CHME3 microglial cell lines, and found that microglia released nanomolar levels of LRPAP1 when inflammatory activated by lipopolysaccharide or when ER stressed by tunicamycin. LRPAP1 was found on the surface of live activated and non-activated microglia, and anti-LRPAP1 antibodies induced internalization. Addition of 10 nM LRPAP1 inhibited microglial phagocytosis of isolated synapses and cells, and the uptake of Aβ. LRPAP1 also inhibited Aβ aggregation in vitro. Thus, activated and stressed microglia release LRPAP1 levels that can inhibit phagocytosis, Aβ uptake and Aβ aggregation. We conclude that LRPAP1 release may regulate microglial functions and Aβ pathology, and more generally that extracellular LRPAP1 may be a physiological and pathological regulator of a wide range of cell functions. [ABSTRACT FROM AUTHOR]

Prodigiosin, a red pigment produced by Hahella chejuensis, a marine-derived microorganism, has several biological functions, including antimicrobial activity and inflammatory relief. In this study, the antibacterial activity of prodigiosin against skin microorganisms was explored. Paper disc assay on skin bacterial cells revealed that Cutibacterium acnes related to acne vulgaris highly susceptible to prodigiosin. MIC (Minimal Inhibitory Concentration) and MBC (Minimal Bactericidal Concentration) were determined on Cutibacterium species. The RNA-seq analysis of prodigiosin-treated C. acnes cells was performed to understand the antibacterial mechanism of prodigiosin. Among changes in the expression of hundreds of genes, the expression of a stress-responsive sigma factor encoded by sigB increased. Conversely, the gene expression of cell wall biosynthesis and energy metabolism was inhibited by prodigiosin. Specifically, the expression of genes related to the metabolism of porphyrin, a pro-inflammatory metabolite, was significantly reduced. Therefore, prodigiosin could be used to control C. acnes. Our study provided new insights into the antimicrobial mechanism of prodigiosin against C. acnes strains. [ABSTRACT FROM AUTHOR]

The emergence of lethal coronaviruses follows a periodic pattern which suggests a recurring cycle of outbreaks. It remains uncertain as to when the next lethal coronavirus will emerge, though its eventual emergence appears to be inevitable. New mutations in evolving SARS-CoV-2 variants have provided resistance to current antiviral drugs, monoclonal antibodies, and vaccines, reducing their therapeutic efficacy. This underscores the urgent need to investigate alternative therapeutic approaches. Sigma receptors have been unexpectedly linked to the SARS-CoV-2 life cycle due to the direct antiviral effect of their ligands. Coronavirus-induced cell stress facilitates the formation of an ER-derived complex conducive to its replication. Sigma receptor ligands are believed to prevent the formation of this complex. Repurposing FDA-approved drugs for COVID-19 offers a timely and cost-efficient strategy to find treatments with established safety profiles. Notably, diphenhydramine, a sigma receptor ligand, is thought to counteract the virus by inhibiting the creation of ER-derived replication vesicles. Furthermore, lactoferrin, a well-characterized immunomodulatory protein, has shown antiviral efficacy against SARS-CoV-2 both in laboratory settings and in living organisms. In the present study, we aimed to explore the impact of sigma receptor ligands on SARS-CoV-2-induced mortality in ACE2-transgenic mice. We assessed the effects of an investigational antiviral drug combination comprising a sigma receptor ligand and an immunomodulatory protein. Mice treated with sigma-2 receptor ligands or diphenhydramine and lactoferrin exhibited improved survival rates and rapid rebound in mass following the SARS-CoV-2 challenge compared to mock-treated animals. Clinical translation of these findings may support the discovery of new treatment and research strategies for SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Bacterial growth, under laboratory conditions or in a natural environment, goes through different growth phases. Some gene expressions are regulated with respect to the growth phase, which allows bacteria to adapt to changing conditions. Among them, many gene transcriptions are controlled by RpoHI or RpoHII in Rhodobacter sphaeroides. In a previous study, it was proven that the alternative sigma factors, RpoE, RpoHI, and RpoHII, are the major regulators of oxidative stress. Moreover, the growth of bacteria reached a stationary phase, and following the outgrowth, rpoE, rpoHI, and rpoHII mRNAs increased with respect to the growth phase. In this study, we demonstrated the regulatory function of alternative sigma factors in the rsp_0557 gene. The gene rsp_0557 is expressed with respect to the growth phase and belongs to the RpoHI/RpoHII regulons. Reporter assays showed that the antisigma factor ChrR turns on or over the RpoE activity to regulate rsp_0557 expression across the growth phase. In the exponential phase, RpoHII and sRNA Pos19 regulate the expression of rsp_0557 to an appropriate level under RpoE control. In the stationary phase, RpoHI and Pos19 stabilize the transcription of rsp_0557 at a high level. During outgrowth, RpoHI negatively regulates the transcription of rsp_0557. Taken together, our data indicate that these regulators are recruited by cells to adapt to or survive under different conditions throughout the growth phase. However, they still did not display all of the regulators involved in growth phase-dependent regulation. More research is still needed to learn more about the interaction between the regulators and the process of adapting to changed growth conditions and environments. [ABSTRACT FROM AUTHOR]

Cyanobacteria are photosynthetic prokaryotes of high ecological and biotechnological relevance that have been cultivated in laboratories around the world for more than 70 years. Prolonged laboratory culturing has led to multiple microevolutionary events and the appearance of a large number of 'domesticated' substrains among model cyanobacteria. Despite its widespread occurrence, strain domestication is still largely ignored. In this work we describe Synechococcus elongatus PCC 7942‐KU, a novel domesticated substrain of the model cyanobacterium S. elongatus PCC 7942, which presents a fast‐sedimenting phenotype. Under higher ionic strengths the sedimentation rate increased leading to complete sedimentation in just 12 h. Through whole genome sequencing and gene deletion, we demonstrated that the Group 3 alternative sigma factor F plays a key role in cell sedimentation. Further analysis showed that significant changes in cell surface structures and a three‐fold increase in released polysaccharides lead to the appearance of a fast‐sedimenting phenotype. This work sheds light on the determinants of the planktonic to benthic transitions and provides genetic targets to generate fast‐sedimenting strains that could unlock cost‐effective cyanobacterial harvesting at scale. [ABSTRACT FROM AUTHOR]

Itch and pain are closely related but distinct sensations that share largely overlapping mediators and receptors. We hypothesized that the novel, multi-target compound E153 has the potential to attenuate pain and pruritus of different origins. After the evaluation of sigma receptor affinity and pharmacokinetic studies, we tested the compound using different procedures and models of pain and pruritus. Additionally, we used pharmacological tools, such as PRE-084, RAMH, JNJ 5207852, and S1RA, to precisely determine the role of histamine H3 and sigma 1 receptors in the analgesic and antipruritic effects of the compound. In vitro studies revealed that the test compound had potent affinity for sigma 1 and sigma 2 receptors, moderate affinity for opioid kappa receptors, and no affinity for delta or μ receptors. Pharmacokinetic studies showed that after intraperitoneal administration, the compound was present at high concentrations in both the peripheral tissues and the central nervous system. The blood–brain barrier-penetrating properties indicate its ability to act centrally at the levels of the brain and spinal cord. Furthermore, the test compound attenuated different types of pain, including acute, inflammatory, and neuropathic. It also showed a broad spectrum of antipruritic activity, attenuating histamine-dependent and histamine-independent itching. Finally, we proved that antagonism of both sigma 1 and histamine H3 receptors is involved in the analgesic activity of the compound, while the antipruritic effect to a greater extent depends on sigma 1 antagonism. [ABSTRACT FROM AUTHOR]

Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane and in the membranes of the endoplasmic reticulum, mitochondria, and nucleus. Until recently, the biology/pharmacology of these proteins focused primarily on their role in neuronal functions in the brain/retina. However, there have been recent developments in the field with the discovery of unexpected roles for these proteins in iron/heme homeostasis. Sigma receptor 1 (S1R) regulates the oxidative stress-related transcription factor NRF2 and protects against ferroptosis, an iron-induced cell death process. Sigma receptor 2 (S2R), which is structurally unrelated to S1R, complexes with progesterone receptor membrane components PGRMC1 and PGRMC2. S2R, PGRMC1, and PGRMC2, either independently or as protein–protein complexes, elicit a multitude of effects with a profound influence on iron/heme homeostasis. This includes the regulation of the secretion of the iron-regulatory hormone hepcidin, the modulation of the activity of mitochondrial ferrochelatase, which catalyzes iron incorporation into protoporphyrin IX to form heme, chaperoning heme to specific hemoproteins thereby influencing their biological activity and stability, and protection against ferroptosis. Consequently, S1R, S2R, PGRMC1, and PGRMC2 potentiate disease progression in hemochromatosis and cancer. These new discoveries usher this intriguing group of non-traditional progesterone receptors into an unchartered territory in biology and medicine. [ABSTRACT FROM AUTHOR]

This letter to the editor discusses the challenges of diagnosing platelet disorders and presents a case study of a patient with a δ-granule storage pool disease. The patient had a history of bleeding symptoms and was diagnosed using flow cytometry analysis of CD63 expression on activated platelets and liquid chromatography tandem mass spectrometry (LC-MS/MS) measurement of plasma serotonin release after platelet activation. The study suggests that these methods may be reliable for diagnosing δ-granule defects in laboratories with the necessary equipment. The authors emphasize the importance of using multiple methods for accurate diagnosis and highlight the limitations of light transmission aggregometry (LTA) in detecting δ-granule defects. [Extracted from the article]

The article discusses coronary artery bypass graft surgery (CABG) and the challenges it faces due to graft remodeling and neointima formation, leading to insufficient blood supply. It highlights the role of endothelial cells (ECs) in mediating vascular homeostasis and their damage, which triggers inflammatory signaling pathways and vascular remodeling.

This article focuses on the development of an efficient method for directly converting somatic cells into induced neural stem cells (iNSCs) without passing through a pluripotent state. It is reported that the researchers used an engineered version of the Sox17 transcription factor, called eSox17FNV, to reprogram embryonic and aged mouse fibroblasts into iNSCs. It is further reported that this approach bypasses pluripotency reprogramming and produces iNSCs more rapidly and efficiently.

The article discusses how interleukin-33 (IL-33) influences the interaction between regulatory T (Treg) cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment. It is reported that IL1RL1+ Treg cells accumulate due to IL-33, promoting immune tolerance and tumor growth. It is further reported that the study identifies the AREG/EGFR axis as a key mediator of communication between these cell types, driving fibrosis and immunosuppression.

Sigma (σ) receptors are a class of unique proteins with two subtypes: the sigma-1 (σ1) receptor which is situated at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), and the sigma-2 (σ2) receptor, located in the ER-resident membrane. Increasing evidence indicates the involvement of both σ1 and σ2 receptors in the pathogenesis of Alzheimer's disease (AD), and thus these receptors represent two potentially effective biomarkers for emerging AD therapies. The availability of optimal radioligands for positron emission tomography (PET) neuroimaging of the σ1 and σ2 receptors in humans will provide tools to monitor AD progression and treatment outcomes. In this review, we first summarize the significance of both receptors in the pathophysiology of AD and highlight AD therapeutic strategies related to the σ1 and σ2 receptors. We then survey the potential PET radioligands, with an emphasis on the requirements of optimal radioligands for imaging the σ1 or σ2 receptors in humans. Finally, we discuss current challenges in the development of PET radioligands for the σ1 or σ2 receptors, and the opportunities for neuroimaging to elucidate the σ1 and σ2 receptors as novel biomarkers for early AD diagnosis, and for monitoring of disease progression and AD drug efficacy. [ABSTRACT FROM AUTHOR]

The article focuses on a study conducted to analyze the impact of extracellular signal-regulated kinase (ERK) pathway phosphorylates DICER1 on lineage flexibility and open chromatin state of tumor cells in lung adenocarcinomas. The study reveals that murine AT2 tumor cells undergo altered chromatin compaction in advanced tumors, leading to the expression of gastric genes and transitioning from a restricted alveolar to a broader endodermal lineage state.

Endoplasmic reticulum (ER)–plasma membrane (PM) contact sites/junctions play important roles in cell physiology including signal transduction, ion and lipid transfer, and membrane dynamics. However, little is known about the dynamic regulation and functional roles of ER–PM junctions in neurons. Using a split green fluorescent protein-based membrane contact probe, we find that the density of ER–PM contact sites changes dynamically in the dendrites of hippocampal neurons undergoing long-term synaptic potentiation (LTP). We show that the Ca2±-sensing membrane tethering protein Extended Synaptotagmin 1 (E-Syt1) mediates the formation of ER–PM contact sites during LTP. We also show that E-Syt1 is required for neuronal activity-dependent surface expression of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptors. These findings implicate ER–PM junctions in the regulation of neurotransmitter receptor trafficking and synaptic plasticity. [ABSTRACT FROM AUTHOR]

N,N-dimethyltryptamine (DMT) is the simplest psychedelic tryptamine and is produced naturally by many plant and animal species, including humans. While classical psychedelics, such as lysergic acid diethylamide, or psilocybin, are gaining interest because of their therapeutic potential, DMT has yet to be fully investigated. However, preliminary clinical evidence suggests that DMT and/or ayahuasca, a DMT-containing psychoactive beverage, both possess antidepressive, anxiolytic, and antiaddictive properties. In addition, the subjective effects of DMT are particularly potent. Both subjective and therapeutic cues can be largely explained via the neuromodulatory properties of DMT. In addition, DMT interacts with several neurochemical systems, including the glutamatergic, monoaminergic, and cholinergic systems. Consequently, large-scale brain dynamics can suffer acute and dramatic shifts in several networks, including visual and auditive networks, and the default-mode network. More broadly, top-down cognitive processes (predictive and contextual processing) can become restricted while bottom-up and stimuli-related processing is enhanced. Furthermore, the acute effects of DMT can crystallize to some extent by virtue of its plastogenic effects which are mediated by sigma 1 receptor, brain-derived neurotrophic factor, tropomyosin receptor kinase B, and serotonin receptor 2A. DMT-induced plasticity has been related mental well-being and therapeutic benefits. Here, I provide an updated review of the neuromodulatory effects of DMT and the mechanisms that underlie these effects. I consider the molecular targets that influence neurochemical systems, changes in large-scale cortical function and structure, and DMT-dependent neuroplasticity. Finally, I highlight the therapeutic relevance and/or risks associated with the neuromodulatory mechanisms of DMT. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer continues to be the number one cause of cancer mortality among women. Because breast cancer is a heterogenous disease there is a need for a more personalized approach to treatment. Such an approach requires the understanding of the molecular root cause of each cancer and the identification of the responsible molecule(s) or pathway(s). SigmaR1 is a receptor implicated in certain types of breast cancer and represents a promising target for a new generation of personalized treatments. However, there is a need for understanding its precise cellular role in order to target it effectively. This article reviews the current knowledge about SigmaR1 in breast cancer biology and potential treatment and proposes a new model as to how SigmaR1 operates within the cell in order to devise new effective ways for utilizing it in the clinic. Despite the major progress in treating breast cancer, recurrence remains a problem and types such as triple-negative breast cancer still lack targeted medicine. The orphan Sigma receptor1 (SigmaR1) has emerged as a target in breast cancer, but its mechanism of action is unclear and hinders clinical utility. SigmaR1 is widely expressed in organ tissues and localized to various sub-cellular compartments, particularly the endoplasmic reticulum (ER), the mitochondrial-associated membranes (MAMs) and the nuclear envelope. As such, it involves diverse cellular functions, including protein quality control/ER stress, calcium signaling, cholesterol homeostasis, mitochondrial integrity and energy metabolism. Consequently, SigmaR1 has been implicated in a number of cancers and degenerative diseases and thus has been intensively pursued as a therapeutic target. Because SigmaR1 binds a number of structurally unrelated ligands, it presents an excellent context-dependent therapeutic target. Here, we review its role in breast cancer and the current therapies that have been considered based on its known functions. As SigmaR1 is not classified as an oncoprotein, we propose a model in which it serves as an oligomerization adaptor in key cellular pathways, which may help illuminate its association with variable diseases and pave the way for clinical utility in personalized medicine. [ABSTRACT FROM AUTHOR]

In several Gram‐negative bacteria, the general stress response is mediated by the alternative sigma factor RpoS, a subunit of RNA polymerase that confers promoter specificity. In Escherichia coli, regulation of protein levels of RpoS involves the adaptor protein RssB, which binds RpoS for presenting it to the ClpXP protease for its degradation. However, in species from the Pseudomonadaceae family, RpoS is also degraded by ClpXP, but an adaptor has not been experimentally demonstrated. Here, we investigated the role of an E. coli RssB‐like protein in two representative Pseudomonadaceae species such as Azotobacter vinelandii and Pseudomonas aeruginosa. In these bacteria, inactivation of the rssB gene increased the levels and stability of RpoS during exponential growth. Downstream of rssB lies a gene that encodes a protein annotated as an anti‐sigma factor antagonist (rssC). However, inactivation of rssC in both A. vinelandii and P. aeruginosa also increased the RpoS protein levels, suggesting that RssB and RssC work together to control RpoS degradation. Furthermore, we identified an in vivo interaction between RssB and RpoS only in the presence of RssC using a bacterial three‐hybrid system. We propose that both RssB and RssC are necessary for the ClpXP‐dependent RpoS degradation during exponential growth in two species of the Pseudomonadaceae family. [ABSTRACT FROM AUTHOR]