indirect pathway
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2022 ◽  
Vol 12 ◽  
Author(s):  
Ewa Kuca-Warnawin ◽  
Marzena Olesińska ◽  
Piotr Szczȩsny ◽  
Ewa Kontny

Objectives: Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are chronic wasting, incurable rheumatic diseases of autoimmune background, in which T cells play a critical pathogenic role. Autologous adipose tissue-derived mesenchymal stem cells (ASCs) may represent an alternative therapeutic option for SLE and SSc patients, but the biology of these cells is poorly understood.Methods: Herein, we evaluated the anti-proliferative impact of ASCs of healthy donors (HD/ASCs, 5 reference cell lines), SLE patients (n = 20), and SSc patients (n = 20) on T lymphocytes. To assess the direct and indirect pathway of ASCs action, peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells of HD were activated and co-cultured in cell-to-cell contact (C-C) and transwell (T-W) conditions with untreated or cytokine (TNF + IFNΥ, TI)-licensed ASCs, then analyzed by flow cytometry to rate the proliferation response of CD8+ and/or CD4+ T cells. The concentrations of kynurenines, prostaglandin E2 (PGE2), interleukin 10 (IL-10), and transforming growth factor β (TGFβ) were measured from culture supernatants. Specific inhibitors of these factors (1-MT, indomethacin, and cytokine-neutralizing antibody) were used to assess their contribution to anti-proliferative ASCs action.Results: All tested ASCs significantly decreased the number of proliferating CD4+ and CD8+ T cells, the number of division/proliferating cell (PI), and fold expansion (RI), and similarly upregulated kynurenines and PGE2, but not cytokine levels, in the co-cultures with both types of target cells. However, TI-treated SLE/ASCs and SSc/ASCs exerted a slightly weaker inhibitory effect on CD4+ T-cell replication than their respective HD/ASCs. All ASCs acted mainly via soluble factors. Their anti-proliferative effect was stronger, and kynurenine levels were higher in the T-W condition than the C-C condition. Blocking experiments indicated an involvement of kynurenine pathway in inhibiting the number of proliferating cells, PI, and RI values as well as PGE2 role in decreasing the number of proliferating cells. TGFβ did not contribute to ASCs anti-proliferative capabilities, while IL-10 seems to be involved in such activity of only SLE/ASCs.Conclusion: The results indicate that SLE/ASCs and SSc/ASCs retain their capability to restrain the expansion of allogeneic CD4+ and CD8+ T cells and act by similar mechanisms as ASCs of healthy donors and thus may have therapeutic value.


2022 ◽  
Author(s):  
Joe C Brague ◽  
Rebecca P Seal

Motor deficits of Parkinsons disease (PD) such as rigidity, bradykinesia and akinesia result from a progressive loss of nigrostriatal dopamine neurons. No therapies exist that slow their degeneration and the most effective treatments for the motor symptoms: L-dopa -the precursor to dopamine, and deep brain stimulation can produce dyskinesias and are highly invasive, respectively. Hence, alternative strategies targeted to slow the progression or delay the onset of motor symptoms are still highly sought. Here we report the identification of a long-term striatal plasticity mechanism that delays for several months, the onset of motor deficits in a mouse PD model. Specifically, we show that a one-week transient daily elevation of midbrain dopamine neuron activity during depletion preserves the connectivity of direct but not indirect pathway projection neurons. The findings are consistent with the balance theory of striatal output pathways and suggest a novel approach for treating the motor symptoms of PD.


2022 ◽  
Vol 12 ◽  
Author(s):  
Takahito Mukai ◽  
Kazuaki Amikura ◽  
Xian Fu ◽  
Dieter Söll ◽  
Ana Crnković

Universally present aminoacyl-tRNA synthetases (aaRSs) stringently recognize their cognate tRNAs and acylate them with one of the proteinogenic amino acids. However, some organisms possess aaRSs that deviate from the accurate translation of the genetic code and exhibit relaxed specificity toward their tRNA and/or amino acid substrates. Typically, these aaRSs are part of an indirect pathway in which multiple enzymes participate in the formation of the correct aminoacyl-tRNA product. The indirect cysteine (Cys)-tRNA pathway, originally thought to be restricted to methanogenic archaea, uses the unique O-phosphoseryl-tRNA synthetase (SepRS), which acylates the non-proteinogenic amino acid O-phosphoserine (Sep) onto tRNACys. Together with Sep-tRNA:Cys-tRNA synthase (SepCysS) and the adapter protein SepCysE, SepRS forms a transsulfursome complex responsible for shuttling Sep-tRNACys to SepCysS for conversion of the tRNA-bound Sep to Cys. Here, we report a comprehensive bioinformatic analysis of the diversity of indirect Cys encoding systems. These systems are present in more diverse groups of bacteria and archaea than previously known. Given the occurrence and distribution of some genes consistently flanking SepRS, it is likely that this gene was part of an ancient operon that suffered a gradual loss of its original components. Newly identified bacterial SepRS sequences strengthen the suggestion that this lineage of enzymes may not rely on the m1G37 identity determinant in tRNA. Some bacterial SepRSs possess an N-terminal fusion resembling a threonyl-tRNA synthetase editing domain, which interestingly is frequently observed in the vicinity of archaeal SepCysS genes. We also found several highly degenerate SepRS genes that likely have altered amino acid specificity. Cross-analysis of selenocysteine (Sec)-utilizing traits confirmed the co-occurrence of SepCysE and the Sec-utilizing machinery in archaea, but also identified an unusual O-phosphoseryl-tRNASec kinase fusion with an archaeal Sec elongation factor in some lineages, where it may serve in place of SepCysE to prevent crosstalk between the two minor aminoacylation systems. These results shed new light on the variations in SepRS and SepCysS enzymes that may reflect adaptation to lifestyle and habitat, and provide new information on the evolution of the genetic code.


Endocrinology ◽  
2021 ◽  
Author(s):  
Chie Umatani ◽  
Nagisa Yoshida ◽  
Eri Yamamoto ◽  
Yasuhisa Akazome ◽  
Yasutaka Mori ◽  
...  

Abstract Animals properly perform sexual behaviors by using multiple sensory cues. However, neural mechanisms integrating multiple sensory cues and regulating motivation for sexual behaviors remain unclear. Here, we focused on peptidergic neurons, terminal nerve gonadotropin-releasing hormone (TN-GnRH) neurons, which receive inputs from various sensory systems and co-express neuropeptide FF (NPFF) in addition to GnRH. Our behavioral analyses using knockout medaka of GnRH (gnrh3) and/or NPFF (npff) demonstrated that some sexual behavioral repertoires were ‘delayed’, not disrupted, in gnrh3 and npff single knockout males, while the double knockout appeared to alleviate the significant defects that were observed in single knockouts. We also found anatomical evidence to show that both neuropeptides modulate the sexual behavior-controlling brain areas. Furthermore, we demonstrated that NPFF activates neurons in the preoptic area via indirect pathway, which is considered to induce the increase in motivation for male sexual behaviors. Considering these results, we propose a novel mechanism by which co-existing peptides of the TN-GnRH neurons, NPFF and GnRH3, coordinately modulate certain neuronal circuit for the control of behavioral motivation. Our results may go a long way toward understanding the functional significance of peptidergic neuromodulation in response to sensory information from the external environments.


2021 ◽  
Author(s):  
Catalina Vich ◽  
Matthew Clapp ◽  
Timothy Verstynen ◽  
Jonathan Rubin

During action selection, mammals exhibit a high degree of flexibility in adapting their decisions in response to environmental changes. Although the cortico-basal ganglia-thalamic (CBGT) network is implicated in this adaptation, it features a synaptic architecture comprising multiple feed-forward, reciprocal, and feedback pathways, complicating efforts to elucidate the roles of specific CBGT populations in the process of evidence accumulation during decision-making. In this paper we apply a strategic sampling approach, based on Latin hypercube sampling, to explore how CBGT network properties, including subpopulation firing rates and synaptic weights, map to parameters of a normative drift diffusion model (DDM) representing algorithmic aspects of information accumulation during decision-making. Through the application of canonical correlation analysis, we find that this relationship can be characterized in terms of three low-dimensional control ensembles impacting specific qualities of the emergent decision policy: responsiveness (associated with overall activity in corticothalamic and direct pathways), pliancy (associated largely with overall activity in components of the indirect pathway of the basal ganglia), and choice (associated with differences in direct and indirect pathways across action channels). These analyses provide key mechanistic predictions about the roles of specific CBGT network elements in shifting different aspects of decision policies.


2021 ◽  
Author(s):  
Jinyong Zhang ◽  
Ryan N Hughes ◽  
Namsoo Kim ◽  
Isabella P Fallon ◽  
Konstantin I bakhurin ◽  
...  

While in vivo calcium imaging makes it possible to record activity in defined neuronal populations with cellular resolution, optogenetics allows selective manipulation of neural activity. Recently, these two tools have been combined to stimulate and record neural activity at the same time, but current approaches often rely on two-photon microscopes that are difficult to use in freely moving animals. To address these limitations, we have developed a new integrated system combining a one-photon endoscope and a digital micromirror device for simultaneous calcium imaging and precise optogenetic photo-stimulation with near cellular resolution (Miniscope with All-optical Patterned Stimulation and Imaging, MAPSI). Using this highly portable system in freely moving mice, we were able to image striatal neurons from either the direct pathway or the indirect pathway while simultaneously activating any neuron of choice in the field of view, or to synthesize arbitrary spatiotemporal patterns of photo-stimulation. We could also select neurons based on their relationship with behavior and recreate the behavior by mimicking the natural neural activity with photo-stimulation. MAPSI thus provides a powerful tool for interrogation of neural circuit function in freely moving animals.


Author(s):  
Oliver Cousins ◽  
Angela Hodges ◽  
Julia Schubert ◽  
Mattia Veronese ◽  
Federico Turkheimer ◽  
...  

Author(s):  
Yan Du ◽  
Fangyu Cheng ◽  
Miaomiao Wang ◽  
Chunmeng Xu ◽  
Huimin Yu

Hyaluronic acid (HA) is composed of alternating d-glucuronic acid and N-acetyl-d-glucosamine, with excellent biocompatibility and water retention capacity. To achieve heterologous biosynthesis of HA, Corynebacterium glutamicum, a safe GRAS (generally recognized as safe) host, was utilized and metabolically engineered previously. In this work, to achieve further enhancement of HA yield, four strategies were proposed and performed separately first, i.e., (1) improvement of glucose uptake via iolR gene knockout, releasing the inhibition of transporter IolT1/IolT2 and glucokinases; (2) intensification of cardiolipin synthesis through overexpression of genes pgsA1/pgsA2/cls involved in cardiolipin synthesis; (3) duly expressed Vitreoscilla hemoglobin in genome, enhancing HA titer coupled with more ATP and improved NAD+/NADH (>7.5) ratio; and (4) identification of the importance of glutamine for HA synthesis through transcriptome analyses and then enhancement of the HA titer via its supplement. After that, we combined different strategies together to further increase the HA titer. As a result, one of the optimal recombinant strains, Cg-dR-CLS, yielded 32 g/L of HA at 60 h in a fed-batch culture, which was increased by 30% compared with that of the starting strain. This high value of HA titer will enable the industrial production of HA via the engineered C. glutamicum.


Author(s):  
Catherin Ouseph ◽  
Praful Patil

The causative agent of the highly infectious pandemic COVID-19 is SARS-CoV-2. According to WHO, as of August 18th 2020, the number of confirmed cases was and confirmed deaths was 771,635 from 216 countries. The most affected organ system in COVID-19 is the respiratory system. Later studies proved that the virus caused multiorgan infections. Several studies shows that SARS-CoV-2 causes damage to the renal system and; critically ill patients with associated renal damage show a higher mortality rate as compared to those patients with an unaffected renal system .This review article aims at updating the knowledge about associated kidney failure in covid-19 cases and its impact on the morbidity and mortality. The virus damages the renal system through two different mechanisms: Direct and Indirect pathway. The direct pathway explains how the virus damages the renal system by directly acting upon the target cells in the kidney.SARS-CoV-2 gains its entry by binding to the ACE2 receptors on the target cell. The SARS-CoV-2 progresses its journey and extensively spread the infection, damaging the kidneys leading to the failure of the renal system. The indirect pathway of damage speaks about the secondary damage caused to the renal system due to cytokine release syndrome caused by SARS-CoV-2.This pathway also points out the formation of microthrombi in the glomerular capillaries and also kidney hypoperfusion. AKI in covid-19 patients can occur secondary to multiorgan failure. This review aims to build a foundation concerning the direct pathway and indirect pathway by means of which SARS-Cov-2 infects the kidneys by summarizing the numerous researches carried out till date to update the knowledge gained thus far to aid in building better protocols for covid-19 management and decrease morbidity caused due to renal damage.


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