Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective

Development of the central nervous system (CNS) depends on accurate spatiotemporal control of signaling pathways and transcriptional programs. Forkhead Box G1 (FOXG1) is one of the master regulators that play fundamental roles in forebrain development; from the timing of neurogenesis, to the patterning of the cerebral cortex. Mutations in the FOXG1 gene cause a rare neurodevelopmental disorder called FOXG1 syndrome, also known as congenital form of Rett syndrome. Patients presenting with FOXG1 syndrome manifest a spectrum of phenotypes, ranging from severe cognitive dysfunction and microcephaly to social withdrawal and communication deficits, with varying severities. To develop and improve therapeutic interventions, there has been considerable progress towards unravelling the multi-faceted functions of FOXG1 in the neurodevelopment and pathogenesis of FOXG1 syndrome. Moreover, recent advances in genome editing and stem cell technologies, as well as the increased yield of information from high throughput omics, have opened promising and important new avenues in FOXG1 research. In this review, we provide a summary of the clinical features and emerging molecular mechanisms underlying FOXG1 syndrome, and explore disease-modelling approaches in animals and human-based systems, to highlight the prospects of research and possible clinical interventions.

Inflammation as A Precursor of Atherothrombosis, Diabetes and Early Vascular Aging

Vascular disease was for a long time considered a disease of the old age, but it is becoming increasingly clear that a cumulus of factors can cause early vascular aging (EVA). Inflammation plays a key role in vascular stiffening and also in other pathologies that induce vascular damage. There is a known and confirmed connection between inflammation and atherosclerosis. However, it has taken a long time to prove the beneficial effects of anti-inflammatory drugs on cardiovascular events. Diabetes can be both a product of inflammation and a cofactor implicated in the progression of vascular disease. When diabetes and inflammation are accompanied by obesity, this ominous trifecta leads to an increased incidence of atherothrombotic events. Research into earlier stages of vascular disease, and documentation of vulnerability to premature vascular disease, might be the key to success in preventing clinical events. Modulation of inflammation, combined with strict control of classical cardiovascular risk factors, seems to be the winning recipe. Identification of population subsets with a successful vascular aging (supernormal vascular aging—SUPERNOVA) pattern could also bring forth novel therapeutic interventions.

THE POSSIBLE ROLE OF TRACE ELEMENTS IN THYROID HYPERTROPHIC AND ADENOMATOUS TRANSFORMATION

Background: Thyroid benign nodules (TBNs) are the most common diseases of this endocrine gland and are common worldwide. Among TBNs the colloid goiter (CG) and thyroid adenoma (TA) are very frequentdiseases. Evaluation of variant of TBNs is clinically important for subsequent therapeutic interventions, as well as for a clearer understanding the etiology of these disorders. The aim of this exploratory study was to examine differences in the content offifty trace elements (TE) in CG and TA tissues. Methods: Thyroid tissue levels of TE have prospectively evaluated in 46 patients with CG and 19 patients with TA. Measurements have performed using a combination of non-destructive and destructive methods: instrumental neutron activation analysis with high resolution spectrometry of long-lived radionuclides (INAA-LLR) and inductively coupled plasma mass spectrometry (ICPMS), respectively. Tissue samples were divided into two portions. One was used for morphological study while the other was intended for TE analysis. Results: It was observed that in both CG and TA tissues the contents of Ag, Al, Cr, Hg, Mn, Th, and Zn increased, whereas the levels of Au, Be, Cs, Pb, Rb, Sb, Sc, Th, Yb, and Zr were unchanged in comparison with normal thyroid tissue. No differences were found between the TE contents of CG and TA. Conclusions: From results obtained, it was possible to conclude that the common characteristics of CG and TA tissue samples were of a high level of Ag, Al, Cr, Hg, Mn, Th, and Zn in comparison with normal thyroid and, therefore, these TE could be involved in etiology and pathogenesis of thyroid disorders such as CG and TA. Peer Review History: Received: 12 November 2021; Revised: 15 December; Accepted: 31 December, Available online: 15 January 2022 Academic Editor: Ahmad Najib, Universitas Muslim Indonesia, Indonesia, [email protected] UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file: Reviewer's Comments: Average Peer review marks at initial stage: 6.5/10 Average Peer review marks at publication stage: 7.5/10 Reviewers: Prof. Dr. Hassan A.H. Al-Shamahy, Sana'a University, Yemen, [email protected] Rima Benatoui, Laboratory of Applied Neuroendocrinology, Department of Biology, Faculty of Science, Badji Mokhtar University Annaba, BP12 E L Hadjar–Algeria, [email protected] Similar Articles: COMPARISON OF LEVELS OF TWENTY CHEMICAL ELEMENTS IN NORMAL THYROID TISSUE AND HYPERTROPHIC THYROID TISSUE

Hepatitis B Virus Reactivation Associated With Therapeutic Interventions

Hepatitis B virus (HBV) reactivation associated with various therapeutic interventions is an important cause of morbidity and mortality in patients with current or resolved HBV infection. Because no curative treatment for HBV infection is yet available, there are many individuals at risk for HBV reactivation in the general population. Populations at risk for HBV reactivation include patients who are currently infected with HBV or who have been exposed to HBV in the past. HBV reactivation and its potential consequences is a concern when these populations are exposed to anti-cancer chemotherapy, immunosuppressive or immunomodulatory therapies for the management of various malignancies, rheumatologic diseases, inflammatory bowel disease, or solid-organ or hematologic stem cell transplantation. Accordingly, it has become important to understand the basics of HBV reactivation and the mechanisms by which certain therapies are more susceptible to HBV reactivation. This review aims to raise the awareness of HBV reactivation and to understand the mechanisms and the risks of HBV reactivation in various clinical settings.

In Silico Prediction and Design of Uropathogenic Escherichia coli Alpha-Hemolysin Generate a Soluble and Hemolytic Recombinant Toxin

The secretion of α-hemolysin by uropathogenic Escherichia coli (UPEC) is commonly associated with the severity of urinary tract infections, which makes it a predictor of poor prognosis among patients. Accordingly, this toxin has become a target for diagnostic tests and therapeutic interventions. However, there are several obstacles associated with the process of α-hemolysin purification, therefore limiting its utilization in scientific investigations. In order to overcome the problems associated with α-hemolysin expression, after in silico prediction, a 20.48 kDa soluble α-hemolysin recombinant denoted rHlyA was constructed. This recombinant is composed by a 182 amino acid sequence localized in the aa542–723 region of the toxin molecule. The antigenic determinants of the rHlyA were estimated by bioinformatics analysis taking into consideration the tertiary form of the toxin, epitope analysis tools, and solubility inference. The results indicated that rHlyA has three antigenic domains localized in the aa555–565, aa600–610, and aa674–717 regions. Functional investigation of rHlyA demonstrated that it has hemolytic activity against sheep red cells, but no cytotoxic effect against epithelial bladder cells. In summary, the results obtained in this study indicate that rHlyA is a soluble recombinant protein that can be used as a tool in studies that aim to understand the mechanisms involved in the hemolytic and cytotoxic activities of α-hemolysin produced by UPEC. In addition, rHlyA can be applied to generate monoclonal and/or polyclonal antibodies that can be utilized in the development of diagnostic tests and therapeutic interventions.

Weight and Glycemic Control Outcomes of Bariatric Surgery and Pharmacotherapy in Patients With Melanocortin-4 Receptor Deficiency

BackgroundMelanocortin-4 receptor (MC4R) mutations are the most common of the rare monogenic forms of obesity. However, the efficacy of bariatric surgery (BS) and pharmacotherapy on weight and glycemic control in individuals with MC4R deficiency (MC4R-d) is not well-established. We investigated and compared the outcomes of BS and pharmacotherapy in patients with and without MC4R-d.MethodsPertinent details were derived from the electronic database among identified patients who had BS with MC4R-d (study group, SG) and wild-type controls (age- and sex-matched control group, CG). Short- and long-term outcomes were reported for the SG. Short-term outcomes were compared between the two groups.ResultsSeventy patients were screened for MC4R-d. The SG [six individuals (four females, two males); 18 (10–27) years old at BS; 50.3 (41.8–61.9) kg/m2 at BS, three patients with homozygous T162I mutations, two patients with heterozygous T162I mutations, and one patient with heterozygous I170V mutation] had a follow-up duration of up to 10 years. Weight loss, which varied depending on mutation type [17.99 (6.10–22.54) %] was stable for 6 months; heterogeneity of results was observed thereafter. BS was found superior to liraglutide on weight and glycemic control outcomes. At a median follow-up of 6 months, no significant difference was observed on weight loss (20.8% vs. 23.0%, p = 0.65) between the SG and the CG [eight individuals (four females, four males); 19.0 (17.8–36.8) years old at BS, 46.2 (42.0–48.3) kg/m2 at BS or phamacotherapeutic intervention]. Glycemic control in patients with MC4R-d and Type 2 diabetes improved post-BS.ConclusionOur data indicate efficacious short-term but varied long-term weight loss and glycemic control outcomes of BS on patients with MC4R-d, suggesting the importance of ongoing monitoring and complementary therapeutic interventions.

Tracking of Melanoma Cell Plasticity by Transcriptional Reporters

Clonal evolution and cellular plasticity are the genetic and non-genetic driving forces of tumor heterogeneity that in turn determines the tumor cell response towards therapeutic drugs. Several lines of evidence suggest that therapeutic interventions foster the selection of drug resistant neural crest stem-like cells (NCSCs) that establish minimal residual disease (MRD) in melanoma. Here we established a dual reporter system enabling the tracking of NGFR expression and mRNA stability, providing insights into the maintenance of NCSC-states. We observed that the transcriptional reporter that contained a 1kb fragment of the human NGFR promoter was activated only in a minor subset (0.72±0.49%, range 0.3-1.5) and ~2-4% of A375 melanoma cells revealed stable NGFR mRNA. The combination of both reporters provided insights into phenotype switching and revealed that both cellular subsets gave rise to cellular heterogeneity. Moreover, whole transcriptome profiling and gene set enrichment analysis (GSEA) of the minor cellular subset revealed hypoxia-associated programs that might serve as potential drivers of an in vitro switching of NGFR-associated phenotypes and relapse of post-BRAF inhibitor treated tumors. Concordantly, we observed that the minor cellular subset increased in response to dabrafenib over time. In summary, our reporter-based approach provided insights into plasticity and identified a cellular subset that might be responsible for the establishment of MRD in melanoma.

Perceptions of Therapeutic Intervention in Suicide Crisis Counseling in Experienced Korean Counselors: A Concept Mapping Study

Within Organization for Economic Cooperation and Development (OECD) nations, South Korea has the highest suicide rate for which immediate prevention measures are sought including effective therapeutic counseling interventions. As such, the present study explored and examined experienced South Korean counselors' perception of therapeutic interventions for the prevention or delaying of completed suicide, using concept mapping methodology. The semi-structured interviews were provided to 15 study participants of experienced counselors having a minimum of 5 years of professional counseling career and at least 10 suicide crisis counseling sessions. A total of 77 statements were extracted with 8 major clusters: “Securing Safety,” “Active Advocacy for Client,” “Coping Skills Training,” “Conceptualization of Suicide Crisis,” “Emotional Identification and Validation,” “Empowerment,” “Counselor Self-Disclosure,” “Counselor Self-Awareness and Regulation.” From the results, the present study described unique findings in Korean counselors' perceptions of suicide crisis therapeutic intervention. Study limitations and future implications are further discussed.

Deciphering the Epigenetic Code of Stem Cells Derived From Dental Tissues

Stem cells derived from dental tissues (DSCs) exhibit multipotent regenerative potential in pioneering tissue engineering regimens. The multipotency of DSCs is critically regulated by an intricate range of factors, of which the epigenetic influence is considered vital. To gain a better understanding of how epigenetic alterations are involved in the DSC fate determination, the present review overviews the current knowledge relating to DSC epigenetic modifications, paying special attention to the landscape of epigenetic modifying agents as well as the related signaling pathways in DSC regulation. In addition, insights into the future opportunities of epigenetic targeted therapies mediated by DSCs are discussed to hold promise for the novel therapeutic interventions in future translational medicine.

Epistatic models predict mutable sites in SARS-CoV-2 proteins and epitopes

The emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major concern given their potential impact on the transmissibility and pathogenicity of the virus as well as the efficacy of therapeutic interventions. Here, we predict the mutability of all positions in SARS-CoV-2 protein domains to forecast the appearance of unseen variants. Using sequence data from other coronaviruses, preexisting to SARS-CoV-2, we build statistical models that not only capture amino acid conservation but also more complex patterns resulting from epistasis. We show that these models are notably superior to conservation profiles in estimating the already observable SARS-CoV-2 variability. In the receptor binding domain of the spike protein, we observe that the predicted mutability correlates well with experimental measures of protein stability and that both are reliable mutability predictors (receiver operating characteristic areas under the curve ∼0.8). Most interestingly, we observe an increasing agreement between our model and the observed variability as more data become available over time, proving the anticipatory capacity of our model. When combined with data concerning the immune response, our approach identifies positions where current variants of concern are highly overrepresented. These results could assist studies on viral evolution and future viral outbreaks and, in particular, guide the exploration and anticipation of potentially harmful future SARS-CoV-2 variants.