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2022 ◽  
Author(s):  
Polymnia Georgiou ◽  
Ta-Chung M Mou ◽  
Liam E Potter ◽  
Xiaoxian An ◽  
Panos Zanos ◽  
...  

In susceptible populations, stress is a major risk factor for the development of mental disorders, including depression. Estradiol, often considered a female hormone, is distributed in the male brain via aromatization of testosterone. The role of estrogen receptors (ERs) in male stress susceptibility and depression is not well understood. We found that absence of ERβ is associated with susceptibility to stress in male mice and that activity of ERβ-projecting neurons from the basolateral amygdala to nucleus accumbens is reduced in hypogonadal mice subjected to stress, while activation of this circuit reverses stress-induced maladaptive behaviors. We identified that absence of estradiol, but not testosterone per se, underlies stress susceptibility and that brain-selective delivery of estradiol prevents the development of depression-related behaviors. Our findings provide evidence for an estrogen-based mechanism underlying stress susceptibility and offer an unexpected therapeutic strategy for treating depression in males.


2022 ◽  
pp. 155982762110493
Author(s):  
Ashok Philip ◽  
Nicole D. White

Growing evidence supports a potential link between dietary gluten intake and neurodegenerative disease in susceptible populations. Observational data supporting this link are described along with interventional study data evaluating the effects of restricting gluten from the diet in patients with neurologic disorders. Suggested underlying mechanisms between gluten intake and neurodegeneration are discussed.


2022 ◽  
Author(s):  
Ola E Salama ◽  
Aleeza C Gerstein

Candida albicans is the most prevalent cause of vulvovaginal candidiasis ('yeast infection') and recurrent vulvovaginal candidiasis, though the incidence of non-albicans yeast species is increasing. The azole fluconazole is the primary antifungal drug used to treat R/VVC yet isolates from some species have intrinsic resistance to fluconazole, and recurrent infection can occur even with fluconazole-susceptible populations. The second-line broad-spectrum antimicrobial drug, boric acid, is an alternative treatment that has been found to successfully treat complicated VVC infections. Far less is known about how boric acid inhibits growth of yeast isolates in different morphologies compared to fluconazole. We found significant differences in drug resistance and drug tolerance (the ability of a subpopulation to grow slowly in high levels of drug) between C. albicans, C. glabrata, and C. parapsilosis isolates, with the specific relationships dependent on both drug and phenotype. Population-level variation for both susceptibility and tolerance was broader for fluconazole than boric acid in all species. Unlike fluconazole, which neither prevented hyphal formation nor disrupted mature biofilms, boric acid inhibited C. albicans hyphal formation and reduced mature biofilm biomass and metabolic activity in all isolates in a dose-dependent manner. Variation in planktonic response did not generally predict biofilm phenotypes. Overall, our findings illustrate that boric acid is broadly effective at inhibiting growth across many isolates and morphologies, which could explain why it is an effective treatment for R/VVC.


Author(s):  
BEYZA NUR KÜÇÜK ◽  
RAHİME ŞİMŞEK ◽  
SELİNAY BAŞAK ERDEMLİ KÖSE ◽  
ANIL YİRÜN ◽  
Pinar Erkekoglu

2021 ◽  
Author(s):  
Roz Laing ◽  
Stephen R Doyle ◽  
Jennifer McIntyre ◽  
Kirsty Maitland ◽  
Alison Morrison ◽  
...  

The antiparasitic drug ivermectin plays an essential role in human and animal health globally. However, ivermectin resistance is widespread in veterinary helminths and there are growing concerns of sub-optimal responses to treatment in related helminths of humans. Despite decades of research, the genetic mechanisms underlying ivermectin resistance are poorly understood in parasitic helminths. This reflects significant uncertainty regarding the mode of action of ivermectin in parasitic helminths, and the genetic complexity of these organisms; parasitic helminths have large, rapidly evolving genomes and differences in evolutionary history and genetic background can confound comparisons between resistant and susceptible populations. We undertook a controlled genetic cross of a multi-drug resistant and a susceptible reference isolate of Haemonchus contortus, an economically important gastrointestinal nematode of sheep, and ivermectin-selected the F2 population for comparison with an untreated F2 control. RNA-seq analyses of male and female adults of all populations identified high transcriptomic differentiation between parental isolates, which was significantly reduced in the F2, allowing differences associated specifically with ivermectin resistance to be identified. In all resistant populations, there was constitutive upregulation of a single gene, HCON_00155390:cky-1, a putative pharyngeal-expressed transcription factor, in a narrow locus on chromosome V previously shown to be under ivermectin selection. In addition, we detected sex-specific differences in gene expression between resistant and susceptible populations, including constitutive upregulation of a P-glycoprotein, HCON_00162780:pgp-11, in resistant males only. After ivermectin selection, we identified differential expression of genes with roles in neuronal function and chloride homeostasis, which is consistent with an adaptive response to ivermectin-induced hyperpolarisation of neuromuscular cells. Overall, we show the utility of a genetic cross to identify differences in gene expression that are specific to ivermectin selection and provide a framework to better understand ivermectin resistance and recovery in parasitic helminths.


Agronomy ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2160
Author(s):  
Charles M. Geddes ◽  
Michael T. Kimmins

Dose-response experiments for confirmation of herbicide-resistant weeds are almost always conducted using weed monocultures, thereby ignoring the interaction of interspecific plant interference with herbicide efficacy. Controlled-environment dose-response bioassays were conducted using three kochia [Bassia scoparia (L.) A.J. Scott] populations with four spring wheat (Triticum aestivum L.) densities (0, 200, 400, and 600 plants m−2) to determine how increasing intensity of interspecific plant interference altered the fluroxypyr dose-response relationship of resistant and susceptible kochia. The resistant population exhibited 10.8-, 15.0-, 7.0-, and 8.1-fold resistance to fluroxypyr in the absence of crop interference based on plant survival, biomass fresh weight, and visible control at two and four weeks after application, respectively. Increased wheat densities suppressed fluroxypyr-resistant kochia the greatest, resulting in a linear reduction in the fluroxypyr rate causing 50% plant mortality (LD50) and visible control (ED50) for the resistant but not the susceptible populations. This reduced the expression of fluroxypyr resistance based on kochia plant survival (from 10.8- to 4.3-fold resistance) and visible control (from 8.1- to 4.6-fold resistance) as wheat density increased from 0 to 600 plants m−2. Therefore, enhanced interspecific plant interference caused by increased wheat densities altered but did not repress the expression of fluroxypyr resistance in kochia.


2021 ◽  
Author(s):  
Yixin Liu ◽  
Su Wang ◽  
Feng Yang ◽  
Wenjing Chi ◽  
Li Ding ◽  
...  

Abstract Background Shanghai, east China has one of the world’s highest burdens of Helicobacter pylori infection. While multidrug regimens can effectively eradicate H. pylori, antibiotic-resistant (AR) H. pylori has been recognized by the WHO as ‘high priority’ for urgent need of new therapies. Moreover, the genetic characteristics of H. pylori AR in Shanghai is under-reported. The purpose of this study was to determine the resistance prevalence, re-substantiate resistance-conferring mutations, and investigate novel genetic elements might be related to H. pylori AR. Results We performed a whole-genomic and phenotypic analysis of 112 H. pylori isolated from gastric biopsy specimens from a population with different gastric diseases and residing in Shanghai. No strains were resistant to amoxicillin. Levofloxacin, metronidazole and clarithromycin resistance was observed in 39, 73 and 18 isolates, respectively. There was no association between gastroscopy diagnosis and resistance phenotypes. We reported the presence or absence of several subsystem proteins including hopE, hofF, spaB, cagY and pflA, and a combination of CRISPRs, which were potentially correlated with resistance phenotypes. The H. pylori isolates were also annotated for AR genes to define a resistome containing 80 genes. A resistome-wide association study (RWAS) was performed for the three antibiotics by correlating the phenotypes with the variation data. The RWAS correctly identified the well-known intrinsic resistance associated mutations for levofloxacin (N87T/I and/or D91G/Y mutations in gyrA), metronidazole (I38V mutation in fdxB), and clarithromycin (A2143G and/or A2142G mutations in 23S rRNA), and added 174 novel variations, with 23 nsSNPs and 48 fsIndels significantly enriched in resistant or susceptible populations. The variant-level linkage disequilibrium analysis demonstrated a series of variations with strong co-occurring correlation with known mutations, and highlighted the underlying role of a protease Lon. Conclusion Our study indicated H. pylori isolates from Shanghai exhibit multidrug antibiotic resistance, and identified specific genomic characteristics in relation to H. pylori AR in Shanghai. Continued surveillance of H. pylori AR in Shanghai is warranted in order to establish appropriate eradication treatment regimens for this population.


2021 ◽  
Vol 2021 ◽  
pp. 1-4
Author(s):  
Patrick Lee ◽  
Brandon K. K. Fields ◽  
Tom Liang ◽  
Michael P. Dubé ◽  
Seth Politano

Veillonella species are commensal bacteria of the human oral, gut, and vaginal microbiota that are rarely identified as clinically relevant pathogens. Here, we describe a novel case of Veillonella atypica bacteremia in a patient with biopsy-proven alcoholic hepatitis. Veillonella species have been correlated with disease severity and hepatic encephalopathy in liver diseases such as autoimmune hepatitis and cirrhosis. Their abundance has also been recently observed to be increased in alcoholic hepatitis, where postinflammatory infections are known to impact mortality. This case report highlights the possible clinical manifestations that result from significant gut dysbiosis in patients with severe alcoholic hepatitis. Early identification and treatment of Veillonella bacteremia in susceptible populations could be crucial to survival given this organism’s predilection for causing life-threatening infections, including meningitis, endocarditis, and osteomyelitis.


2021 ◽  
Vol 8 ◽  
Author(s):  
Gentzon Hall ◽  
Christina M. Wyatt

Proteinuria is common in the setting of HIV infection, and may reflect comorbid kidney disease, treatment-related nephrotoxicity, and HIV-related glomerular diseases. The mechanisms of podocyte and tubulointerstial injury in HIV-associated nephropathy (HIVAN) have been the subject of intense investigation over the past four decades. The pathologic contributions of viral gene expression, dysregulated innate immune signaling, and ancestry-driven genetic risk modifiers have been explored in sophisticated cellular and whole animal models of disease. These studies provide evidence that injury-induced podocyte dedifferentiation, hyperplasia, cytoskeletal dysregulation, and apoptosis may cause the loss of glomerular filtration barrier integrity and slit diaphragm performance that facilitates proteinuria and tuft collapse in HIVAN. Although the incidence of HIVAN has declined with the introduction of antiretroviral therapy, the collapsing FSGS lesion has been observed in the context of other viral infections and chronic autoimmune disorders, and with the use of interferon-based therapies in genetically susceptible populations. This highlights the fact that the lesion is not specific to HIVAN and that the role of the immune system in aggravating podocyte injury warrants further exploration. This review will summarize our progress in characterizing the molecular mechanisms of podocyte dysfunction in HIVAN and other forms of HIV-associated kidney disease.


2021 ◽  
Author(s):  
Huiqian Yu ◽  
Dantong Gu ◽  
Huawei Li ◽  
Qingzhong Li

Abstract Background: Preventing or reducing the attacks of acute otitis media (AOM) is a major worldwide healthcare problem in children. It is therefore urgent to evaluate the additional, unintended benefits of social segregation in cutting down the prevalence of AOM in children of various ages, especially during coronavirus disease 2019 (COVID-19) periods.Methods: Children aged from 6 months to 12 years who suffer from AOM and attended the outpatient clinic of tertiary hospital in the Eye Ear Nose Throat Hospital Affiliated to Fudan University in Shanghai were investigated from January 2015 to December 2020. The change in daily outpatient attendance for AOM and time-series analyses were estimated following both non-pandemic and COVID-19 period, and age and gender were taken into account. Results: 24543 outpatients (male:13529, female:11014) were enrolled in this clinic population. The epidemic trend of AOM in 2015-2019 was characterized by seasonal fluctuations, with a higher incidence in December and January but relatively lower outpatient records in winter and summer vacations (February, June and August). There was an estimated 63.6% (54.32%-70.36%) reduction in the daily outpatient attendance of AOM associated with the introduction of social segregation in COVID-19 period. When age was taken into account, children aged 4-6 who are in kindergarten were more vulnerable to AOM (66.2%), especially during the school period. Meanwhile, the outpatient attendance of AOM in preschoolers (before the age of three) was mainly in autumn and winter, with no significant relationship with semester change. And age structure of AOM in COVID-19 period broadly in line with that in non-pandemic period. Conclusions: Data from non-pandemic and COVID-19 periods indicated that AOM might spread into susceptible populations by close contact, and social segregation could effectively reduce the likelihood of catching AOM. In tandem with broader consequences, certain interpersonal distance, mask effects and good hand hygiene can significantly reduce the incidence of AOM, which provides a preventive and therapeutic point of view for AOM.


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