Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression. METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). RESULTS: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. CONCLUSIONS: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).

Effects of dietary chromium supplementation on blood biochemical parameters in dairy cows: A multilevel meta-analytical approach.

Chromium (Cr) has been reported to modulate blood biochemistry in dairy cows. However, there is a discrepancy in the literature regarding the effects of dietary Cr supplementation on various blood parameters. This meta-analysis aimed to evaluate the effects of Cr supplementation in dairy cows on blood glucose, insulin, glucagon, nonesterified fatty acid (NEFA), cortisol, and serum total protein (STP) concentrations. Following relevant literature data extraction, a 3-level meta-analytical random effect model was fitted to the data expressed as standardized mean difference (SMD) of outcome measures of control versus Cr-supplemented cows (i.e., difference in mean between control and treatment group or pooled standard deviation). The SMD can be categorized as having a small effect (0.20), a moderate effect (0.50), and a large effect (0.80). The meta-regression identified the potential sources of heterogeneity, including the body weight of cows, experimental duration/duration of Cr supplementation, blood sampling time (3 wk before parturition until 4 wk after parturition categorized as the transition period, else as the nontransition period), and form of Cr complexes. Blood glucose did not differ significantly between control and Cr-supplemented cows with an estimated SMD of µ = 0.0071 (95% confidence interval [CI]: -0.212 to 0.226). The effect of Cr supplementation on blood insulin was also nonsignificant with an SMD of µ = 0.0007 (95% CI: -0.191 to 0.193). Cows receiving Cr supplements had significantly higher levels of glucagon than controls (95% CI: 0.116 to 0.489), with an estimated SMD = 0.303. Combined transition and nontransition data suggest Cr supplementation did not affect the concentration of NEFA. However, in transition cows, Cr supplementation significantly decreased blood NEFA levels as compared with controls (95% CI: -0.522 to -0.0039), with estimated SMD = -0.263. The estimated SMD was µ = -0.1983 (95% CI: -0.734 to 0.337) for cortisol and -0.0923 (95% CI: -0.316 to 0.131) for total protein. In summary, Cr supplementation in the transition cows decreased NEFA concentration. Blood glucose, insulin, cortisol, and STP concentrations were unaffected. However, Cr supplementation increased glucagon concentration.

Using decapsulated local brine shrimp cysts on feeding common carp larvae in hatcheries.

The current study aims at using non-hatchable artemia eggs of local origin and making use of these eggs by decapsulating and presenting them as food for the larvae of the Cyprinus carpio as a source of animal protein with high nutritional value instead of throwing them away. The results showed that the second parameter (A2) was highly significant at the level (P≤0.05) in the growth rates of the larvae that were fed on decapsulated artemia eggs alone, and it was better than the two control parameters (A1), in which the larvae were fed with feed designated for Cyprinus carpio fish. It also outperformed the third parameter (A3), in which the feed was mixed with artemia eggs with 50% decapsulation, which also outperformed the control parameter with high significance at the same level (P≤0.05).

Redesigning therapies for pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is an incurable rare genetic disorder of children and young adults caused by mutations in the PANK2 gene, which encodes an enzyme critical for the biosynthesis of coenzyme A. Although PKAN affects only a small number of patients, it shares several hallmarks of more common neurodegenerative diseases of older adults such as Alzheimer's disease and Parkinson's disease. Advances in etiological understanding and treatment of PKAN could therefore have implications for our understanding of more common diseases and may shed new lights on the physiological importance of coenzyme A, a cofactor critical for the operation of various cellular metabolic processes. The large body of knowledge that accumulated over the years around PKAN pathology, including but not limited to studies of various PKAN models and therapies, has contributed not only to progress in our understanding of the disease but also, importantly, to the crystallization of key questions that guide future investigations of the disease. In this review, we will summarize this knowledge and demonstrate how it forms the backdrop to new avenues of research.

Strikingly conserved gene expression changes of polyamine regulating enzymes among various forms of acute and chronic kidney injury.

The polyamines spermidine and spermine and their common precursor molecule putrescine are involved in tissue injury and repair. Here, we test the hypothesis that impaired polyamine homeostasis contributes to various kidney pathologies in mice during experimental models of ischemia-reperfusion, transplantation, rhabdomyolysis, cyclosporine treatment, arterial hypertension, diabetes, unilateral ureteral obstruction, high oxalate feeding, and adenine-induced injuries. We found a remarkably similar pattern in most kidney pathologies with reduced expression of enzymes involved in polyamine synthesis together with increased expression of polyamine degrading enzymes. Transcript levels of amine oxidase copper-containing 1 (Aoc1), an enzyme which catalyzes the breakdown of putrescine, were barely detectable by in situ mRNA hybridization in healthy kidneys. Aoc1 was highly expressed upon various experimental kidney injuries resulting in a significant reduction of kidney putrescine content. Kidney levels of spermine were also significantly reduced, whereas spermidine was increased in response to ischemia-reperfusion injury. Increased Aoc1 expression in injured kidneys was mainly accounted for by an Aoc1 isoform that harbors 22 additional amino acids at its N-terminus and shows increased secretion. Mice with germline deletion of Aoc1 and injured kidneys showed no decrease of kidney putrescine content; although they displayed no overt phenotype, they had fewer tubular casts upon ischemia-reperfusion injury. Hyperosmotic stress stimulated AOC1 expression at the transcriptional and post-transcription levels in metanephric explants and kidney cell lines. AOC1 expression was also significantly enhanced after kidney transplantation in humans. These data demonstrate that the kidneys respond to various forms of injury with down-regulation of polyamine synthesis and activation of the polyamine breakdown pathway. Thus, an imbalance in kidney polyamines may contribute to various etiologies of kidney injury.

Late-Onset Autosomal Dominant Macular Degeneration Caused by Deletion of the CRX Gene.

PURPOSE: To characterize the phenotype observed in a case series with macular disease and determine the cause. DESIGN: Multicenter case series. PARTICIPANTS: Six families (7 patients) with sporadic or multiplex macular disease with onset at 20 to 78 years, and 1 patient with age-related macular degeneration. METHODS: Patients underwent ophthalmic examination; exome, genome, or targeted sequencing; and/or polymerase chain reaction (PCR) amplification of the breakpoint, followed by cloning and Sanger sequencing or direct Sanger sequencing. MAIN OUTCOME MEASURES: Clinical phenotypes, genomic findings, and a hypothesis explaining the mechanism underlying disease in these patients. RESULTS: All 8 cases carried the same deletion encompassing the genes TPRX1, CRX, and SULT2A1, which was absent from 382 control individuals screened by breakpoint PCR and 13 096 Clinical Genetics patients with a range of other inherited conditions screened by array comparative genomic hybridization. Microsatellite genotypes showed that these 7 families are not closely related, but genotypes immediately adjacent to the deletion breakpoints suggest they may share a distant common ancestor. CONCLUSIONS: Previous studies had found that carriers for a single defective CRX allele that was predicted to produce no functional CRX protein had a normal ocular phenotype. Here, we show that CRX whole-gene deletion in fact does cause a dominant late-onset macular disease.

Ziziphus spina-christi extract-stabilized novel silver nanoparticle synthesis for combating Fusarium oxysporum-causing pepper wilt disease: in vitro and in vivo studies.

The novelty of the present study is studying the ability of aqueous Ziziphus spina-christi leaves' extract (ZSCE) to produce eco-friendly and cost-effective silver nanoparticles (Ag NPs) against Fusarium wilt disease. Phytochemical screening of ZSCE by HPLC showed that they contain important antimicrobial substances such as Rutin, Naringin, Myricetin, Quercetin, Kaempferol, Hesperidin, Syringeic, Eugenol, Pyrogallol, Gallic and Ferulic. Characterization methods reveal a stable Ag NPs with a crystalline structure, spherical in shape with average particle size about 11.25 nm. ZSCE and Ag NPs showed antifungal potential against F. oxysporum at different concentrations with MIC of Ag NPs as 0.125 mM. Ag NPs treatment was the most effective, as it gave the least disease severity (20.8%) and the highest protection rate (75%). The application of ZSCE or Ag NPs showed a clear recovery, and its effectiveness was not limited for improving growth and metabolic characteristics only, but also inducing substances responsible for defense against pathogens and activating plant immunity (such as increasing phenols and strong expression of peroxidase and polyphenol oxidase as well as isozymes). Owing to beneficial properties such as antifungal activity, and the eco-friendly approach of cost and safety, they can be applied in agricultural field as novel therapeutic nutrients.

Real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression.

BACKGROUND: Clinical trials have demonstrated rapid antidepressant effects with intravenous (IV) ketamine for major depressive disorder, with relatively less research specifically for bipolar depression. Herein, we describe the real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression. METHODS: This study was conducted in a community clinic in Mississauga, Ontario (Canadian Rapid Treatment Centre of Excellence; Braxia Health). In this observational study (NCT04209296), patients with treatment-resistant bipolar I/II depression (n = 66) received four sub-anesthetic doses of IV ketamine (0.5-0.75 mg/kg) over a two-week period. Symptoms of depression, suicidality, anxiety, and functioning were assessed with validated self-report measures. RESULTS: Statistically and clinically significant antidepressant effects were observed in the overall sample, as measured by the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16 ) with further reductions in depressive symptoms observed after each subsequent infusion (n = 66; mean QIDS-SR16 reduction of 6.08+/-1.39; p < 0.0001). Significant reductions of suicidal thoughts (QIDS-SR16 -Suicide Item) and anxiety (Generalized Anxiety Disorder-7) were also observed with functional improvements on the Sheehan Disability Scale (p < 0.0001 on all measures). Moreover, the response rate (QIDS-SR16 total score decrease ≥50% from baseline) was 35% and remission rate (QIDS-SR16 total score ≤5) was 20% after four infusions. Infusions were generally well tolerated with treatment-emergent hypomania observed in only three patients (4.5%) with zero cases of mania or psychosis. CONCLUSIONS: Real-world effectiveness of IV ketamine for bipolar depression was observed. Repeated doses were associated with greater symptom reduction and adequate tolerability.

Frailty and postoperative outcomes in brain tumor patients: a systematic review subdivided by tumor etiology.

PURPOSE: Frailty has gained prominence in neurosurgical oncology, with more studies exploring its relationship to postoperative outcomes in brain tumor patients. As this body of literature continues to grow, concisely reviewing recent developments in the field is necessary. Here we provide a systematic review of frailty in brain tumor patients subdivided by tumor type, incorporating both modern frailty indices and traditional Karnofsky Performance Status (KPS) metrics. METHODS: Systematic literature review was performed using PRISMA guidelines. PubMed and Google Scholar were queried for articles related to frailty, KPS, and brain tumor outcomes. Only articles describing novel associations between frailty or KPS and primary intracranial tumors were included. RESULTS: After exclusion criteria, systematic review yielded 52 publications. Amongst malignant lesions, 16 studies focused on glioblastoma. Amongst benign tumors, 13 focused on meningiomas, and 6 focused on vestibular schwannomas. Seventeen studies grouped all brain tumor patients together. Seven studies incorporated both frailty indices and KPS into their analyses. Studies correlated frailty with various postoperative outcomes, including complications and mortality. CONCLUSION: Our review identified several patterns of overall postsurgical outcomes reporting for patients with brain tumors and frailty. To date, reviews of frailty in patients with brain tumors have been largely limited to certain frailty indices, analyzing all patients together regardless of lesion etiology. Although this technique is beneficial in providing a general overview of frailty's use for brain tumor patients, given each tumor pathology has its own unique etiology, this combined approach potentially neglects key nuances governing frailty's use and prognostic value.

Associations between peripheral inflammation and clinical phenotypes of bipolar depression in a lower-middle income country.

OBJECTIVE: There has been increased interest in repurposing anti-inflammatories for the treatment of bipolar depression. Evidence from high-income countries suggests that these agents may work best for specific depressive symptoms in a subset of patients with biochemical evidence of inflammation but data from lower-middle income countries (LMICs) is scarce. This secondary analysis explored the relationship between pretreatment inflammatory markers and specific depressive symptoms, clinical measures, and demographic variables in participants with bipolar depression in Pakistan. METHODS: The current study is a cross-sectional secondary analysis of a randomized controlled trial of two anti-inflammatory medications (minocycline and celecoxib) for bipolar depression (n = 266). A series of logistic and linear regression models were completed to assess the relationship between C-reactive protein (CRP) (CRP > or < 3 mg/L and log10CRP) and clinical and demographic features of interest and symptoms of depression. Baseline clinical trial data was used to extract clinical and demographic features and symptoms of depression were assessed using the 24-item Hamilton Depression Rating Scale. RESULTS: The prevalence of low-grade inflammation (CRP > 3 mg/L) in the sample was 70.9%. After adjusting for baseline body mass index, socioeconomic status, age, gender, symptoms related to anhedonia, fatigue, and motor retardation were most associated with low-grade inflammation. CONCLUSIONS: Bipolar disorder (BD) patients from LMICs may experience higher rates of peripheral inflammation than have been reported in Western populations with BD. Future trials of repurposed anti-inflammatory agents that enrich for participants with these symptom profiles may inform the development of personalized treatment for bipolar depression in LMICs.

Dermabrasion Versus Microneedling in Transplantation of Autologous Noncultured Melanocyte-Keratinocyte Cell Suspension in Patients With Vitiligo.

BACKGROUND: Autologous noncultured melanocyte-keratinocyte transplantation is one of the procedures used to treat stable vitiligo with varying reported results. Recipient site preparation is one of the variables that could affect repigmentation outcomes. OBJECTIVE: To assess the effectiveness of transplanting autologous melanocyte-keratinocyte suspension in patients with stable vitiligo and to compare recipient site preparation using dermabrasion versus microneedling. METHODS: From March 2020 to September 2022, this randomized comparative study included 40 patients with 40 stable vitiligo lesions managed by suspension transplants of melanocytes. Patients were divided into 2 groups: group A, where the recipient site was prepared using dermabrasion, and group B, which was done by microneedling. The assessment was performed 3 months after the treatment based on the degree of repigmentation (excellent, ≥90%; good, 50%-89%; fair, 20%-49%; and poor response, <20%). RESULTS: Both modalities resulted in effective repigmentation, but the dermabrasion group showed a statistically significant improvement and a satisfactory repigmentation rate. CONCLUSION: Autologous melanocyte transplantation is a safe and effective treatment method for stable vitiligo lesions that have not responded to other therapies. When compared with microneedling, dermabrasion produced better outcomes for recipient site preparation.

Effect of eCG dose on ovarian haemodynamics, hormonal profiles and prolificacy rate when oestrus was induced during low-breeding season in Beetal goats.

The objectives of the experiment were to determine the effect of two doses of equine chorionic gonadotropin (eCG) in a standard synchronization protocol based on a short-term progesterone (P4 ) priming on ovarian structures and haemodynamics, concentrations of steroid hormones and prolificacy rate when oestrus was induced during low-breeding season (LBS) in Beetal dairy goats. We hypothesized that inclusion of eCG in a short-term P4 priming-based synchronization protocol would increase the blood perfusion to ovarian structures leading to enhance oestrous and ovulatory responses and prolificacy rate in goats. Forty-two multiparous acyclic goats were blocked by body condition and, within block, assigned randomly to receive saline as control (CON), low eCG (L-eCG; 300 IU) or high eCG (H-eCG; 600 IU) dose. Initially, a controlled internal drug release (CIDR) device was placed in the anterior vagina on d -8, followed by removal of CIDR on d -3, concurrent with the administration of PGF2α and eCG according to their respective treatments. Goats were monitored for oestrous response. B-mode and Doppler ultrasonography was performed with 12-h interval, starting from day -3 until natural breeding (day 0), and then on days 5, 10, 15 and 20 post-breeding to monitor follicular and luteal dynamics and blood flow, respectively. Blood was sampled at 0, 12, 24, 36 and 60 h after CIDR removal to quantify plasma concentrations of estradiol-17ß (E2 ), whereas plasma concentrations of P4 were assayed at days 5, 10, 15 and 20 after breeding. Pregnancy and prolificacy rates were determined at day 30 and 150 after breeding, respectively. Data were analysed with mixed-effects models, and orthogonal contrasts were used to evaluate the effect of treatment [Con vs. (½ L-eCG + ½ H-eCG)] and dose of eCG (L-eCG vs. H-eCG). Data are presented in sequence as CON, L-eCG, H-eCG (LSM ± SEM). The oestrous intensity score (152.9 vs. 182.7 vs. 186.5 ± 15.1; p = .02) was greater in eCG-treated goats as compared to CON. Administration of eCG reduced the intervals to standing oestrus (66.2 vs. 41.8 vs. 48.9 h ± 5.5; p = .05), breeding (70.2 vs. 44.4 vs. 45.4 h ± 4.5; p = .03) and ovulation (84.5 vs. 61.2 vs. 63.4 h ± 6.2; p = .05) compared with CON goats. The mean growth rate of pre-ovulatory follicle was greater (1.11 vs. 1.49 vs. 1.45 mm ± 0.08; p = .01) in eCG-treated goats resulting in an increased diameter of pre-ovulatory follicle (6.27 vs. 7.20 vs. 7.31 mm ± 0.07; p < .01) and corpora lutea (6.75 vs. 8.26 vs. 8.07 mm ± 0.42; p = .04) than CON. The mean follicular blood flow did not differ among treatments; however, the mean luteal blood flow was greater in L-eCG-treated goats (0.81 vs. 1.61 vs. 1.07 cm2 ± 0.12; p = .001). The mean concentrations of E2 (4.03 vs. 5.21 vs. 4.78 pg/ml ± 0.42; p = .04) and P4 (4.85 vs. 6.39 vs. 6.22 ng/ml ± 0.34; p = .04) were greater in eCG-treated goats. The twinning rate did not differ between treatments; nevertheless, prolificacy rate was greater (p = .04) in L-eCG-treated goats. Collectively, our data suggest that the administration of eCG improves the induction of oestrous and ovarian dynamics. Administration of L-eCG enhances prolificacy rate, therefore, a low dose of eCG might be practically beneficial to improve reproduction during LBS in acyclic Beetal dairy goats.

In Silico Targeting of Fascin Protein for Cancer Therapy: Benchmarking, Virtual Screening and Molecular Dynamics Approaches.

Fascin is an actin-bundling protein overexpressed in various invasive metastatic carcinomas through promoting cell migration and invasion. Therefore, blocking Fascin binding sites is considered a vital target for antimetastatic drugs. This inspired us to find new Fascin binding site blockers. First, we built an active compound set by collecting reported small molecules binding to Fascin's binding site 2. Consequently, a high-quality decoys set was generated employing DEKOIS 2.0 protocol to be applied in conducting the benchmarking analysis against the selected Fascin structures. Four docking programs, MOE, AutoDock Vina, VinaXB, and PLANTS were evaluated in the benchmarking study. All tools indicated better-than-random performance reflected by their pROC-AUC values against the Fascin crystal structure (PDB: ID 6I18). Interestingly, PLANTS exhibited the best screening performance and recognized potent actives at early enrichment. Accordingly, PLANTS was utilized in the prospective virtual screening effort for repurposing FDA-approved drugs (DrugBank database) and natural products (NANPDB). Further assessment via molecular dynamics simulations for 100 ns endorsed Remdesivir (DrugBank) and NANPDB3 (NANPDB) as potential binders to Fascin binding site 2. In conclusion, this study delivers a model for implementing a customized DEKOIS 2.0 benchmark set to enhance the VS success rate against new potential targets for cancer therapies.

Thermo- and Photocatalytic Activation of CO2 in Ionic Liquids Nanodomains.

Ionic liquids (ILs) are considered to be potential material devices for CO2 capturing and conversion to energy-adducts. They form a cage (confined-space) around the catalyst providing an ionic nano-container environment which serves as physical-chemical barrier that selectively controls the diffusion of reactants, intermediates, and products to the catalytic active sites via their hydrophobicity and contact ion pairs. Hence, the electronic properties of the catalysts in ILs can be tuned by the proper choice of the IL-cations and anions that strongly influence the residence time/diffusion of the reactants, intermediates, and products in the nano-environment. On the other hand, ILs provide driving force towards photocatalytic redox process to increase the CO2 photoreduction. By combining ILs with the semiconductor, unique solid semiconductor-liquid commodities are generated that can lower the CO2 activation energy barrier by modulating the electronic properties of the semiconductor surface. This mini-review provides a brief overview of the recent advances in IL assisted thermal conversion of CO2 to hydrocarbons, formic acid, methanol, dimethyl carbonate, and cyclic carbonates as well as its photo-conversion to solar fuels.

Geographical contrasts of Y-chromosomal haplogroups from wild and domestic goats reveal ancient migrations and recent introgressions.

By their paternal transmission, Y-chromosomal haplotypes are sensitive markers of population history and male-mediated introgression. Previous studies identified biallelic single-nucleotide variants in the SRY, ZFY and DDX3Y genes, which in domestic goats identified four major Y-chromosomal haplotypes, Y1A, Y1B, Y2A and Y2B, with a marked geographical partitioning. Here, we extracted goat Y-chromosomal variants from whole-genome sequences of 386 domestic goats (75 breeds) and seven wild goat species, which were generated by the VarGoats goat genome project. Phylogenetic analyses indicated domestic haplogroups corresponding to Y1B, Y2A and Y2B, respectively, whereas Y1A is split into Y1AA and Y1AB. All five haplogroups were detected in 26 ancient DNA samples from southeast Europe or Asia. Haplotypes from present-day bezoars are not shared with domestic goats and are attached to deep nodes of the trees and networks. Haplogroup distributions for 186 domestic breeds indicate ancient paternal population bottlenecks and expansions during migrations into northern Europe, eastern and southern Asia, and Africa south of the Sahara. In addition, sharing of haplogroups indicates male-mediated introgressions, most notably an early gene flow from Asian goats into Madagascar and the crossbreeding that in the 19th century resulted in the popular Boer and Anglo-Nubian breeds. More recent introgressions are those from European goats into the native Korean goat population and from Boer goat into Uganda, Kenya, Tanzania, Malawi and Zimbabwe. This study illustrates the power of the Y-chromosomal variants for reconstructing the history of domestic species with a wide geographical range.

A recurrent rare intronic variant in CAPN3 alters mRNA splicing and causes autosomal recessive limb-girdle muscular dystrophy-1 in three Pakistani pedigrees.

Autosomal recessive limb-girdle muscular dystrophy-1 (LGMDR1) is an autosomal recessive disorder characterized by progressive weakness of the proximal limb and girdle muscles. Biallelic mutations in CAPN3 are reported frequently to cause LGMDR1. Here, we describe 11 individuals from three unrelated consanguineous families that present with typical features of LGMDR1 that include proximal muscle wasting, weakness of the upper and lower limbs, and elevated serum creatine kinase. Whole-exome sequencing identified a rare homozygous CAPN3 variant near the exon 2 splice donor site that segregates with disease in all three families. mRNA splicing studies showed partial retention of intronic sequence and subsequent introduction of a premature stop codon (NM_000070.3: c.379 + 3A>G; p.Asp128Glyfs*15). Furthermore, we observe reduced CAPN3 expression in primary dermal fibroblasts derived from an affected individual, suggesting instability and/or nonsense-mediated decay of mutation-bearing mRNA. Genome-wide homozygosity mapping and single-nucleotide polymorphism analysis identified a shared haplotype and supports a possible founder effect for the CAPN3 variant. Together, our data extend the mutational spectrum of LGMDR1 and have implications for improved diagnostics for individuals of Pakistani origin.

The genetic architecture underlying body-size traits plasticity over different temperatures and developmental stages in Caenorhabditis elegans.

Most ectotherms obey the temperature-size rule, meaning they grow larger in a colder environment. This raises the question of how the interplay between genes and temperature affects the body size of ectotherms. Despite the growing body of literature on the physiological life-history and molecular genetic mechanism underlying the temperature-size rule, the overall genetic architecture orchestrating this complex phenotype is not yet fully understood. One approach to identify genetic regulators of complex phenotypes is quantitative trait locus (QTL) mapping. Here, we explore the genetic architecture of body-size phenotypes, and plasticity of body-size phenotypes at different temperatures using Caenorhabditis elegans as a model ectotherm. We used 40 recombinant inbred lines (RILs) derived from N2 and CB4856, which were reared at four different temperatures (16, 20, 24, and 26 °C) and measured at two developmental stages (L4 and adult). The animals were measured for body length, width at vulva, body volume, length/width ratio, and seven other body-size traits. The genetically diverse RILs varied in their body-size phenotypes with heritabilities ranging from 0.0 to 0.99. We detected 18 QTL underlying the body-size traits across all treatment combinations, with the majority clustering on Chromosome X. We hypothesize that the Chromosome X QTL could result from a known pleiotropic regulator-npr-1-known to affect the body size of C. elegans through behavioral changes. We also found five plasticity QTL of body-size traits where three colocalized with body-size QTL. In conclusion, our findings shed more light on multiple loci affecting body-size plasticity and the possibility of co-regulation of traits and traits plasticity by the same loci under different environments.

Identification of Endocannabinoid Predictors of Treatment Outcomes in Major Depressive Disorder: A Secondary Analysis of the First Canadian Biomarker Integration Network in Depression (CAN-BIND 1) Study.

INTRODUCTION: An increasing number of studies are examining the link between the endocannabinoidome and major depressive disorder (MDD). We conducted an exploratory analysis of this system to identify potential markers of treatment outcomes. METHODS: The dataset of the Canadian Biomarker Integration Network in Depression-1 study, consisting of 180 patients with MDD treated for eight weeks with escitalopram followed by eight weeks with escitalopram alone or augmented with aripiprazole was analyzed. Association between response Montgomery-Asberg Depression Rating Scale (MADRS; score reduction≥50%) or remission (MADRS score≤10) at weeks 8 and 16 and single nucleotide polymorphisms (SNPs), methylation, and mRNA levels of 33 endocannabinoid markers were examined. A standard genome-wide association studies protocol was used for identifying SNPs, and logistic regression was used to assess methylation and mRNA levels. RESULTS: Lower methylation of CpG islands of the diacylglycerol lipase alpha gene (DAGLA) was associated with non-remission at week 16 (DAGLA; OR=0.337, p<0.003, q=0.050). Methylation of DAGLA was correlated with improvement in Clinical Global Impression (p=0.026), Quick Inventory of Depressive Symptomatology (p=0.010), and Snaith-Hamilton Pleasure scales (p=0.028). We did not find any association between SNPs or mRNA levels and treatment outcomes. DISCUSSION: Methylation of DAGLA is a promising candidate as a marker of treatment outcomes for MDD and needs to be explored further.

Heat treatment of colostrum at 60°C decreases colostrum immunoglobulins but increases serum immunoglobulins and serum total protein: A meta-analysis.

Calves are born hypogammaglobulinemic; thus, the newborn calf's immune defense relies on the ingestion and absorption of colostrum, which provides energy, immunoglobulins, immune cells, and cytokines to the newborn calf. A heat treatment applied to colostrum for 60 min at 60°C has been found to be effective at reducing the total bacterial count while preserving the colostrum IgG levels. The objective of this work was to perform a meta-analysis on the association between the characteristics of heat-treated colostrum and the concentration of colostrum IgG, serum IgG concentration, and serum total protein (STP). A meta-analysis was carried out based on existing peer-reviewed literature. Publications comparing colostrum IgG, serum IgG, and STP for heat-treated or raw frozen colostrum were included. The different heating temperatures applied to the colostrum were divided into 2 subgroups: high temperature (HT; >60°C) and low temperature (LT; ≤60°C). Twelve studies, including 21 trials, met the inclusion criteria for colostrum IgG concentration. The results indicated decreases in colostrum IgG by 20.6 g/L [95% confidence interval (CI) = 11.8-29.4] for HT and 5.38 g/L (95% CI = 2.9-7.8) for LT when colostrum was heat-treated compared with raw or frozen colostrum. Heterogeneity was high to moderate (I2 = 82% for HT and 65% for LT). The heat treatment of colostrum was also associated with a nonsignificant decrease in serum IgG by 3.40 g/L for HT (95% CI = 7.54-0.74) but a significant increase in serum IgG by 2.65 g/L for LT (95% CI = 1.51-3.79). The regression model indicated that heterogeneity was not explained by any moderators. The heat treatment of colostrum was also associated with a significant increase in STP by 0.21 g/dL for LT (95% CI = 0.07-0.35). In conclusion, the present work demonstrated that the heat treatment of colostrum ≤60°C decreased colostrum IgG by 5.38 g/L for LT and increased serum IgG by 2.65 g/L and STP by 0.21 g/dL. When compared with the range of values observed in the field for serum IgG, the present results are of high interest for the cattle industry. Because immune colostrum benefits also include cytokines and immune cells, further work is required to evaluate the effect of colostrum heat treatment on these 2 immune components of colostrum.

Diversity and distribution of thermophilic microorganisms and their applications in biotechnology.

Hot springs ecosystem is the most ancient continuously inhabited ecosystem on earth which harbors diverse thermophilic bacteria and archaea distributed worldwide. Life in extreme environments is very challenging so there is a great potential biological dark matter and their adaptation to harsh environments eventually producing thermostable enzymes which are very vital for the welfare of mankind. There is an enormous need for a new generation of stable enzymes that can endure harsh conditions in industrial processes and can either substitute or complement conventional chemical processes. Here, we review at the variety and distribution of thermophilic microbes, as well as the different thermostable enzymes that help them survive at high temperatures, such as proteases, amylases, lipases, cellulases, pullulanase, xylanases, and DNA polymerases, as well as their special properties, such as high-temperature stability. We have documented the novel isolated thermophilic and hyperthermophilic microorganisms, as well as the discovery of their enzymes, demonstrating their immense potential in the scientific community and in industry.