Trust your gut, lest thou be anxious.

Can gut-residing bacteria influence mood and anxiety? And can targeting bacteria-produced metabolites reduce anxiety? Based on two Nature and Nature Medicine papers, the answers to these questions are likely yes. Needham, Campbell, and colleagues identified bacteria that enhance anxiety-like behaviors in mice and ways to mitigate anxiety in autistic patients.

Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut.

Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.

Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond.

Fungal infections are a major contributor to infectious disease-related deaths across the globe. Candida species are among the most common causes of invasive mycotic disease, with Candida albicans reigning as the leading cause of invasive candidiasis. Given that fungi are eukaryotes like their human host, the number of unique molecular targets that can be exploited for antifungal development remains limited. Currently, there are only three major classes of drugs approved for the treatment of invasive mycoses, and the efficacy of these agents is compromised by the development of drug resistance in pathogen populations. Notably, the emergence of additional drug-resistant species, such as Candida auris and Candida glabrata, further threatens the limited armamentarium of antifungals available to treat these serious infections. Here, we describe our current arsenal of antifungals and elaborate on the resistance mechanisms Candida species possess that render them recalcitrant to therapeutic intervention. Finally, we highlight some of the most promising therapeutic strategies that may help combat antifungal resistance, including combination therapy, targeting fungal-virulence traits, and modulating host immunity. Overall, a thorough understanding of the mechanistic principles governing antifungal drug resistance is fundamental for the development of novel therapeutics to combat current and emerging fungal threats.

Correlations between clinical parameters of dry eye disease and serologic profiles in Sjögren's syndrome.

PURPOSE: To investigate the difference in clinical parameters of dry eye disease (DED) according to the presence of serum anti-La antibodies and evaluate the correlations of autoantibody titers with DED parameters in patients with primary Sjögren's syndrome (pSS). METHODS: Sixty-two patients diagnosed with pSS according to the 2016 ACR-EULAR classification criteria were classified into two groups depending on the presence of anti-La antibodies: group 1 (anti-Ro positive alone, n = 31) and group 2 (both anti-Ro and anti-La positive, n = 31). DED parameters (conjunctival and corneal ocular staining score (OSS), tear film break-up time (TBUT), Schirmer I test, lipid layer thickness (LLT), meiboscore, and ocular surface disease index), serum autoantibodies (anti-Ro, anti-La, rheumatoid factor (RF), and antinuclear antibody) and focus score were assessed. RESULTS: The DED parameters were not significantly different between the two groups (P > 0.05). The anti-Ro titers, RF-positive rate, and the focus score were significantly higher in group 2 than in group 1 (P = 0.001, P = 0.049, P = 0.001, respectively). The anti-Ro titers had a significant positive correlation with conjunctival OSS (r = 0.273, P = 0.033) and the focus score had a positive correlation with LLT and meiboscore (r = - 0.358, P = 0.072; r = 0.379, P = 0.056). CONCLUSION: In this study, anti-Ro titers significantly correlated with conjunctival staining score, whereas anti-La did not statistically correlated with clinical DED parameters in SS. Meanwhile, anti-Ro titers and focus score were significantly higher in patients positive for both anti-Ro and anti-La, which suggests that examining anti-La with anti-Ro would be helpful in predicting clinical severities of SS patients.

Matrix metalloproteinase 9 is associated with conjunctival microbiota culture positivity in Korean patients with chronic Stevens-Johnson syndrome.

BACKGROUND: Stevens-Johnson syndrome (SJS) is an abnormal immune-response causing extensive exfoliation of the mucocutaneous tissue including conjunctiva. While several factors are associated with the alteration of conjunctival microbiota, the conjunctiva of SJS patients are found to harbor a different microbiota compared to healthy subjects. We investigated the conjunctival microbiota of Korean SJS patients, and identified factors associated with the conjunctival microbiota and its positive culture. METHODS: Medical records were retrospectively reviewed in 30 chronic SJS patients who had undergone conjunctival swab culture sampling. Demographic factors, chronic ocular surface complications score (COCS), tear break-up time (TBUT), tear secretion, tear matrix metalloproteinase 9 (MMP9), and results of conjunctival swab culture were assessed. RESULTS: Positive culture was seen in 58.1%. Gram positive bacteria was most commonly isolated, among which Coagulase-negative Staphylococci (45.5%) and Corynebacterium species (40.9%) were predominantly observed. Tear MMP9 positivity was observed significantly more in the positive culture group (100%) compared to the negative culture group (70%) (P = 0.041). Topical cyclosporine and corticosteroid were not associated with repetitive positive cultures. No significant differences in COCS, TBUT, and tear secretion were found between culture-positive and culture-negative groups. CONCLUSION: Our study suggests that tear MMP9 positivity may be related with the presence of an abnormal ocular surface microbiota in chronic SJS patients.

Characteristics of dry eye patients with thick tear film lipid layers evaluated by a LipiView II interferometer.

PURPOSE: To investigate the characteristics of eyes with dry eye disease (DED) whose lipid layer thickness (LLT) measured 100 nm on a LipiView II interferometer and compare the DED parameters of them to those with LLT below 100 nm. METHODS: A total of 201 eyes of 102 enrolled DED patients (mean age 56.4 ± 11.8 years) were classified into 3 groups according to their average LLT; < 60 nm as thin-LLT (n = 49), 60-99 nm as normal-LLT (n = 77), and 100 nm as thick-LLT (n = 75). LLT, meiboscore, Schirmer I test, tear film break-up time (TBUT), ocular surface staining (OSS), and ocular surface disease index (OSDI) were assessed. RESULTS: The OSS and TBUT were significantly worse in the thick-LLT group than in the normal-LLT group (p = 0.020, and p = 0.028, respectively). The OSDI was significantly higher in the thick-LLT group than in the thin-LLT group (p = 0.006). However, the meiboscore was not different among the three groups (p = 0.33). Age, OSS, and OSDI showed a positive correlation with LLT (r = 0.16, p = 0.023; r = 0.213, p = 0.003; and r = 0.338, p = 0.001, respectively). In sensitivity analyses, eyes with corneal erosions had a significantly higher average LLT (p = 0.015), higher OSDI (p = 0.009), shorter TBUT (p < 0.001), and shorter Schirmer I value (p = 0.024) than those with clear corneas. CONCLUSION: The average LLT of eyes with corneal erosions was thicker than those without erosions, suggesting that the LLT of 100 nm in the eyes with corneal erosions should not be regarded as a stable physiologic condition. Cautious interpretation of LLT along with other dry eye parameters is required.

Longitudinal changes in insulin resistance in children with epilepsy on ketogenic diet: Prevalence and risk factors.

INTRODUCTION: The aim of the study was to evaluate the incidence of insulin resistance (IR) and the associated risk factors in children with epilepsy on a ketogenic diet (KD). METHODS: This longitudinal cohort study analyzed data of children with epilepsy on KD. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). The HOMA-IR value, fasting serum insulin levels, fasting glucose (FG) levels, and lipid profiles were measured before the initiation of the KD and at 6- to 12-month intervals. RESULTS: A total of 28 children were enrolled. The median age at the initiation of KD was 2.7 ±â€¯2.4 years, and the median follow-up duration was 2.1 ±â€¯1.4 years. The median HOMA-IR (HOMA-IR-1) value before the initiation of KD was 1.2 ±â€¯0.2, which significantly increased to 1.8 ±â€¯0.3 at the last follow-up (HOMA-IR-2; ∆HOMA-IR = 0.6 ±â€¯0.3, p < 0.001). The following factors were associated with patients with higher HOMA-IR-2 values (≥1.9): younger age at seizure onset (0.3 ±â€¯0.2 years, p < 0.001), at the initiation of antiepileptic drugs (AEDs; 0.3 ±â€¯0.3 years, p < 0.001), and at the initiation of KD (1.3 ±â€¯0.5 years, p < 0.001) and higher serum alanine transaminase (ALT; 84.0 ±â€¯17.8 U/L, p = 0.022), total cholesterol (TC; 245.0 ±â€¯20.1 mg/dL, p = 0.001), low-density lipoprotein cholesterol (LDL-C, 103.0 ±â€¯6.7 mg/dL, p = 0.003), and triglyceride (387.0 ±â€¯28.8 mg/dL, p < 0.001) levels. Multivariate regression analysis revealed that the age at seizure onset (p = 0.002), at initiation of AEDs (p = 0.021), and at initiation of KD (p = 0.022) and serum levels of LDL-C (p = 0.012) and triglycerides (p = 0.026) were associated with a significantly high HOMA-IR-2 value. CONCLUSION: Close monitoring of serum lipids levels, especially at younger age, may aid in detecting exacerbation of IR.

Cerebrospinal fluid non-pleocytosis in pediatric enteroviral meningitis: Large-scale review.

BACKGROUND: Lack of cerebrospinal fluid (CSF) pleocytosis has been reported in some children with enteroviral meningitis (EVM). The aim of this paper was to investigate the clinical spectrum and related factors in EVM with CSF non-pleocytosis. METHODS: The databases of children diagnosed with EVM on CSF polymerase chain reaction between 2011 and 2014 were retrospectively reviewed. CSF pleocytosis was defined at each age using the criteria. Clinical and laboratory variables were compared between patients with CSF pleocytosis and non-pleocytosis. RESULTS: Of the 802 children of EVM, 25.4% (204/802) had CSF non-pleocytosis. In particular, CSF non-pleocytosis was found in 63.3% of the neonates versus in 22.2% of the children aged ≥1 year old, indicating that the ratio of CSF non-pleocytosis had a negative correlation with age (P < 0.001). As the main symptoms, fever (91.8% vs 86.8%, P = 0.038), headache (80.3% vs 63.7%, P < 0.001), and vomiting (75.9% vs 61.8%, P < 0.001) were significantly more frequent in CSF pleocytosis than in CSF non-pleocytosis. Patients with CSF non-pleocytosis had much lower peripheral leukocytosis (10 656 ± 3,662 vs 12 403 ± 4,207/mm3 , P = 0.014) and C-reactive protein (0.7±0.8 vs 1.2±1.5 mg/dL, P < 0.001), and earlier lumbar puncture <24 h after onset (42.6% vs 21.4%, p<0.001). No significant difference during the summer and autumn months was seen between the two groups (76.9% vs 81.9%, P = 0.169). CONCLUSION: CSF non-pleocytosis in childhood EVM was frequently observed, especially in young infants, regardless of season. We propose that CSF PCR testing for enterovirus can be helpful to recognize EVM in children with CSF non-pleocytosis.

High diagnostic yield of clinically unidentifiable syndromic growth disorders by targeted exome sequencing.

BACKGROUND: As syndromic short stature and overgrowth are heterogeneous and the list of causative genes is rapidly expanding, there is an unmet need for identifying genetic causes based on conventional gene testing or karyotyping. Early diagnosis leads to the proper management of the patient and providing genetic counseling for family members at risk in a timely manner. MATERIALS AND METHODS: We conducted targeted exome sequencing to identify the genetic causes of undiagnosed syndromic short stature or overgrowth in 15 pediatric patients from 13 families in Korea. We applied targeted exome sequencing using the Next Seq platform and a TruSight One panel. RESULTS: Among the 13 families, 6 different disorders in 8 patients with short stature or overgrowth were identified, and the diagnostic yield was 46.2%. One boy with overgrowth had a TGFB3 gene mutation. In the short stature group, Coffin-Lowry syndrome (CLS), trichorhinophalangeal syndrome, DYRK1A haploinsufficiency syndrome, short stature with optic atrophy and Pelger-Huët anomaly syndrome with recurrent hepatitis, and type 4 Meier-Gorlin syndrome were identified. One CLS patient had a co-existing monogenic disease, congenital glaucoma, caused by the compound heterozygote mutations of the CYP1B1 gene. CONCLUSION: Targeted exome sequencing is a powerful method for diagnosing syndromic growth disorders. It enables us to understand molecular pathophysiology and investigate new treatments for growth disorders.

Discovery of novel purine-based heterocyclic P2X7 receptor antagonists.

The pyridine core skeleton of the previously reported dichloropyridine-based potent hP2X7 receptor antagonist 5 (IC50 = 13 nM in hP2X7-expressing HEK293 cells) was modified with various heterocyclic scaffolds. Among the derivatives with quinoline, quinazoline, acridine, and purine scaffolds, the chloropurine-based analog 9o exhibited the most potent antagonistic activity, with an IC50 value of 176 ± 37 nM in an ethidium bromide uptake assay. In addition, 9o significantly inhibited IL-1ß release in THP-1 cells stimulated with LPS/IFN-γ/BzATP (IC50 = 120 ± 15 nM). Although 9o was less active than the previous antagonist 5, 9o exhibited greatly improved metabolic stability in the in vitro evaluation (71.4% in human, 72.3% in mouse).

Secondary neurulation of human embryos: morphological changes and the expression of neuronal antigens.

PURPOSE: The morphological changes and expression patterns of neuronal antigens of human embryos, obtained from the therapeutic termination of pregnancy or from surgical procedures, were analyzed in order to characterize the secondary neurulation. METHODS: A total of 21 human embryos from Carnegie stages 12 to 23 and two fetuses in early stages were studied. The markers used for immunohistochemical study were neural cell adhesion molecule (N-CAM), neuronal nuclear antigen (NeuN), neurofilament-associated protein (3A10), synaptophysin, and glial fibrillary acidic protein (GFAP). RESULTS: The formation of the caudal neural tube to the tip of the caudal portion of the embryo was finished at stage 17. The postcloacal gut had completely disappeared at stage 18, and multiple cavities of the caudal neural tube were clearly visible. The caudal portion of the neural tube showed findings suggestive of involution at stage 19. The expression patterns of neuronal antigens were as follows: N-CAM and NeuN showed immunoreactivity at the germinal layer of the spinal cord at stages 17 and 18. Neurofilament-associated protein (3A10) showed persistent immunoreactivity at the caudal cell mass and notochord during the observation period, along with the spinal cord, and the positive reactions were mainly located at the dorsal white matter at stage 17. Synaptophysin showed a weak positive reaction at the caudal cell mass and notochord at stages 13 and 14, evident by staining observed at the spinal cord at stages 15 and 16. There was no definite positive reaction for GFAP. CONCLUSIONS: These characteristic patterns might be helpful for the understanding of human congenital anomalies involving secondary neurulation processes.

Artificial Tear Instillation-Induced Changes in Corneal Topography.

This study aims to compare changes of corneal topography (Galilei G4) before and after the instillation of artificial tears in patients with dry eye disease (DED). Corneal topography was performed in patients 1 min before and after artificial tear instillation. Two types of artificial tears were used: 1% polysorbate 80 (PSB) and 0.5% carboxymethylcellulose (CMC). Of 135 patients, PSB and CMC were instilled in 101 and 34 eyes, respectively. The average value of Sim K increased significantly after instillation (44.07 ± 2.26 diopter (D)) compared to before (43.90 ± 2.02 D, p = 0.006) the instillation of artificial tears. Mean Sim K astigmatism was statistically increased after PSB instillation (1.48 ± 2.17 D) compared to before instillation (1.31 ± 2.10 D, p = 0.049). An axis change of astigmatism 10° or more after artificial tear instillation was found in 51.9% of patients, and 30° or more in 20.0% of patients. Increased Sim K value and significant changes in the astigmatic axis in the corneal topography were observed after instillation of artificial tears in DED patients. PSB instillation had a greater effect on corneal keratometry values than CMC instillation.

Clinical use of whole exome sequencing in children with developmental delay/intellectual disability.

BACKGROUND: Identifying the underlying etiology of developmental delay/intellectual disability (DD/ID) is challenging but important. The genetic diagnosis of unexplained DD/ID helps in the treatment and prognosis of the disability in patients. In this study, we reported our experience of using whole exome sequencing (WES) of children with unexplained DD/ID. METHODS: We conducted a retrospective analysis of WES results of children under 19 years of age with unexplained DD/ID between January 2020 and December 2021. The demographic data of all patients and variants identified through WES were evaluated. Furthermore, we evaluated the clinical characteristics that influenced the identification of genetic causes. RESULTS: Forty-one patients with DD/ID were included, of whom 21 (51.2 %) were male. The average age at symptom onset was 1.6 ± 1.3 years, and the duration from symptom onset to diagnosis was 3.1 ± 3.7 years. Hypotonia was the most common symptom (17 patients, 41.5 %), and epilepsy was confirmed in 10 patients (24.4 %). Twenty-two pathogenic/likely pathogenic variants were identified in 20 patients, and three variants of uncertain significance were identified in three patients. Family-based trio Sanger sequencing for candidate variants of 12 families was conducted; 10 variants were de novo, one variant paternally inherited, and two variants compound heterozygous. The diagnostic yield of WES for DD/ID was 48.8 % and was significantly high in patients with an early onset of DD/ID and facial dysmorphism. In contrast, patients with autism spectrum disorder (ASD) were more likely to have negative WES results compared with others without ASD. CONCLUSION: The diagnostic yield of WES was 48.8 %. We conclude that patients' characteristics, such as dysmorphic features and the age of symptom onset, can predict the likelihood that WES will identify a causal variant of a phenotype.

Molecular mechanisms governing antifungal drug resistance.

Fungal pathogens are a severe public health problem. The leading causative agents of systemic fungal infections include species from the Candida, Cryptococcus, and Aspergillus genera. As opportunistic pathogens, these fungi are generally harmless in healthy hosts; however, they can cause significant morbidity and mortality in immunocompromised patients. Despite the profound impact of pathogenic fungi on global human health, the current antifungal armamentarium is limited to only three major classes of drugs, all of which face complications, including host toxicity, unfavourable pharmacokinetics, or limited spectrum of activity. Further exacerbating this issue is the growing prevalence of antifungal-resistant infections and the emergence of multidrug-resistant pathogens. In this review, we discuss the diverse strategies employed by leading fungal pathogens to evolve antifungal resistance, including drug target alterations, enhanced drug efflux, and induction of cellular stress response pathways. Such mechanisms of resistance occur through diverse genetic alterations, including point mutations, aneuploidy formation, and epigenetic changes given the significant plasticity observed in many fungal genomes. Additionally, we highlight recent literature surrounding the mechanisms governing resistance in emerging multidrug-resistant pathogens including Candida auris and Candida glabrata. Advancing our knowledge of the molecular mechanisms by which fungi adapt to the challenge of antifungal exposure is imperative for designing therapeutic strategies to tackle the emerging threat of antifungal resistance.

Functional genomic analysis of Candida albicans protein kinases reveals modulators of morphogenesis in diverse environments.

Candida albicans is a leading cause of mycotic infection. The ability to transition between yeast and filamentous forms is critical to C. albicans virulence and complex signaling pathways regulate this process. Here, we screened a C. albicans protein kinase mutant library in six environmental conditions to identify regulators of morphogenesis. We identified the uncharacterized gene orf19.3751 as a negative regulator of filamentation and follow-up investigations implicated a role for orf19.3751 in cell cycle regulation. We also uncovered a dual role for the kinases Ire1 and protein kinase A (Tpk1 and Tpk2) in C. albicans morphogenesis, specifically as negative regulators of wrinkly colony formation on solid medium but positive regulators of filamentation in liquid medium. Further analyses suggested Ire1 modulates morphogenesis in both media states in part through the transcription factor Hac1 and in part through independent mechanisms. Overall, this work provides insights into the signaling governing morphogenesis in C. albicans.

A Comprehensive Analysis of the Influence of Temperature and Humidity on Dry Eye Disease.

PURPOSE: To investigate the effects of humidity and temperature on dry eye disease (DED). METHODS: A retrospective, clinic-based study was conducted on DED patients undergoing dry eye treatment. Patients were followed up at least twice, and symptoms and signs were evaluated using the Symptoms Assessment Questionnaire in Dry Eye (SANDE) score, tear secretion, tear film breakup time (TBUT), ocular staining score, and tear osmolarity. Mean humidity and temperature values for 1 week before ocular examinations were used as the environmental exposure level. The relationship between humidity and temperature, with DED clinical parameters was analyzed in single- and multi-environmental factor models. RESULTS: The study included 33 patients with a mean age of 53.9 ± 12.2 years. The low humidity group showed significantly higher SANDE scores (p = 0.023) and tear osmolarity (p = 0.008), and the low temperature group had higher SANDE scores (p = 0.004), ocular staining scores (p = 0.036), and tear osmolarity (p < 0.001). In the linear mixed model, single factor analysis showed that an increase in humidity resulted in decreased SANDE scores (p = 0.043), and an increase in temperature led to a decrease in SANDE score (p = 0.007), ocular staining score (p = 0.007), and tear osmolarity (p = 0.012). In the multifactor analysis, changes in humidity had no significant effect on dry eye parameters, but an increase in temperature was significantly correlated with decreased SANDE score (p = 0.026), ocular staining score (p = 0.024), and tear osmolarity (p = 0.002). CONCLUSIONS: Lower temperature led to aggravated symptoms and signs of DED and the effect of temperature on DED was more pronounced than humidity. Tear osmolarity was the most sensitive clinical parameter to be affected by climate factors in DED patients.

Potent Antifungal Activity of Penta-O-galloyl-ß-d-Glucose against Drug-Resistant Candida albicans, Candida auris, and Other Non-albicans Candida Species.

Among fungal pathogens, infections by drug-resistant Candida species continue to pose a major challenge to healthcare. This study aimed to evaluate the activity of the bioactive natural product, penta-O-galloyl-ß-d-glucose (PGG) against multidrug-resistant (MDR) Candida albicans, MDR Candida auris, and other MDR non-albicans Candida species. Here, we show that PGG has a minimum inhibitory concentration (MIC) of 0.25-8 µg mL-1 (0.265-8.5 µM) against three clinical strains of C. auris and a MIC of 0.25-4 µg mL-1 (0.265-4.25 µM) against a panel of other MDR Candida species. Our cytotoxicity studies found that PGG was well tolerated by human kidney, liver, and epithelial cells with an IC50 > 256 µg mL-1 (>272 µM). We also show that PGG is a high-capacity iron chelator and that deletion of key iron homeostasis genes in C. albicans rendered strains hypersensitive to PGG. In conclusion, PGG displayed potent anti-Candida activity with minimal cytotoxicity for human cells. We also found that the antifungal activity of PGG is mediated through an iron-chelating mechanism, suggesting that the compound could prove useful as a topical treatment for superficial Candida infections.

Intraocular lens power calculation in eyes with a shallow anterior chamber depth and normal axial length.

We compared the accuracy of three intraocular lens (IOL) calculation formulas in eyes with a shallow anterior chamber depth (ACD) and normal axial length (AXL) and control eyes. We retrospectively reviewed eyes with a shallow ACD (<2.5 mm from the corneal epithelium) with normal AXL (22.5≤AXL<24.0 mm) and controls (3.0≤ACD<3.5 mm and normal AXL). Prediction error (PE) and median absolute error (MedAE) were evaluated with SRK/T, Barrett Universal II (BUII), and Kane formulas after adjusting the mean PE to zero for all patients. Percentages of eyes achieving a PE within 0.25 to 1.00 D, and correlations between ACD, lens thickness (LT), and PE were analyzed. Thirty-five shallow ACD and 63 control eyes were included. PE in the shallow ACD group showed more hyperopic results with BUII and Kane but not with SRK/T compared to controls. Within the shallow ACD group, PE showed more hyperopic results in BUII and Kane compared to SRK/T. However, the standard deviation (SD) of PE among formulas was not different. In the shallow ACD group, SRK/T showed a higher percentage of PE within 0.25 D than BUII and Kane, but the percentages within 0.50 to 1.00 D were similar. PE was negatively correlated with ACD in BUII and Kane, and positively correlated with LT in all formulas. BUII and Kane may induce slight hyperopic shift in eyes with a shallow ACD and normal AXL. However, the performance of the three formulas was comparable in the shallow ACD group in terms of MedAE, the SD of PE, and the percentage of eyes achieving PE within 0.50 D.

Coffin-Siris Syndrome: Case Series of Three Patients and a Novel ARID2 Variant.

Coffin-Siris syndrome (CSS) is a rare congenital disorder characterized by coarse facial features, intellectual disability or developmental delay, and aplasia or hypoplasia of the tips of the fifth finger and/or toes. Mutations in genes affecting the switch/sucrose non-fermenting ATP-dependent chromatin remodeling complex are reported to cause CSS. Here, we describe three CSS patients. Two girls aged 3 and 2 years old presented with global developmental delay, poor growth, and a dysmorphic face. Whole-exome sequencing (WES) was performed and they were diagnosed with CSS due to heterozygous frameshift variants (c.3443_3444del, p.Lys1148ArgfsTer9 and c.2869_2890del, p.Pro957CysfsTer20) in ARID1B A 2-year-old girl presented with gross motor delay and dysmorphic face. She was diagnosed with CSS due to a novel heterozygous frameshift variant (c.4942_4943del: p.Gln1648GlyfsTer8) in ARID2.

Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility.

Candida albicans is a leading cause of death due to systemic fungal infections. Poor patient outcomes are attributable to the limited number of antifungal classes and the increasing prevalence of drug resistance. Protein kinases have emerged as rewarding targets in the development of drugs for diverse diseases, yet kinases remain untapped in the quest for new antifungals. Here, we performed a comprehensive analysis of the C. albicans kinome to identify genes for which loss-of-function confers hypersensitivity to the two most widely deployed antifungals, echinocandins and azoles. Through this analysis, we found a role for the casein kinase 1 (CK1) homologue Hrr25 in regulating tolerance to both antifungals as well as target-mediated echinocandin resistance. Follow-up investigations established that Hrr25 regulates these responses through its interaction with the SBF transcription factor. Thus, we provide insights into the circuitry governing cellular responses to antifungals and implicate Hrr25 as a key mediator of drug resistance.