Nystagmus and Foveal Hypoplasia in a Carrier of Oculocutaneous Albinism.

We report a 23-year-old female patient with ophthalmic features of albinism, including refractive errors, nystagmus, depigmented fundus, and foveal hypoplasia. She presented for a rhegmatogenous retinal detachment, which was surgically reattached with no complications. Further genetic testing revealed the presence of a heterozygous pathogenic oculocutaneous albinism OCA2 gene mutation, conferring carrier status. To the best of our knowledge, this is the first reported case of typical ocular phenotype of albinism, specifically nystagmus, in a patient who is carrier for oculo-cutaneous albinism. Further research is required to expand the genotype-phenotype relationship in carriers of oculocutaneous albinism. [Ophthalmic Surg Lasers Imaging Retina 2024;55:349-353.].

Lysophosphatidylcholine acyltransferase 1 suppresses nanoclustering and function of KRAS.

KRAS is frequently mutated in cancer, contributing to 20% of all human cancer especially pancreatic, colorectal and lung cancer. Signaling of the constitutively active KRAS oncogenic mutants is mostly compartmentalized to proteolipid nanoclusters on the plasma membrane (PM). Signaling nanoclusters of many KRAS mutants selectively enrich phosphatidylserine (PS) lipids with unsaturated sn-2 acyl chains, but not the fully saturated PS species. Thus, remodeling PS acyl chains may suppress KRAS oncogenesis. Lysophosphatidylcholine acyltransferases (LPCATs) remodel sn-2 acyl chains of phospholipids, with LPCAT1 preferentially generating the fully saturated lipids. Here, we show that stable expression of LPCAT1 depletes major PS species with unsaturated sn-2 chains while decreasing minor phosphatidylcholine (PC) species with the corresponding acyl chains. LPCAT1 expression more effectively disrupts the nanoclustering of oncogenic GFP-KRAS G12V , which is restored by acute addback of exogenous unsaturated PS. LPCAT1 expression compromises signaling and oncogenic activities of the KRAS-dependent pancreatic tumor lines. LPCAT1 expression sensitizes human pancreatic tumor MiaPaCa-2 cells to KRAS G12C specific inhibitor, Sotorasib. Statistical analyses of patient data further reveal that pancreatic cancer patients with KRAS mutations express less LPCAT1. Higher LPCAT1 expression also improves survival probability of pancreatic and lung adenocarcinoma patients with KRAS mutations. Thus, PS acyl chain remodeling selectively suppresses KRAS oncogenesis.

A dynamic in vitro model of Down syndrome neurogenesis with trisomy 21 gene dosage correction.

Excess gene dosage from chromosome 21 (chr21) causes Down syndrome (DS), spanning developmental and acute phenotypes in terminal cell types. Which phenotypes remain amenable to intervention after development is unknown. To address this question in a model of DS neurogenesis, we derived trisomy 21 (T21) human induced pluripotent stem cells (iPSCs) alongside, otherwise, isogenic euploid controls from mosaic DS fibroblasts and equipped one chr21 copy with an inducible XIST transgene. Monoallelic chr21 silencing by XIST is near-complete and irreversible in iPSCs. Differential expression reveals that T21 neural lineages and iPSCs share suppressed translation and mitochondrial pathways and activate cellular stress responses. When XIST is induced before the neural progenitor stage, T21 dosage correction suppresses a pronounced skew toward astrogenesis in neural differentiation. Because our transgene remains inducible in postmitotic T21 neurons and astrocytes, we demonstrate that XIST efficiently represses genes even after terminal differentiation, which will empower exploration of cell type-specific T21 phenotypes that remain responsive to chr21 dosage.

A common cis-regulatory variant impacts normal-range and disease-associated human facial shape through regulation of PKDCC during chondrogenesis.

Genome-wide association studies (GWAS) identified thousands of genetic variants linked to phenotypic traits and disease risk. However, mechanistic understanding of how GWAS variants influence complex morphological traits and can, in certain cases, simultaneously confer normal-range phenotypic variation and disease predisposition, is still largely lacking. Here, we focus on rs6740960, a single nucleotide polymorphism (SNP) at the 2p21 locus, which in GWAS studies has been associated both with normal-range variation in jaw shape and with an increased risk of non-syndromic orofacial clefting. Using in vitro derived embryonic cell types relevant for human facial morphogenesis, we show that this SNP resides in an enhancer that regulates chondrocytic expression of PKDCC - a gene encoding a tyrosine kinase involved in chondrogenesis and skeletal development. In agreement, we demonstrate that the rs6740960 SNP is sufficient to confer chondrocyte-specific differences in PKDCC expression. By deploying dense landmark morphometric analysis of skull elements in mice, we show that changes in Pkdcc dosage are associated with quantitative changes in the maxilla, mandible, and palatine bone shape that are concordant with the facial phenotypes and disease predisposition seen in humans. We further demonstrate that the frequency of the rs6740960 variant strongly deviated among different human populations, and that the activity of its cognate enhancer diverged in hominids. Our study provides a mechanistic explanation of how a common SNP can mediate normal-range and disease-associated morphological variation, with implications for the evolution of human facial features.

RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains.

Mutant RAS are major contributors to cancer and signal primarily from nanoclusters on the plasma membrane (PM). Their C-terminal membrane anchors are main features of membrane association. However, the same RAS isoform bound to different guanine nucleotides spatially segregate. Different RAS nanoclusters all enrich a phospholipid, phosphatidylserine (PS). These findings suggest more complex membrane interactions. Our electron microscopy-spatial analysis shows that wild-types, G12V mutants, and membrane anchors of isoforms HRAS, KRAS4A, and KRAS4B prefer distinct PS species. Mechanistically, reorientation of KRAS4B G-domain exposes distinct residues, such as Arg 135 in orientation state 1 (OS1) and Arg 73/Arg 102 in OS2, to the PM and differentially facilitates the recognition of PS acyl chains. Allele-specific oncogenic mutations of KRAS4B also shift G-domain reorientation equilibrium. Indeed, KRAS4BG12V, KRAS4BG12D, KRAS4BG12C, KRAS4BG13D, and KRAS4BQ61H associate with PM lipids with headgroup and acyl chain specificities. Distribution of these KRAS4B oncogenic mutants favors different nanoscale membrane topography. Thus, RAS G-domains allosterically facilitate membrane lateral distribution.

Ichthyosis Skin Changes in a Patient With Hereditary Hemochromatosis.

Hereditary hemochromatosis (HH) is characterized by elevated iron absorption in the body, leading to iron accumulation with subsequent dysfunction and end-organ damage. While the progression of the disease can result in arthralgias, hepatomegaly, cardiomyopathies, and diabetes, over a third of HH patients present with cutaneous manifestations. We present the case of a 56-year-old male with HH who presented to dermatology with a rash and diffuse scaling. The patient exhibited brown plate-like scales clinically consistent with diffuse ichthyosis vulgaris. While ichthyosis has been seen in patients with idiopathic hemochromatosis, its association with HH is not well reported. Due to the high prevalence of cutaneous involvement in hereditary hemochromatosis, physicians should familiarize themselves with ichthyosis and the other dermatologic manifestations of this disease.

Assessing medical students' confidence in promoting high value care in clinical practice.

Background: Medical students who are exposed to value-based care early in their education may be more likely to practice it. Our study aimed to understand medical students' knowledge of and ability to implement the principles of high-value care in clinical settings. Additionally, we assessed students' confidence in using high-value care practices to both influence care decisions and educate patients. Methods: We surveyed third-year medical students at Texas A&M School of Medicine during their clerkship rotations using a 7-question Likert-scale survey. Students were asked to evaluate their confidence in performing cost-conscious high-value care behaviors. Results: Of the 114 students offered the survey, 34 (30%) completed it fully. The greatest variance in response occurred in students' attitudes toward their role in controlling healthcare costs. Half of respondents agreed or strongly agreed that they played a part in cost control as medical students, with 35% somewhat or strongly disagreeing. A majority of students felt confident initiating a conversation about costs with patients, while 21% somewhat or strongly disagreed that they were confident. Conclusion: Overall, our results reveal that the main area lacking in students' education in value-based care is instilling the belief that they, as medical students, have a role to play in controlling healthcare costs.

Using Real-World Data to Explore the Impact of One-Time Financial Grants Among Young Adult Cancer Survivors.

Young adult (YA) cancer survivors experience worse financial outcomes than older survivors. This analysis used data from Expect Miracles Foundation to explore the impact of one-time financial grants on financial well-being and access to health care. Among 300 respondents, the average grant was $1526 (standard deviation = $587; range $300-$3000). Respondents reported improved ability to pay expenses (t = 4.45, p < 0.001), increased financial decision-making power (t = 2.79, p = 0.06), decreased medical debt impact (t = 2.1, p = 0.04), improved transportation access (t = 2.38, p = 0.02), and fewer challenges in accessing care (t = 3.0, p = 0.005) 6 months after receiving a financial grant. Financial assistance offers YAs an opportunity to meet medical and nonmedical expenses.

Cultural Adaptation of Patient Health Questionnaire-9 in Hindi for Use with Patients with Cancer in Community Palliative Care Settings.

Objectives: Patient Health Questionnaire-9 (PHQ-9) in Indian settings is yet not very often used in palliative care with the Hindi-speaking population. The Hindi version of PHQ-9 is available but its cultural adaptation to the Hindi-speaking population in North India receiving palliative care services is required to be tested. PHQ-9 as a depression screening questionnaire may help to identify depression symptoms among patients with cancer. This study aimed to examine the cultural equivalence of PHQ-9 Hindi for use with patients with cancer receiving palliative care services in North India. Material and Methods: Based on the standard methodology of translation and adaptation of the scale, the following process was used: (i) Two focused group discussions with 17 experts working in a cancer palliative care setting, (ii) qualitative interviewing with 11 patients, and (iii) research team review. All interviews were audio recorded, transcribed, and item-wise content analysis was conducted. Results: A few difficult phrases in the original PHQ-9 were 'dilchaspi', 'avasadgrast', 'kam urja', 'nakaam', parivar ko neecha dhikhana and 'ashthir' which were changed to Kam Mann Lagna, Mann Dukhi hona, kamjori, saksham nahi hain' 'asafal', Parivar ko nirash karna' and 'bechain,' respectively. Two items, namely no. 6 and 8 were changed to shorten the length for appropriately conveying the meaning. Conclusion: Hindi language involves various dialects which change from region to region bringing variations in understanding the meaning of the words. It is recommended that culturally equivalent scales are used in practice and research. PHQ-9 is now culturally adapted for the Hindi-speaking population in North India. PHQ-9 will help identidy depressive symptoms at an early stage. Psychometric testing of PHQ-9 is underway.

Champion Device Architectures for Low-Cost and Stable Single-Junction Perovskite Solar Cells.

High power conversion efficiencies (PCE), low energy payback time (EPBT), and low manufacturing costs render perovskite solar cells (PSCs) competitive; however, a relatively low operational stability impedes their large-scale deployment. In addition, state-of-the-art PSCs are made of expensive materials, including the organic hole transport materials (HTMs) and the noble metals used as the charge collection electrode, which induce degradation in PSCs. Thus, developing inexpensive alternatives is crucial to fostering the transition from academic research to industrial development. Combining a carbon-based electrode with an inorganic HTM has shown the highest potential and should replace noble metals and organic HTMs. In this review, we illustrate the incorporation of a carbon layer as a back contact instead of noble metals and inorganic HTMs instead of organic ones as two cornerstones for achieving optimal stability and economic viability for PSCs. We discuss the primary considerations for the selection of the absorbing layer as well as the electron-transporting layer to be compatible with the champion designs and ultimate architecture for single-junction PSCs. More studies regarding the long-term stability are still required. Using the recommended device architecture presented in this work would pave the way toward constructing low-cost and stable PSCs.

A novel case of limbal stem cell deficiency in a patient with acrodermatitis enteropathica.

An 18-year-old male diagnosed with acrodermatitis enteropathica (AE) since early childhood presented with worsening of dermatitis along with photophobia and watering in both eyes. Systemic evaluation by dermatology and gastroenterology specialists confirmed a diagnosis of acute exacerbation of AE, and oral zinc supplements were initiated. A best-corrected visual acuity of 20/20 was documented in both eyes. Slit-lamp examination revealed bilateral subepithelial corneal opacities in a radial fan-like pattern extending from the superior limbus toward the center. A whorled appearance of fluorescein staining and small epithelial erosions was noted in both eyes. Ocular involvements in AE such as blepharitis, cataracts, and radial corneal opacities have been reported previously. We report a new association of AE with limbal stem cell deficiency with its classical features of linear subepithelial corneal opacities with a whorling uptake of fluorescein stain and corneal erosions.

Direct Modulators of K-Ras-Membrane Interactions.

Protein-membrane interactions (PMIs) are ubiquitous in cellular signaling. Initial steps of signal transduction cascades often rely on transient and dynamic interactions with the inner plasma membrane leaflet to populate and regulate signaling hotspots. Methods to target and modulate these interactions could yield attractive tool compounds and drug candidates. Here, we demonstrate that the conjugation of a medium-chain lipid tail to the covalent K-Ras(G12C) binder MRTX849 at a solvent-exposed site enables such direct modulation of PMIs. The conjugated lipid tail interacts with the tethered membrane and changes the relative membrane orientation and conformation of K-Ras(G12C), as shown by molecular dynamics (MD) simulation-supported NMR studies. In cells, this PMI modulation restricts the lateral mobility of K-Ras(G12C) and disrupts nanoclusters. The described strategy could be broadly applicable to selectively modulate transient PMIs.

Financial conflicts of interest of physicians followed by oncology journals on Twitter.

BACKGROUND: Physicians have increasingly adopted Twitter as a discussion and distribution platform for oncology research. While the influence of financial conflicts of interests (FCOI) on medical research is well documented, their role in the dissemination of research on social media platforms is not well known. In this study, we sought to evaluate the FCOIs of physicians followed by the top three oncology journals on Twitter. MATERIALS AND METHODS: We used the Open Payments Search Tool ( https://openpaymentsdata.cms.gov ) to assess FCOIs between 2016 and 2021 of United States (US) physicians followed by three oncology journals (Journal of Clinical Oncology, The Lancet Oncology, and Annals of Oncology) on Twitter. RESULTS: Of 1914 Twitter accounts followed by the top three oncology journals on Twitter, 547 (28.6%) belonged to US physicians. Of these, 463 (84.6%) received general payments between 2016 and 2021. After excluding 30 US physicians currently in residency or fellowship, this percentage increased to 88.2% (n = 456/517). Combined, the median (interquartile range) general payment amount was $8100 ($200-90,000). Additionally, over $42 million in general payments were made between 2016 and 2021. CONCLUSION: Our findings offer insight on FCOIs between oncology journals and US physicians on Twitter. These findings may serve as the foundation for future research regarding optimal medical journal conduct on social media platforms.

Evaluation of the mechanisms underlying altered fatty acid biosynthesis in heterotrophic microalgal strain Chlorella sorokiniana during biodegradation of phenol and p-nitrophenol.

Phenolic compounds have become a severe environmental concern due to water contamination, affecting the sustainability of the ecosystem. The microalgae enzymes have enticed for the efficient involvement in the biodegradation of phenolics compound in metabolic processes. In this investigation, the oleaginous microalgae Chlorella sorokiniana was cultured heterotrophically under the influence of phenol and p-nitrophenol. The enzymatic assays of algal cell extracts were used to decipher the underlying mechanisms for phenol and p-nitrophenol biodegradation. A reduction of 99.58% and 97.21% in phenol and p-nitrophenol values, respectively, was recorded after the 10th day of microalgae cultivation. Also, the biochemical components in phenol, p-nitrophenol, and control were found to be 39.6 ± 2.3%, 36.7 ± 1.3%, and 30.9 ± 1.8% (total lipids); 27.4 ± 1.4%, 28.3 ± 1.8%, and 19.7 ± 1.5% (total carbohydrates); and 26.7 ± 1.9%, 28.3 ± 1.9%, and 39.9 ± 1.2% (total proteins), respectively. The GC-MS and 1H-NMR spectroscopy attested the incidence of fatty acid methyl esters in the synthesized microalgal biodiesel. The activity of catechol 2,3-dioxygenase and hydroquinone 1,2-dioxygenase in microalgae under heterotrophic conditions has conferred the ortho- and hydroquinone pathways for phenol and p-nitrophenol biodegradation, respectively. Also, the acceleration of fatty acid profiles in microalgae is deliberated under the impact of the phenol and p-nitrophenol biodegradation process. Thus, microalgae enzymes in the metabolic degradation process of phenolic compounds encourage ecosystem sustainability and biodiesel prospects due to the increased lipid profiles of microalgae.

RAS GTPases and Interleaflet Coupling in the Plasma Membrane.

RAS genes are frequently mutated in cancer. The primary signaling compartment of wild-type and constitutively active oncogenic mutant RAS proteins is the inner leaflet of the plasma membrane (PM). Thus, a better understanding of the unique environment of the PM inner leaflet is important to shed further light on RAS function. Over the past few decades, an integrated approach of superresolution imaging, molecular dynamic simulations, and biophysical assays has yielded new insights into the capacity of RAS proteins to sort lipids with specific headgroups and acyl chains, to assemble signaling nanoclusters on the inner PM. RAS proteins also sense and respond to changes in components of the outer PM leaflet, including glycophosphatidylinositol-anchored proteins, sphingophospholipids, glycosphingolipids, and galectins, as well as cholesterol that translocates between the two leaflets. Such communication between the inner and outer leaflets of the PM, called interleaflet coupling, allows RAS to potentially integrate extracellular mechanical and electrostatic information with intracellular biochemical signaling events, and reciprocally allows mutant RAS-transformed tumor cells to modify tumor microenvironments. Here, we review RAS-lipid interactions and speculate on potential mechanisms that allow communication between the opposing leaflets of the PM.

Macular Hole in a patient with Pentosan Polysulfate Maculopathy.

PURPOSE: Pentosan polysulfate (PPS), a drug used for interstitial cystitis, has recently been detected to cause maculopathy in a dose-dependent manner. Outer retinal atrophy is the hallmark of this condition. METHODS: History, examination and multimodal imaging were used to guide diagnosis and management. RESULTS: We report a case of PPS-related maculopathy in a 77-year-old lady, who presented with florid retinal atrophy at the posterior pole in both eyes, and a concurrent macular hole in the left eye. She had been diagnosed with interstitial cystitis several years prior for which she was prescribed PPS (Elmiron). She had noticed a drop in vision 5 years following initiation of PPS and self-discontinued the drug after 24 years of use. A diagnosis of PPS-related maculopathy with a macular hole was made. She was counselled regarding the prognosis and was advised to avoid PPS. Surgery for macular hole was deferred in view of the severe retinal atrophy. CONCLUSIONS: PPS-related maculopathy can lead to severe retinal atrophy and a subsequent degenerative macular hole. A high index of suspicion is required for early detection and cessation of drug to prevent this irreversible vision loss.