Single-cell network biology characterizes cell type gene regulation for drug repurposing and phenotype prediction in Alzheimer's disease.

Dysregulation of gene expression in Alzheimer's disease (AD) remains elusive, especially at the cell type level. Gene regulatory network, a key molecular mechanism linking transcription factors (TFs) and regulatory elements to govern gene expression, can change across cell types in the human brain and thus serve as a model for studying gene dysregulation in AD. However, AD-induced regulatory changes across brain cell types remains uncharted. To address this, we integrated single-cell multi-omics datasets to predict the gene regulatory networks of four major cell types, excitatory and inhibitory neurons, microglia and oligodendrocytes, in control and AD brains. Importantly, we analyzed and compared the structural and topological features of networks across cell types and examined changes in AD. Our analysis shows that hub TFs are largely common across cell types and AD-related changes are relatively more prominent in some cell types (e.g., microglia). The regulatory logics of enriched network motifs (e.g., feed-forward loops) further uncover cell type-specific TF-TF cooperativities in gene regulation. The cell type networks are also highly modular and several network modules with cell-type-specific expression changes in AD pathology are enriched with AD-risk genes. The further disease-module-drug association analysis suggests cell-type candidate drugs and their potential target genes. Finally, our network-based machine learning analysis systematically prioritized cell type risk genes likely involved in AD. Our strategy is validated using an independent dataset which showed that top ranked genes can predict clinical phenotypes (e.g., cognitive impairment) of AD with reasonable accuracy. Overall, this single-cell network biology analysis provides a comprehensive map linking genes, regulatory networks, cell types and drug targets and reveals cell-type gene dysregulation in AD.

QTLs and Candidate Loci Associated with Drought Tolerance Traits of Kaybonnet x ZHE733 Recombinant Inbred Lines Rice Population.

Rice is the most important staple crop for the sustenance of the world's population, and drought is a major factor limiting rice production. Quantitative trait locus (QTL) analysis of drought-resistance-related traits was conducted on a recombinant inbred line (RIL) population derived from the self-fed progeny of a cross between the drought-resistant tropical japonica U.S. adapted cultivar Kaybonnet and the drought-sensitive indica cultivar ZHE733. K/Z RIL population of 198 lines was screened in the field at Fayetteville (AR) for three consecutive years under controlled drought stress (DS) and well-watered (WW) treatment during the reproductive stage. The effects of DS were quantified by measuring morphological traits, grain yield components, and root architectural traits. A QTL analysis using a set of 4133 single nucleotide polymorphism (SNP) markers and the QTL IciMapping identified 41 QTLs and 184 candidate genes for drought-related traits within the DR-QTL regions. RT-qPCR in parental lines was used to confirm the putative candidate genes. The comparison between the drought-resistant parent (Kaybonnet) and the drought-sensitive parent (ZHE733) under DS conditions revealed that the gene expression of 15 candidate DR genes with known annotations and two candidate DR genes with unknown annotations within the DR-QTL regions was up-regulated in the drought-resistant parent (Kaybonnet). The outcomes of this research provide essential information that can be utilized in developing drought-resistant rice cultivars that have higher productivity when DS conditions are prevalent.

The FATTY ACID DESATURASE2 Family in Tomato Contributes to Primary Metabolism and Stress Responses.

The conversion of oleic acid (C18:1) to linoleic acid (C18:2) in the endoplasmic reticulum is critical to the accumulation of polyunsaturated fatty acids in seeds and other tissues, and this reaction is catalyzed by a Δ12-desaturase, FATTY ACID DESATURASE2 (FAD2). Here, we report that the tomato (Solanum lycopersicum) genome harbors two genes, SlFAD2-1 and SlFAD2-2, which encode proteins with in vitro Δ12-desaturase activity. In addition, tomato has seven divergent FAD2 members that lack Δ12-desaturase activity and differ from canonical FAD2 enzymes at multiple amino acid positions important to enzyme function. Whereas SlFAD2-1 and SlFAD2-2 are downregulated by biotic stress, the majority of divergent FAD2 genes in tomato are upregulated by one or more stresses. In particular, SlFAD2-7 is induced by the potato aphid (Macrosiphum euphorbiae) and has elevated constitutive expression levels in suppressor of prosystemin-mediated responses2 (spr2), a tomato mutant with enhanced aphid resistance and altered fatty acid profiles. Virus-induced gene silencing of SlFAD2-7 in spr2 results in significant increases in aphid population growth, indicating that a divergent FAD2 gene contributes to aphid resistance in this genotype. Thus, the FAD2 gene family in tomato is important both to primary fatty acid metabolism and to responses to biotic stress.

Combined endoscopic cyclophotocoagulation and phacoemulsification versus phacoemulsification alone in the treatment of mild to moderate glaucoma.

BACKGROUND: To evaluate the long-term effects of combined endoscopic cyclophotocoagulation and phacoemulsification (phaco) versus phacoemulsification alone on intraocular pressure control and medication reliance in the treatment of mild to moderate glaucoma. DESIGN: Retrospective chart review in private practice setting by glaucoma fellowship trained surgeons. PARTICIPANTS: A total of 261 eyes in the combined phaco-endoscopic cyclophotocoagulation group with 52 eyes in the phaco-alone group. METHODS: Comparison of phaco-endoscopic cyclophotocoagulation with phaco alone over 36 months. MAIN OUTCOME MEASURES: Full and qualified success cumulative survival, intraocular pressure and medication reliance 6-36 months compared with baseline. Full success was defined as minimum 20% intraocular pressure reduction with a decrease of at least one ocular hypertensive medication. Qualified success was defined as intraocular pressure no higher than baseline with a decrease of at least one ocular hypertensive medication. RESULTS: At 36 months, mean intraocular pressure in the combined phaco-endoscopic cyclophotocoagulation group was 14.6 mmHg, whereas the phaco-alone group was 15.5 mmHg (P = 0.34). Mean medication reliance in the combined phaco-endoscopic cyclophotocoagulation group was 0.2 medications, whereas the phaco-alone group was 1.2 (P < 0.001). Full success in the phaco-endoscopic cyclophotocoagulation group was 61.4%; the phaco-alone group was 23.3% (P < 0.001). Qualified success survival was 72.6% in the phaco-endoscopic cyclophotocoagulation group and 23.3% in the phaco-alone group (P < 0.001). CONCLUSIONS: Combined phaco-endoscopic cyclophotocoagulation effectively lowers or maintains intraocular pressure and results in ocular hypertensive medication reduction up to 36 months when compared with phaco alone. Therefore, phaco-endoscopic cyclophotocoagulation may help to increase medication compliance and reduce glaucoma progression in mild to moderate glaucoma.

Durvalumab-associated limbal stem cell deficiency and secondary corneal perforation.

Purpose: We report a patient with bilateral limbal stem cell deficiency (LSCD) like clinical manifestations and secondary corneal perforation presumably induced by durvalumab following its use for the treatment of non-small cell lung carcinoma. Observations: A 65-year-old male diagnosed with non-small cell lung carcinoma was treated with monthly durvalumab infusions. Two months after starting durvalumab, the patient was found to have bilateral severe keratoconjunctivitis and LSCD-like clinical findings. Despite topical management and oral prednisone for presumed ocular cicatricial pemphigoid, the patient continued to worsen clinically. The patient was transferred to our institution about one year later with persistent inflammation. The patient eventually developed a corneal perforation of the left eye, which required the application of cyanoacrylic tissue adhesive. Due to the lack of response to oral prednisone, durvalumab was discontinued with the approval of the patient's oncologist. Several months following the discontinuation of durvalumab, the conjunctival inflammation subsided, and corneal epithelial breakdown and ulceration resolved. Conclusions: We report an association between durvalumab and the development of bilateral LSCD-like clinical findings with subsequent corneal perforation. We hope this case reinforces the importance of routine ophthalmologic follow-up after starting any cancer treatment, especially in patients with symptoms and signs suggesting ocular surface disease or inflammation.

Bilateral peripheral ulcerative keratitis in a patient with known Sézary syndrome.

Purpose: To report a case of bilateral peripheral ulcerative keratitis (PUK) in a patient with underlying Sézary syndrome. Observations: A 58-year-old male presented with bilateral corneal ulceration with stromal thinning and was diagnosed with PUK. He was actively being treated for Sézary syndrome, a cutaneous T-cell lymphoma. He had no lagophthalmos or other adnexal abnormalities that would lead to ocular surface breakdown. A systemic autoimmune and infectious workup for PUK was unremarkable. His keratitis resolved after treatment with oral prednisone. Conclusions and importance: We describe a previously undocumented association of PUK with Sézary syndrome in a patient without adnexal disease.

Single-cell genomics and regulatory networks for 388 human brains.

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

Single-cell genomics and regulatory networks for 388 human brains.

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

Exploring the Multifaceted Causes of Ischemic Stroke: A Narrative Review.

Neurologists are well-versed with acute ischemic stroke, a serious public health concern. Effective acute stroke treatment is built on the rapid application of reperfusion therapy. This calls for prompt symptom recognition by the general population as well as emergency workers, proper referral to specialized stroke centers, and thorough examination and assessment by the on-site stroke team. The main goal of treatment for certain individuals is to restore blood flow to the ischemic penumbra by using intravenous thrombolysis and/or endovascular thrombectomy. Acute stroke patients must be hospitalized and continuously monitored for early neurological decline in order to avoid subsequent problems. After swiftly determining the stroke mechanism, patients can start the proper secondary preventative actions.

Long-Term Use of a Temporary Keratoprosthesis and Perfluorocarbon in Traumatic Retinal Detachment Repair.

Purpose: To present a technique for optimizing repair of traumatic retinal detachments (RDs). Methods: A patient was followed in an outpatient setting with clinical examinations, optical coherence tomography, widefield fundus photography, and anterior segment imaging. Results: The patient presented with a total RD after ruptured globe repair. The patient had combined corneal and retinal surgery with placement of a temporary keratoprosthesis (TKP) and vitrectomy with perfluorocarbon liquid (PFCL) to reattach the retina. The TKP and PFCL were left in the eye for 2 weeks before a planned silicone oil exchange and penetrating keratoplasty were performed. Four months postoperatively, the patient presented with a partially attached retina and improved vision. Conclusions: In this case, a ruptured globe decompensated several months after primary repair. The prolonged use of the TKP allowed for optimal surgical visualization, enhanced office-based assessment, and limited endothelial cell loss of the donor corneal tissue.

TEMPORARY KERATOPROSTHESIS WITH PENETRATING KERATOPLASTY IN CONJUNCTION WITH PARS PLANA VITRECTOMY FOR REPAIR OF RETINAL DETACHMENTS IN PATIENTS WITH ANTERIOR AND POSTERIOR SEGMENT PATHOLOGY.

PURPOSE: To review the visual and anatomical outcomes of combined anterior and posterior segment surgery for retinal detachment repair. METHODS AND PATIENTS: Eight patients with combined retinal and corneal disease underwent combined temporary keratoprosthesis with penetrating keratoplasty combined with pars plana vitrectomy for retinal detachment repair with silicone oil tamponade. Visual and anatomical outcomes were reviewed retrospectively. Follow-up ranged from 12 months to 37 months. RESULTS: Preoperative visual acuity ranged from light perception to hand motion. All but one case had proliferative vitreoretinopathy present at the time of surgery. Postoperative visual acuity ranged from hand motion to light perception. At the most recent follow-up visit, all of the patients had attached retinas, no patients had phthisis bulbi, and all but one patient had a clear cornea. However, 3 of these cases (38%) required repeat retinal detachment repair and one of them also required repeat penetrating keratoplasty, which was performed at the time of retinal repair. CONCLUSION: Combined full-thickness penetrating keratoplasty and retinal detachment repair has good anatomical outcomes and is an efficient way to treat complex anterior and posterior segment abnormality. Although postoperative visual function is limited; almost all patients were agreeable to repeat surgery if they were presented with the choice again.

Detection of vitrector shavings on OCT.

PURPOSE: To describe multiple retained intraocular foreign bodies felt to be from a vitrectomy instrument. METHODS: Observational case report. PATIENT: A 66-year-old male with history of rhegmatogenous retinal detachment repaired with PPV, scleral buckle, endolaser, and fluid-air exchange presented with dyschromatopsia OD. RESULTS: OCT demonstrated metallic vitrector shavings detected on OCT above the optic nerve head and macula. Repeat OCT 9 months later demonstrated movement of the vitrector shavings throughout the vitreous. CONCLUSION: We demonstrate retained intraocular foreign body shavings which are rarely seen following vitrectomy. These can be confirmed using OCT.

Intrastromal keratopigmentation for photophobia secondary to traumatic aniridia.

Purpose: To present a case of therapeutic intrastromal keratopigmentation to resolve intractable photophobia secondary to traumatic aniridia in a hypotonus eye. Observations: A 66-year-old male presented with intractable photophobia for several years in the left eye following a ruptured globe and multiple subsequent retinal surgeries for retinal detachments complicated by proliferative vitreoretinopathy. The patient underwent intrastromal keratopigmentation given surgical limitations due to the presence of hypotony and silicone oil dependence. The patient's symptoms were fully resolved, and the pigmentation remained stable at 18 months. Conclusions/Importance: Keratopigmentation can be an effective surgical approach to managing patients with symptomatic photophobia in eyes where intraocular surgery is not an amenable option.

Effect of Stress and Caffeine on Male Infertility.

Caffeine is a natural psychoactive chemical found in beverages made from coffee. In addition, it is added by the manufacturers of a large number of sodas and energy drinks. It does this by stimulating both the brain and the central nervous system, enabling you to avoid being sleepy while still keeping you attentive. A state of emotional or physical tension is defined as stress. It can be induced through the experience of something or thinking of something that causes you to feel uncomfortable, irritated, or nervous. Your body's response to adversity or demand is what we call stress. Among couples, male infertility is common. A failure in spermatogenesis is accountable for nearly half of all occurrences of infertility in marriage. Ageing, psychological stress, diet, physical exercise, coffee, hot water, hot scrotum, and cell phone usage are some of the few modifiable lifestyle variables that have a role in the development of infertility. Many hypotheses have been proposed to establish the link between stress in the workplace, life events (war, earthquake, etc.), and inability to conceive have been linked to inferior or degraded semen quality. In this review, we will discuss the effect on male fertility of elements including quality of life (such as exercise, diet, and other alterations to one's daily routine) and psychological stress. In addition, the effects on male fertility of elevated scrotal temperature, improper dietary habits, and physical inactivity will be discussed. The loss in male fertility, mainly due to ageing, inappropriate lifestyles, and environmental factors, is a significant public health concern in this century. Couples can enhance their quality of life and increase their chances of naturally conceiving a child by altering their way of life and supplementing it with nutraceutical antioxidants and an organised educational, environmental, dietary, and physical exercise program.

Reviewing the Impact of Social Media on the Mental Health of Adolescents and Young Adults.

Adolescents now cannot imagine their lives without social media. Practitioners want to be able to assess risk, and social media may be a new factor to take into account. The impression of the link between social networks and intellectual health holds a strong emphasis on adolescent and professional perspectives, although there is little research that underlies these beliefs. Sexting, privacy concerns, cyberbullying, and negative impacts on education and mental health are dangers connected with social media use in this population. However, ethical social media use can increase opportunities for connection and communication, boosting one's self-esteem, promoting one's health, and getting access to crucial medical information. Despite rising evidence of the harmful impacts of social media on adolescent mental health, there is still a paucity of empirical research on how teenagers understand social media, notably as a body of wisdom, or how they can use the larger modern media discourses to voice an opinion. The youth use smartphones and other media in high numbers, which leads to chronic sleep deprivation, having a detrimental impact on cognitive ability, school performance, and socio-emotional functioning. Smartphone and social media use among teenagers are associated with an increase in mental distress, self-harming behaviours, and suicidality, according to evidence from numerous cross-sectional, longitudinal, and empirical studies. Clinicians can collaborate with young people and their families to mitigate the potential risks associated with social media and smartphone use by employing open, nonjudgmental, and developmentally appropriate strategies, such as education and practical problem-solving.

Autoimmune polyglandular syndrome type II presenting as subacute combined degeneration of spinal cord: a neuroendocrinology crossroad.

Introduction: Autoimmune polyglandular syndrome (APS) is a condition having multiple endocrine abnormalities. It is divided into three types depending on the involvement of various endocrinopathies. It is also associated with other systemic involvement. The basic pathophysiology of this syndrome revolves around autoimmunity.Case presentation: We discuss the case of a 50-year-old gentleman who presented to us in emergency with subacute onset progressive weakness of both lower limbs followed by upper limbs. On examination, patient was confused and disoriented. General examination findings include hypotension, pallor, facial puffiness and vitiligo. Neurological examination revealed spasticity and motor weakness in all four limbs with extensor planter response. Sensory examination during hospital course revealed posterior column involvement. Laboratory and radiological investigations confirmed subacute combined degeneration of spinal cord secondary to pernicious anaemia, Addison's disease and autoimmune thyroid disease. The final diagnosis of autoimmune polyglandular syndrome type II was made after fulfilment of the required criteria.Conclusion: Autoimmune polyglandular syndrome type II can rarely present to neurologist as subacute combined degeneration of spinal cord. This syndrome and its systemic association should be kept in mind in order to reach the final diagnosis.

Bringing machine learning to research on intellectual and developmental disabilities: taking inspiration from neurological diseases.

Intellectual and Developmental Disabilities (IDDs), such as Down syndrome, Fragile X syndrome, Rett syndrome, and autism spectrum disorder, usually manifest at birth or early childhood. IDDs are characterized by significant impairment in intellectual and adaptive functioning, and both genetic and environmental factors underpin IDD biology. Molecular and genetic stratification of IDDs remain challenging mainly due to overlapping factors and comorbidity. Advances in high throughput sequencing, imaging, and tools to record behavioral data at scale have greatly enhanced our understanding of the molecular, cellular, structural, and environmental basis of some IDDs. Fueled by the "big data" revolution, artificial intelligence (AI) and machine learning (ML) technologies have brought a whole new paradigm shift in computational biology. Evidently, the ML-driven approach to clinical diagnoses has the potential to augment classical methods that use symptoms and external observations, hoping to push the personalized treatment plan forward. Therefore, integrative analyses and applications of ML technology have a direct bearing on discoveries in IDDs. The application of ML to IDDs can potentially improve screening and early diagnosis, advance our understanding of the complexity of comorbidity, and accelerate the identification of biomarkers for clinical research and drug development. For more than five decades, the IDDRC network has supported a nexus of investigators at centers across the USA, all striving to understand the interplay between various factors underlying IDDs. In this review, we introduced fast-increasing multi-modal data types, highlighted example studies that employed ML technologies to illuminate factors and biological mechanisms underlying IDDs, as well as recent advances in ML technologies and their applications to IDDs and other neurological diseases. We discussed various molecular, clinical, and environmental data collection modes, including genetic, imaging, phenotypical, and behavioral data types, along with multiple repositories that store and share such data. Furthermore, we outlined some fundamental concepts of machine learning algorithms and presented our opinion on specific gaps that will need to be filled to accomplish, for example, reliable implementation of ML-based diagnosis technology in IDD clinics. We anticipate that this review will guide researchers to formulate AI and ML-based approaches to investigate IDDs and related conditions.