KSR1 regulates small-cell lung carcinoma tumor initiation and therapy resistance.

Small-cell lung cancer (SCLC) is designated a recalcitrant cancer due to its five-year relative survival rate of less than 7%. First line SCLC treatment has not changed in the last 40 years. The NeuroD1 subtype of SCLC (SCLC-N) commonly harbors MYC amplifications and other hallmarks of aggressive behavior. Finding novel therapeutic options that effectively eliminate residual disease observed after initial response to therapy is essential to improving SCLC patient outcome. Tumor-initiating cells (TICs) are reported as the sanctuary population within the bulk tumor responsible for therapeutic resistance and relapse. In contrast to earlier studies in which ERK activation is reported to be inhibitory to growth and tumor development, we show that KSR1 signaling is conserved in SCLC-N and that it regulates tumor initiation through ERK. Thus, KSR1 function in SCLC-N serves as a novel model for understanding the role of KSR1-dependent signaling in normal and malignant tissues. We further show that KSR1 mediates cisplatin resistance in SCLC-N cells. CRISPR/Cas9-mediated KSR1 knockout causes a dramatic increase in sensitivity to cisplatin and is coincident with a marked decrease in TICs, indicating that targeting KSR1 might be selectively toxic to cells responsible for therapeutic resistance and tumor initiation. Our data show that KSR1, a molecular scaffold for the Raf/MEK/ERK signaling cascade, is critical for tumor initiation and clonogenicity, both in vitro and in vivo in the highly aggressive, metastatic and therapy resistant NeuroD1 subtype of SCLC. These findings shed light on a key distinct protein responsible for regulation in SCLC-N tumors, and a potential subtype specific therapeutic target.

SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status.

KRAS is the most commonly mutated oncogene. Targeted therapies have been developed against mediators of key downstream signaling pathways, predominantly components of the RAF/MEK/ERK kinase cascade. Unfortunately, single-agent efficacy of these agents is limited both by intrinsic and acquired resistance. Survival of drug-tolerant persister cells within the heterogeneous tumor population and/or acquired mutations that reactivate receptor tyrosine kinase (RTK)/RAS signaling can lead to outgrowth of tumor-initiating cells (TICs) and drive therapeutic resistance. Here, we show that targeting the key RTK/RAS pathway signaling intermediates SOS1 (Son of Sevenless 1) or KSR1 (Kinase Suppressor of RAS 1) both enhances the efficacy of, and prevents resistance to, the MEK inhibitor trametinib in KRAS-mutated lung (LUAD) and colorectal (COAD) adenocarcinoma cell lines depending on the specific mutational landscape. The SOS1 inhibitor BI-3406 enhanced the efficacy of trametinib and prevented trametinib resistance by targeting spheroid-initiating cells in KRASG12/G13-mutated LUAD and COAD cell lines that lacked PIK3CA comutations. Cell lines with KRASQ61 and/or PIK3CA mutations were insensitive to trametinib and BI-3406 combination therapy. In contrast, deletion of the RAF/MEK/ERK scaffold protein KSR1 prevented drug-induced SIC upregulation and restored trametinib sensitivity across all tested KRAS mutant cell lines in both PIK3CA-mutated and PIK3CA wild-type cancers. Our findings demonstrate that vertical inhibition of RTK/RAS signaling is an effective strategy to prevent therapeutic resistance in KRAS-mutated cancers, but therapeutic efficacy is dependent on both the specific KRAS mutant and underlying comutations. Thus, selection of optimal therapeutic combinations in KRAS-mutated cancers will require a detailed understanding of functional dependencies imposed by allele-specific KRAS mutations.

Association of digital measures and self-reported fatigue: a remote observational study in healthy participants and participants with chronic inflammatory rheumatic disease.

Background: Fatigue is a subjective, complex and multi-faceted phenomenon, commonly experienced as tiredness. However, pathological fatigue is a major debilitating symptom associated with overwhelming feelings of physical and mental exhaustion. It is a well-recognized manifestation in chronic inflammatory rheumatic diseases, such as Sjögren's Syndrome and Systemic Lupus Erythematosus and an important predictor of patient's health-related quality of life (HRQoL). Patient reported outcome questions are the key instruments to assess fatigue. To date, there is no consensus about reliable quantitative assessments of fatigue. Method: Observational data for a period of one month were collected from 296 participants in the United States. Data comprised continuous multimodal digital data from Fitbit, including heart rate, physical activity and sleep features, and app-based daily and weekly questions covering various HRQoL factors including pain, mood, general physical activity and fatigue. Descriptive statistics and hierarchical clustering of digital data were used to describe behavioural phenotypes. Gradient boosting classifiers were trained to classify participant-reported weekly fatigue and daily tiredness from multi-sensor and other participant-reported data, and extract a set of key predictive features. Results: Cluster analysis of Fitbit parameters highlighted multiple digital phenotypes, including sleep-affected, fatigued and healthy phenotypes. Features from participant-reported data and Fitbit data both contributed as key predictive features of weekly physical and mental fatigue and daily tiredness. Participant answers to pain and depressed mood-related daily questions contributed the most as top features for predicting physical and mental fatigue, respectively. To classify daily tiredness, participant answers to questions on pain, mood and ability to perform daily activities contributed the most. Features related to daily resting heart rate and step counts and bouts were overall the most important Fitbit features for the classification models. Conclusion: These results demonstrate that multimodal digital data can be used to quantitatively and more frequently augment pathological and non-pathological participant-reported fatigue.

PGC-1ß and ERRα Promote Glutamine Metabolism and Colorectal Cancer Survival via Transcriptional Upregulation of PCK2.

BACKGROUND: Previous studies have shown that Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Beta (PGC-1ß) and Estrogen-Related Receptor Alpha (ERRα) are over-expressed in colorectal cancer and promote tumor survival. METHODS: In this study, we use immunoprecipitation of epitope tagged endogenous PGC-1ß and inducible PGC-1ß mutants to show that amino acid motif LRELL on PGC-1ß is responsible for the physical interaction with ERRα and promotes ERRα mRNA and protein expression. We use RNAsequencing to determine the genes regulated by both PGC-1ß & ERRα and find that mitochondrial Phosphoenolpyruvate Carboxykinase 2 (PCK2) is the gene that decreased most significantly after depletion of both genes. RESULTS: Depletion of PCK2 in colorectal cancer cells was sufficient to reduce anchorage-independent growth and inhibit glutamine utilization by the TCA cycle. Lastly, shRNA-mediated depletion of ERRα decreased anchorage-independent growth and glutamine metabolism, which could not be rescued by plasmid derived expression of PCK2. DISCUSSION: These findings suggest that transcriptional control of PCK2 is one mechanism used by PGC-1ß and ERRα to promote glutamine metabolism and colorectal cancer cell survival.

Association of Serum Iron Studies in COVID Associated Mucormycosis with Stage of the Disease.

Mucormycosis (Zygomycosis) is a rare and lethal invasive fungal infection, often acute and extremely severe caused by opportunist and ubiquitous fungi belonging to the class Phygomycetes, subclass Zygomycetes, order Mucorales, family Mucoraceae. India has reported surge in cases of post COVID 19 Mucormycosis over the past few months due to the increasing frequency of risk factors like corticosteroid therapy, uncontrolled diabetes, DKA, neutropenia and iron overload. Patients with a history of COVID-19 infection are at increased risk of developing fungal infections like Mucormycosis. The emergence of COVID-19 associated mucormycosis (CAM) across several nations, particularly India, warrants a detailed study to identify potential contributing factors. MATERIAL: This cross sectional study conducted at Bowring and Lady Curzon Hospital, Bangalore, involving 75 subjects diagnosed with CAM either clinically, radiological or microbiologically. The objective was to study the clinical profile of patients with COVID associated Mucormycosis and to correlate the levels of Serum ferritin and iron profile with severity and extent of disease in COVID associated Mucormycosis patients Data was collected on demographic details, co morbidities, vaccination status, history of treatment with remedesvir, oxygen therapy or steroid use, complications of past COVID 19 infection and stage of current Mucormycosis infection. Clinical outcome of the patients measured based on Iron profile, length of hospital stay, need for ICU admission, presence of diabetic ketoacidosis and mortality. The blood investigations which included were CBC with differential leukocyte count, qCRP, FBS, PPBS, HbA1c serum iron studies and serum ferritin. OBSERVATION: The mean age of the subjects was 48.19 with 52 males, 23 females. Among 75 patients with CAM, 90.7% were unvaccinated against COVID-19, 62.7% had oxygen usage and steroid therapy, 44% had use of remedesvir. Most common co morbidity was diabetes mellitus 60% with 20% of patients having DKA. Rhino orbital-cerebral mucormycosis(Stage 4- 44.6%) was the most common clinical presentation. The mean serum iron (50.37) and TIBC (255.37) were significantly higher in Stage 4 CAM cases compared with less invasive stage 2 CAM cases. Patients with Stage 4 CAM had elevated levels of inflammatory markers LDH (292) DDimer (457) CRP(74.64). Case fatality rates of CAM was 12%. CONCLUSION: The results of this study revealed significant correlation between the clinical severity of CAM and higher mortality, increased serum iron levels and inflammatory markers in this population of patients. Therefore, patients with elevated levels of available serum iron are uniquely susceptible to mucormycosis infection, suggesting dysregulated iron metabolism in its pathogenesis.

KSR1- and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition.

The epithelial-to-mesenchymal transition (EMT) is considered a transcriptional process that induces a switch in cells from a polarized state to a migratory phenotype. Here, we show that KSR1 and ERK promote EMT-like phenotype through the preferential translation of Epithelial-Stromal Interaction 1 (EPSTI1), which is required to induce the switch from E- to N-cadherin and coordinate migratory and invasive behavior. EPSTI1 is overexpressed in human colorectal cancer (CRC) cells. Disruption of KSR1 or EPSTI1 significantly impairs cell migration and invasion in vitro, and reverses EMT-like phenotype, in part, by decreasing the expression of N-cadherin and the transcriptional repressors of E-cadherin expression, ZEB1 and Slug. In CRC cells lacking KSR1, ectopic EPSTI1 expression restored the E- to N-cadherin switch, migration, invasion, and anchorage-independent growth. KSR1-dependent induction of EMT-like phenotype via selective translation of mRNAs reveals its underappreciated role in remodeling the translational landscape of CRC cells to promote their migratory and invasive behavior.

The majority of cancer deaths result from tumor cells spreading to other parts of the body via a process known as metastasis. 90% of all cancers originate in epithelial cells that line the inner and outer surface of organs in our bodies. Epithelial cells, however, are typically stationary and must undergo various chemical and physical changes to transform in to migratory cells that can invade other tissues. This transformation process alters the amount of protein cells use to interact with one another. For example, epithelial cells from the colon produce less of a protein called E-cadherin as they transition into migrating cancer cells and make another protein called N-cadherin instead. A protein called KSR1 is a key component of a signaling pathway that is responsible for generating the proteins colon cancer cells need to survive. But it is unknown which proteins KSR1 helps synthesize and whether it plays a role in the metastasis of colon cancer cells. To investigate this, Rao et al. studied the proteins generated by cancerous colon cells cultured in the laboratory, in the presence and absence of KSR1. The experiment showed that KSR1 increases the levels of a protein called EPSTI1, which colon cancer cells need to transform into migratory cells. Depleting KSR1 caused cancer cells to generate less EPSTI1 and to share more features with healthy cells, such as higher levels of E-cadherin on their surface and reduced mobility. Adding EPSTI1 to the cancer cells that lacked KSR1 restored the traits associated with metastasis, such as high levels of N-cadherin, and allowed the cells to move more easily. These findings suggest that KSR1 and EPSTI1 could be new drug targets for reducing, or potentially reversing, the invasive behavior of colon cancer cells. However, further investigation is needed to reveal how EPSTI1 is generated and how this protein helps colon cancer cells move and invade other tissues.

Development and standardization of the DALI-DAB (dyslexia assessment for languages of India - dyslexia assessment battery).

A majority of Indian schoolchildren are biliterate in that they acquire literacy in at least two language systems, necessitating dyslexia assessment in both. The DALI-DAB assesses risk for dyslexia by evaluating reading ability and literacy-learning potential through a battery including literacy tests (letter and word reading, spelling, nonword reading, reading comprehension), and mediator skills (phonological awareness, processing automaticity and executive fluency, oral language) in multiple languages. DALI-DAB was developed in three languages - English, Hindi, and Marathi - and standardized on a sample of 1013 children. Reliability analyses revealed high internal consistency (α > 0.8) in most tests in all three languages. Low standard error of measurement values supported DALI-DAB score stability over repeated testing. Construct validity was variously reinforced through, (i) selection of culture-referenced, research-based tests, (ii) approval of test materials by schoolteachers (face validity) and (iii) grade-correlated performance increases on all DALI-DAB tests, besides robust correlations between (iv) literacy and mediator skill test scores (p < .001, concurrent validity), (v) equivalent tests across languages (p < .01, convergent validity), and (vi) DALI-DAB and WJ III ACH literacy scores (p < .01, criterion validity), in contrast to (vii) low correlation between DALI-DAB and WJ III ACH math scores (p > .05, discriminant validity). Overall, the DALI-DAB represents the first standardized dyslexia assessment tool for bilingual-biliterate children.

STEMI in Young Befogged by Aluminum Phosphide Toxicity-Role of ECMO as Salvage Therapy and Trimetazidine and Magnesium to Suppress Arrhythmias.

INTRODUCTION: Aluminum phosphide poisoning (ALP) has a high-mortality rate despite intensive care management, primarily because it causes severe myocardial depression. This case report highlights the subset of ALP patients presenting as ST elevation myocardial infarction (STEMI) with profound myocardial dysfunction and multiorgan failure and successfully treated with extracorporeal membrane oxygenation (ECMO), trimetazidine, and magnesium. CASE DESCRIPTION: A 25-year-old man without any comorbidities was brought to emergency department with dyspnea and hypotension. His electrocardiograph (ECG) revealed STEMI with elevated troponin levels, arterial blood gas (ABG) showed severe metabolic acidosis, and echocardiography (echo) revealed ejection fraction 15%. He was initiated on venoarterial (VA) ECMO in view of refractory hypotension. History of consumption of three tabs of celphos was revealed later by the family members. He progressed to cardiogenic shock, arrhythmias, respiratory failure, acute kidney injury with severe lactic acidosis, liver injury, pancreatitis, and disseminated intravascular coagulation (DIC). He was successfully supported by ECMO, hemodialysis, magnesium, trimetazidine, N-acetyl cysteine, inotropes, and blood products. He was weaned off ECMO on day 6 and was discharged home on day 12. Despite his severe and confounding clinical presentation, he had complete normalization of end-organ dysfunction with no neurological sequela. This case demonstrates the high index of suspicion required for ALP, given the potential for rapid progression and severe multiorgan toxicity. This report also highlights the importance of early referral to a tertiary care center with ECMO capability and also the role of magnesium and trimetazidine to suppress arrhythmias. CONCLUSION: Aluminum phosphide poisoning can present as STEMI with cardiogenic shock resulting in acute kidney injury, liver injury, pancreatitis, and DIC. Venoarterial ECMO provides an effective means of support until the recovery of organ function. Trimetazidine and magnesium are helpful in suppressing fatal arrhythmias. This report emphasizes that early recognition and early institution of ECMO can save many young lives who succumb to toxic effects of this poison. HOW TO CITE THIS ARTICLE: Rao CC, Himaaldev GJ. STEMI in Young Befogged by Aluminum Phosphide Toxicity-Role of ECMO as Salvage Therapy and Trimetazidine and Magnesium to Suppress Arrhythmias. Indian J Crit Care Med 2020;24(8):727-730.

A Gene Expression High-Throughput Screen (GE-HTS) for Coordinated Detection of Functionally Similar Effectors in Cancer.

Genome-wide, loss-of-function screening can be used to identify novel vulnerabilities upon which specific tumor cells depend for survival. Functional Signature Ontology (FUSION) is a gene expression-based high-throughput screening (GE-HTS) method that allows researchers to identify functionally similar proteins, small molecules, and microRNA mimics, revealing novel therapeutic targets. FUSION uses cell-based high-throughput screening and computational analysis to match gene expression signatures produced by natural products to those produced by small interfering RNA (siRNA) and synthetic microRNA libraries to identify putative protein targets and mechanisms of action (MoA) for several previously undescribed natural products. We have used FUSION to screen for functional analogues to Kinase suppressor of Ras 1 (KSR1), a scaffold protein downstream of Ras in the Raf-MEK-ERK kinase cascade, and biologically validated several proteins with functional similarity to KSR1. FUSION incorporates bioinformatics analysis that may offer higher resolution of the endpoint readout than other screens which utilize Boolean outputs regarding a single pathway activation (i.e., synthetic lethal and cell proliferation). Challenges associated with FUSION and other high-content genome-wide screens include variation, batch effects, and controlling for potential off-target effects. In this review, we discuss the efficacy of FUSION to identify novel inhibitors and oncogene-induced changes that may be cancer cell-specific as well as several potential pitfalls within FUSION and best practices to avoid them.

Geographical distribution of primary & secondary dengue cases in India - 2017: A cross-sectional multicentric study.

Background & objectives: Dengue virus infection is endemic in India with all the four serotypes of dengue virus in circulation. This study was aimed to determine the geographic distribution of the primary and secondary dengue cases in India. Methods: A multicentre cross-sectional study was conducted at Department of Health Research / Indian Council of Medical Research (DHR)/(ICMR) viral research and diagnostic laboratories (VRDLs) and selected ICMR institutes located in India. Only laboratory-confirmed dengue cases with date of onset of illness less than or equal to seven days were included between September and October 2017. Dengue NS1 antigen ELISA and anti-dengue IgM capture ELISA were used to diagnose dengue cases while anti-dengue IgG capture ELISA was used for identifying the secondary dengue cases. Results: Of the 1372 dengue cases, 897 (65%) were classified as primary dengue and 475 (35%) as secondary dengue cases. However, the proportion varied widely geographically, with Theni, Tamil Nadu; Tirupati, Andhra Pradesh and Udupi-Manipal, Karnataka reporting more than 65 per cent secondary dengue cases while Srinagar, Jammu and Kashmir reporting as low as 10 per cent of the same. The median age of primary dengue cases was 25 yr [interquartile range (IQR 17-35] while that of secondary dengue cases was 23 yr (IQR 13.5-34). Secondary dengue was around 50 per cent among the children belonging to the age group 6-10 yr while it ranged between 20-43 per cent among other age groups. Interpretation & conclusions: Our findings showed a wide geographical variation in the distribution of primary and secondary dengue cases in India. It would prove beneficial to include primary and secondary dengue differentiation protocol in the national dengue surveillance programme.

Modifying effects of δ-Aminolevulinate dehydratase polymorphism on blood lead levels and ALAD activity.

Lead is an environmental hazard with great public health concern and has been known to inhibit delta-aminolevulinate dehydratase (ALAD) activity involved in the heme biosynthetic pathway. The study aimed to investigate the influence of ALAD polymorphism (G177C) on retention of Pb-B levels and ALAD activity on occupationally exposed lead workers. In the present study, we enrolled 561 lead exposed and 317 non-occupationally exposed subjects and performed a comprehensive analysis of Pb-B levels along with ALAD activity and genotyping. The frequency of ALAD variants observed in the total subjects (n = 878) was 70.04% for ALAD 1-1, 27.44% for heterozygous ALAD 1-2 and 2.5% for homozygous mutant ALAD 2-2. Our study revealed that ALAD 1-2 carriers presented higher Pb-B levels compared to wild type ALAD 1-1 carriers. Further, a significant difference was observed in the activity of ALAD between ALAD 1-2/ 2-2 and ALAD 1-1 carriers of non-occupationally exposed group indicating that the polymorphic nature of the enzyme may contribute to altered activity of ALAD irrespective of lead exposure. Hence, ALAD 2 allele might contribute to increased susceptibility to high Pb-B retention, and genotyping of ALAD in lead exposed subjects might be used as a prediction marker to impede tissue/organ damage due to lead toxicity.

PTAP motif duplication in the p6 Gag protein confers a replication advantage on HIV-1 subtype C.

HIV-1 subtype C (HIV-1C) may duplicate longer amino acid stretches in the p6 Gag protein, leading to the creation of an additional Pro-Thr/Ser-Ala-Pro (PTAP) motif necessary for viral packaging. However, the biological significance of a duplication of the PTAP motif for HIV-1 replication and pathogenesis has not been experimentally validated. In a longitudinal study of two different clinical cohorts of select HIV-1 seropositive, drug-naive individuals from India, we found that 8 of 50 of these individuals harbored a mixed infection of viral strains discordant for the PTAP duplication. Conventional and next-generation sequencing of six primary viral quasispecies at multiple time points disclosed that in a mixed infection, the viral strains containing the PTAP duplication dominated the infection. The dominance of the double-PTAP viral strains over a genetically similar single-PTAP viral clone was confirmed in viral proliferation and pairwise competition assays. Of note, in the proximity ligation assay, double-PTAP Gag proteins exhibited a significantly enhanced interaction with the host protein tumor susceptibility gene 101 (Tsg101). Moreover, Tsg101 overexpression resulted in a biphasic effect on HIV-1C proliferation, an enhanced effect at low concentration and an inhibitory effect only at higher concentrations, unlike a uniformly inhibitory effect on subtype B strains. In summary, our results indicate that the duplication of the PTAP motif in the p6 Gag protein enhances the replication fitness of HIV-1C by engaging the Tsg101 host protein with a higher affinity. Our results have implications for HIV-1 pathogenesis, especially of HIV-1C.

Outcome of Patients Admitted to a Tertiary Referral Intensive Care Unit with Urosepsis Needing Source Control.

INTRODUCTION: Urosepsis is one of the common causes of admission to the Intensive Care Unit (ICU). It has traditionally been treated with antibiotics, but surgical management with Double J [DJ] ureteral stents is gaining popularity. This study compares patients with complicated urosepsis who underwent surgical source control by ureteral stenting with those managed medically. MATERIALS AND METHODS: The study enrolled patients admitted to a tertiary adult ICU with a diagnosis of urosepsis over a period of 2 years. The primary outcomes were renal replacement therapy (RRT) requirement and ICU mortality. The secondary outcomes were ICU and hospital length of stay, ventilator-free days, and inotrope free days. Patients were divided those with obstructive and nonobstructive urinary tract infection (UTI). RESULTS: A total of 58 patients met the criteria, of who 32 had obstructive UTI and were included in Group A, with the remaining 26 with nonobstructive UTI comprised Group B. In Group A, 27 patients underwent source control with ureteral DJ stenting, three patients recovered with medical management, and two who were advised source control did not consent to the procedure. Seventeen patients in Group A and seven patients in Group B required RRT (P = 0.044). There was no significant difference in ICU mortality, hospital mortality, and 28 days survival between the two groups. CONCLUSION: With early source control, obstructive UTI outcomes were comparable to nonobstructive UTI. However, despite undergoing ureteric stenting, more patients with obstructive UTI required RRT than those with nonobstructive UTI.

Bilinguals' Plausibility Judgments for Phrases with a Literal vs. Non-literal Meaning: The Influence of Language Brokering Experience.

Previous work has shown that prior experience in language brokering (informal translation) may facilitate the processing of meaning within and across language boundaries. The present investigation examined the influence of brokering on bilinguals' processing of two word collocations with either a literal or a figurative meaning in each language. Proficient Spanish-English bilinguals classified as brokers or non-brokers were asked to judge if adjective+noun phrases presented in each language made sense or not. Phrases with a literal meaning (e.g., stinging insect) were interspersed with phrases with a figurative meaning (e.g., stinging insult) and non-sensical phrases (e.g., stinging picnic). It was hypothesized that plausibility judgments would be facilitated for literal relative to figurative meanings in each language but that experience in language brokering would be associated with a more equivalent pattern of responding across languages. These predictions were confirmed. The findings add to the body of empirical work on individual differences in language processing in bilinguals associated with prior language brokering experience.

Morphology, orthography, and the two hemispheres: A divided visual field study with Hindi/Urdu biliterates.

Although identical on the spoken level, Hindi and Urdu differ markedly on the written level in terms of reading/writing direction and orthographic depth, with discernible processing consequences. The present study used a divided field paradigm to study the impact of writing system characteristics of Hindi and Urdu on word naming latencies in skilled biliterate users of these languages. Hindi (read/written from left to right) was hypothesized to show a larger right field advantage than Urdu (read/written from right to left); Hindi words sharing form overlap with primes were expected to show a significant priming effect in the left visual field, but a significant right field effect for morphologically-primed naming. Both these expectations were confirmed. An overall right field advantage was obtained for one syllable Hindi and Urdu words; two syllable Urdu words showed either no visual field differences or a left field advantage, and the right field advantage for Hindi was significantly greater for two syllable than one syllable words. Further, Hindi words showed significant form priming (relative to control stimuli) in the left visual field and significant morphological priming (relative to form priming) in the right visual field. By contrast, Urdu words showed no significant form priming in either visual field, and significantly greater morphological than form priming in the left visual field. These results are taken to suggest that visual field asymmetries in word naming are sensitive to differences in reading habit-related scanning biases and to orthographic depth-related differences in word recognition processes.

Visuospatial complexity modulates reading in the brain.

Neurocognitive processing of orthographic visuospatial complexity was examined through fMRI-based overt naming (n=16) of phonologically transparent, high and low frequency Hindi/Devanagari words that were visually simple (पालक, चातक) or complex (, चकली). Participants' overt behavior was modestly influenced by visuospatial complexity (accuracy: main effect p=.01, complexity×frequency interaction p<.07), while neuroimaging data revealed a robust effect of complexity (main effect FWE p<10(-4), complexity×frequency interaction FWE p<7×10(-8)). Interaction-based RoIs showed higher BOLD response in the VWFA to complex and left posterior temporal cortex to simple words, with greater right lingual de-activation to complex than simple words. Subtractions confirmed additional recruitment of VWFA, right frontal, inferior orbitofrontal, mid-temporal pole and left cerebellum by visuospatially complex over simple words. Finally, low frequency words activated bilateral occipital and putamen areas, left IPL, SPL, IFG and VWFA, suggesting that effortful phonological processing in alphasyllabic Hindi/Devanagari requires neural resources specialized for both visuospatially simple and complex orthographies.

Reading in Devanagari: Insights from functional neuroimaging.

OBJECTIVES: The current study used functional MRI (fMRI) to obtain a comprehensive understanding of the neural network underlying visual word recognition in Hindi/Devanagari, an alphasyllabic - partly alphabetic and partly syllabic Indian writing system on which little research has hitherto been carried out. MATERIALS AND METHODS: Sixteen (5F, 11M) neurologically healthy, native Hindi/Devanagari readers aged 21 to 50 named aloud 240 Devanagari words which were either visually linear - had no diacritics or consonant ligatures above or below central plane of text, e.g. फल, वाहन, or nonlinear - had at least one diacritic and/or ligature, e.g. फूल, किरण, and which further included 120 words each of high and low frequency. Words were presented in alternating high and low frequency blocks of 10 words each at 2s/word in a block design, with linear and nonlinear words in separate runs. Word reading accuracy was manually coded, while fMRI images were acquired on a 3T scanner with an 8-channel head-coil, using a T2*-weighted EPI sequence (TR/TE = 2s/35ms). RESULTS: After ensuring high word naming accuracy (M = 97.6%, SD = 2.3), fMRI data analyses (at FDR P < 0.005) revealed that reading Devanagari words elicited robust activations in bilateral occipito-temporal, inferior frontal and precentral regions as well as both cerebellar hemispheres. Other common areas of activation included left inferior parietal and right superior temporal cortices. Primary differences seen between nonlinear and linear word reading networks were in the right temporal areas and cerebellum. CONCLUSION: Distinct from alphabetic scripts, which are linear in their spatial organization, and recruit a primarily left-lateralized network for word reading, our results revealed a bilateral reading network for Devanagari. We attribute the additional activations in Devanagari to increased visual processing demands arising from the complex visuospatial arrangement of symbols in this ancient script.

'Cost in transliteration': the neurocognitive processing of Romanized writing.

Romanized transliteration is widely used in internet communication and global commerce, yet we know little about its behavioural and neural processing. Here, we show that Romanized text imposes a significant neurocognitive load. Readers faced greater difficulty in identifying concrete words written in Romanized transliteration (Romanagari) compared to L1 and L2. Functional neuroimaging revealed that the neural cost of processing transliterations arose from significantly greater recruitment of language (left precentral gyrus, left inferior parietal lobule) and attention networks (left mid-cingulum). Additionally, transliterated text uniquely activated attention and control areas compared to both L1 (cerebellar vermis) and L2 (pre-supplementary motor area/pre-SMA). We attribute the neural effort of reading Romanized transliteration to (i) effortful phonological retrieval from unfamiliar orthographic forms and (ii) conflicting attentional demands imposed by mapping orthographic forms of one language to phonological-semantic representations in another. Finally, significant brain-behaviour correlation suggests that the left mid-cingulum modulates cognitive-linguistic conflict.

The case of the neglected alphasyllabary: orthographic processing in Devanagari.

We applaud Ram Frost for highlighting the need for multicultural perspectives while developing universal models of visual word recognition. We second Frost's proposal that factors like lexical morphology should be incorporated besides purely orthographic features in modeling word recognition. In support, we provide fresh evidence from Hindi (written in Devanagari), an example of hitherto under-represented alphasyllabic orthographies, in which flexible encoding of aksara (character) position is constrained by the morphological structure of words.