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Psychological perspectives on diversity and social development
This book is a collection of essays covering a range of issues related to socioeconomic inequalities and diversities. The authors, leading social scientists of diverse nationalities, represent varied perspectives. The book has essays on multiculturalism, social inclusion and exclusion of minorities and other marginalized groups such as low castes, linguistic minorities, Adivasis (tribals), persons with disability and unemployed youth. The book focuses on some innovative concepts considered necessary to understand the very process and evolution of aspects of social development such as pro-sociality, authentic responsible self and leadership ideology. The book deals with the challenges for achieving social development and societal harmony. The book will be a very useful resource for social science scholars and particularly for social and cultural psychologists, development professionals and administrators interested in the issues related to social development, social diversity and inter-group relations. The book will also be useful for policy formulation and action.
Book
Understanding and managing acute encephalitis version 1; peer review: awaiting peer review
Encephalitis is an important cause of morbidity, mortality, and permanent neurologic sequelae globally. Causes are diverse and include viral and non-viral infections of the brain as well as autoimmune processes. In the West, the autoimmune encephalitides are now more common than any single infectious cause, but, in Asia, infectious causes are still more common. In 2006, the World Health Organization coined the term \"acute encephalitis syndrome\", which simply means acute onset of fever with convulsions or altered consciousness or both. In 2013, the International Encephalitis Consortium set criteria for diagnosis of encephalitis on basis of clinical and laboratory features.
The most important infectious cause in the West is herpes simplex virus, but globally Japanese encephalitis (JE) remains the single largest cause. Etiologic diagnosis is difficult because of the large number of agents that can cause encephalitis. Also, the responsible virus may be detectable only in the brain and is either absent or transiently found in blood or cerebrospinal fluid (CSF). Virological diagnosis is complex, expensive, and time-consuming. Different centres could make their own algorithms for investigation in accordance with the local etiologic scenarios. Magnetic resonance imaging (MRI) and electroencephalography are specific for few agents. Clinically, severity may vary widely. A severe case may manifest with fever, convulsions, coma, neurologic deficits, and death.
Autoimmune encephalitis (AIE) includes two major categories: (i) classic paraneoplastic limbic encephalitis (LE) with autoantibodies against intracellular neuronal antigens (Eg: Hu and Ma2) and (ii) new-type AIE with autoantibodies to neuronal surface or synaptic antigens (Eg: anti-N-methyl-D-aspartate receptor). AIE has prominent psychiatric manifestations: psychosis, aggression, mutism, memory loss, euphoria, or fear. Seizures, cognitive decline, coma, and abnormal movements are common. Symptoms may fluctuate rapidly.
Treatment is largely supportive. Specific treatment is available for herpesvirus group and non-viral infections. Various forms of immunotherapy are used for AIE.
Journal Article
MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis
Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS–STING-mediated signalling and tumour suppression
1
–
3
. However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA)
4
–
10
. Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation. We demonstrate that binding of the MRE11–RAD50–NBN complex to nucleosome fragments is necessary to displace cGAS from acidic-patch-mediated sequestration, which enables its mobilization and activation by dsDNA. MRE11 is therefore essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA and ionizing radiation. Furthermore, MRE11-dependent cGAS activation promotes ZBP1–RIPK3–MLKL-mediated necroptosis, which is essential to suppress oncogenic proliferation and breast tumorigenesis. Notably, downregulation of
ZBP1
in human triple-negative breast cancer is associated with increased genome instability, immune suppression and poor patient prognosis. These findings establish MRE11 as a crucial mediator that links DNA damage and cGAS activation, resulting in tumour suppression through ZBP1-dependent necroptosis.
The double-strand break sensor MRE11 is identified as a pivotal mediator of cGAS activation in response to multiple types of DNA damage.
Journal Article
Genetic determinants of cellular addiction to DNA polymerase theta
Polymerase theta (Pol θ, gene name
Polq
) is a widely conserved DNA polymerase that mediates a microhomology-mediated, error-prone, double strand break (DSB) repair pathway, referred to as Theta Mediated End Joining (TMEJ). Cells with homologous recombination deficiency are reliant on TMEJ for DSB repair. It is unknown whether deficiencies in other components of the DNA damage response (DDR) also result in Pol θ addiction. Here we use a CRISPR genetic screen to uncover 140
Polq
synthetic lethal (PolqSL) genes, the majority of which were previously unknown. Functional analyses indicate that Pol θ/TMEJ addiction is associated with increased levels of replication-associated DSBs, regardless of the initial source of damage. We further demonstrate that approximately 30% of TCGA breast cancers have genetic alterations in PolqSL genes and exhibit genomic scars of Pol θ/TMEJ hyperactivity, thereby substantially expanding the subset of human cancers for which Pol θ inhibition represents a promising therapeutic strategy.
Polymerase theta is a widely conserved DNA polymerase that mediates Theta Mediated End Joining. Here authors present a synthetic lethal CRISPR screen to identify DDR gene mutations that induce cellular addiction to Pol theta.
Journal Article
Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration
Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson’s disease, Huntington’s disease and Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) and complex II (CII) by toxins 1-methyl-4-phenylpyridinium (MPP
+
) and 3-nitropropionic acid (3-NPA) respectively, induced degenerative changes noted in such neurodegenerative diseases. We aimed to unravel the down-stream pathways associated with CII inhibition and compared with CI inhibition and the Manganese (Mn) neurotoxicity. Genome-wide transcriptomics of N27 neuronal cells exposed to 3-NPA, compared with MPP
+
and Mn revealed varied transcriptomic profile. Along with mitochondrial and synaptic pathways, Autophagy was the predominant pathway differentially regulated in the 3-NPA model with implications for neuronal survival. This pathway was unique to 3-NPA, as substantiated by in silico modelling of the three toxins. Morphological and biochemical validation of autophagy markers in the cell model of 3-NPA revealed incomplete autophagy mediated by mechanistic Target of Rapamycin Complex 2 (mTORC2) pathway. Interestingly, Brain Derived Neurotrophic Factor (BDNF), which was elevated in the 3-NPA model could confer neuroprotection against 3-NPA. We propose that, different downstream events are activated upon neurotoxin-dependent CII inhibition compared to other neurotoxins, with implications for movement disorders and regulation of autophagy could potentially offer neuroprotection.
Journal Article
Evidence that the human cell cycle is a series of uncoupled, memoryless phases
The cell cycle is canonically described as a series of four consecutive phases: G1, S, G2, and M. In single cells, the duration of each phase varies, but the quantitative laws that govern phase durations are not well understood. Using time‐lapse microscopy, we found that each phase duration follows an Erlang distribution and is statistically independent from other phases. We challenged this observation by perturbing phase durations through oncogene activation, inhibition of DNA synthesis, reduced temperature, and DNA damage. Despite large changes in durations in cell populations, phase durations remained uncoupled in individual cells. These results suggested that the independence of phase durations may arise from a large number of molecular factors that each exerts a minor influence on the rate of cell cycle progression. We tested this model by experimentally forcing phase coupling through inhibition of cyclin‐dependent kinase 2 (CDK2) or overexpression of cyclin D. Our work provides an explanation for the historical observation that phase durations are both inherited and independent and suggests how cell cycle progression may be altered in disease states.
Synopsis
Time‐lapse imaging of cell‐cycle phase transitions reveals that phase durations are uncoupled and can be modeled as an Erlang process. Phase coupling can be forced by perturbing a strong cell‐cycle regulator acting on multiple phases.
Cell‐cycle phase durations are uncoupled in three human cell lines.
Each cell‐cycle phase proceeds like a sequence of memoryless steps that can be modeled as an Erlang process.
A “many‐for‐all model”, in which large number of factors each exerting minor influence on phase duration, explains the stochastic but heritable nature of cell cycle progression.
Coupling between cell‐cycle phases can be introduced by perturbing a cell‐cycle regulator of multiple phases.
Graphical Abstract
Time‐lapse imaging of cell‐cycle phase transitions reveals that phase durations are uncoupled and can be modeled as an Erlang process. Phase coupling can be forced by perturbing a strong cell‐cycle regulator acting on multiple phases. This article has been featured on the
April cover
of the journal.
Journal Article
Could the shaking of infants in early childhood be a leading source of unexplained intellectual disability in India?
Background
Data from India and other low and middle-income countries reveal high rates of parent-reported shaking of infants. Very high rates of developmental disability have been reported in India. The convergence of these observations provides an opportunity to understand the nature and consequences of a potentially harmful child discipline practice.
Objective
To study whether caregiver shaking of an infant, even shaking insufficient to lead to an acute medical encounter, is associated with subsequent intellectual disability (ID).
Methods
We conducted a matched case-control study at an academic medical center in Lucknow, India. We compared 75 children with ID of unknown etiology to 75 control children aged 24–72 months, matched by age, gender, maternal age, and maternal education. All children received a neurological evaluation and were IQ and lead tested. We questioned parents about early discipline practices, including shaking. If parents reported shaking, we asked them to demonstrate using a shaken baby simulator. We examined the association between ID and shaking using conditional logistic regression.
Results
Children’s median age was 43.4 (IQR: 25.1) months; 64% were boys. 24% of all study children were reported shaken before 24 months: 38.% of the case children and 9% of the controls. The adjusted odds of reported shaking of children with ID, before age 24 months, is 8.3 (95% CI: 2.4, 28.2) times higher than controls.
Conclusion
Shaking children < 2 years of age in northern India is common; a strong association exists between early shaking and unexplained intellectual disability. Possibly contributing to intellectual disability, the role of infant shaking needs to be explored further.
Journal Article
Bone marrow lympho-myeloid malfunction in obesity requires precursor cell-autonomous TLR4
Obesity, a prevalent condition in adults and children, impairs bone marrow (BM) function. However, the underlying mechanisms are unclear. Here, we show that obese mice exhibit poor emergency immune responses in a toll-like receptor 4 (TLR4)-dependent manner. Canonical myeloid genes (
Csf1r
,
Spi1
,
Runx1
) are enhanced, and lymphoid genes (
Flt3
,
Tcf3
,
Ebf1
) are reduced. Using adoptive transfer and mixed BM chimera approaches we demonstrate that myeloid>lymphoid bias arises after 6 weeks of high-fat diet and depends on precursor cell-autonomous TLR4. Further, lean mice exposed to the TLR4 ligand lipopolysaccharide (LPS) at doses similar to that detectable in obese serum recapitulates BM lympho-myeloid alterations. Together, these results establish a mechanistic contribution of BM cell-intrinsic TLR4 to obesity-driven BM malfunction and demonstrate the importance of LPS. Our findings raises important questions about the impact of maternal obesity and endotoxemia to fetal hematopoiesis, as fetal immune precursors are also sensitive to TLR4 signals.
Obesity can affect bone marrow cell differentiation and the generation of myeloid and lymphoid cells. Here, the authors show that diet and obesity, as well as low-dose lipopolysaccharide, can alter Toll-like receptor 4 signaling bone marrow cells to skew the myeloid-lymphoid homeostasis in mice.
Journal Article
Prevalence of rotavirus infection among children with acute diarrhoea after rotavirus vaccine introduction in Kenya, a hospital cross-sectional study
Background
Rotavirus infection is the most common cause of acute gastroenteritis globally in children under 5 years of age and is responsible for approximately 5% of all child deaths yearly. Rotavirus vaccination is considered an effective public health strategy to prevent infection and reduce the severity of disease. Multi-centre country trials on rotavirus vaccines demonstrated efficacy rates of more than 85% in developed countries but only about 65% in developing nations. Rotavirus vaccination was introduced into the Kenya Expanded Programme on Immunization (KEPI) in 2014. The objective of our study was to determine the prevalence of rotavirus infection, severity of acute diarrhoea and to determine the rotavirus vaccination status among children aged 3–24 months presenting with acute diarrhoea at Kenyatta National Hospital after introduction of rotavirus vaccine in Kenya.
Methods
A total of 365 children aged 3–24 months presenting with acute diarrhoea at KNH were recruited from August 2016 to April 2017. Data on rotavirus vaccination status, nutritional status, feeding practices and sociodemographic characteristics were obtained and a full clinical evaluation of the patients was done. Severity of the gastroenteritis was assessed using the 20 point Vesikari Clinical Severity Scoring System. The children who were admitted were followed up for 7 days using hospital ward registers. Comorbid conditions were established from patient’s clinical records and physical examination. Stool specimens from study participants were tested for rotavirus using a commercially available enzyme linked immunosorbent immunoassay kit- ProSpecT Rotavirus Microplate Assay.
Results
Majority of the children (96.7%) had received rotavirus vaccinations. The overall rotavirus prevalence was 14.5% and was higher among 17–24 months at 19.5%. The prevalence somewhat differed by gender, nutritional status, exclusive breastfeeding status, age and education level of mother/caregiver. Overall, a half of the children had severe acute diarrhoea and there were some differences in severity by child/mother characteristics.
Conclusion
There is still burden of rotavirus diarrhoea after introduction of rotavirus vaccine and the prevalence varies by child characteristics.
Journal Article
Consistency and quality in written accreditation protocols for pediatrician training programs: a mixed-methods analysis of a global sample, and directions for improvement
Background
The World Federation for Medical Education (WFME) defines accreditation as 'certification of the suitability of medical education programs, and of…competence…in the delivery of medical education.' Accreditation bodies function at national, regional and global levels. In 2015, WFME published quality standards for accreditation of postgraduate medical education (PGME). We compared accreditation of pediatric PGME programs to these standards to understand variability in accreditation and areas for improvement.
Methods
We examined 19 accreditation protocols representing all country income levels and world regions. For each, two raters assessed 36 WFME-defined accreditation sub-areas as present, partially present, or absent. When rating “partially present” or “absent”, raters noted the rationale for the rating. Using an inductive approach, authors qualitatively analyzed notes, generating themes in reasons for divergence from the benchmark.
Results
A median of 56% (IQR 43–77%) of WFME sub-areas were present in individual protocols; 22% (IQR 15–39%) were partially present; and 8.3% (IQR 5.5–21%) were absent. Inter-rater agreement was 74% (SD 11%). Sub-areas least addressed included number of trainees, educational expertise, and performance of qualified doctors. Qualitative themes of divergence included (1) variation in protocols related to heterogeneity in program structure; (2) limited engagement with stakeholders, especially regarding educational outcomes and community/health system needs; (3) a trainee-centered approach, including equity considerations, was not universal; and (4) less emphasis on quality of education, particularly faculty development in teaching.
Conclusions
Heterogeneity in accreditation can be appropriate, considering cultural or regulatory context. However, we identified broadly applicable areas for improvement: ensuring equitable access to training, taking a trainee-centered approach, emphasizing quality of teaching, and ensuring diverse stakeholder feedback.
Journal Article