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Papers by abhishek malhotra

Nucleic Acids Research, 2010

The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidat... more The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidative and electrophilic environmental stresses by circumventing repression by Keap1, translocating to the nucleus, and activating cytoprotective genes. Nrf2 responses provide protection against chemical carcinogenesis, chronic inflammation, neurodegeneration, emphysema, asthma and sepsis in murine models. Nrf2 regulates the expression of a plethora of genes that detoxify oxidants and electrophiles and repair or remove damaged macromolecules, such as through proteasomal processing. However, many direct targets of Nrf2 remain undefined. Here, mouse embryonic fibroblasts (MEF) with either constitutive nuclear accumulation (Keap1 À/À ) or depletion (Nrf2 À/À ) of Nrf2 were utilized to perform chromatin-immunoprecipitation with parallel sequencing (ChIP-Seq) and global transcription profiling. This unique Nrf2 ChIP-Seq dataset is highly enriched for Nrf2-binding motifs. Integrating ChIP-Seq and microarray analyses, we identified 645 basal and 654 inducible direct targets of Nrf2, with 244 genes at the intersection. Modulated pathways in stress response and cell proliferation distinguish the inducible and basal programs. Results were confirmed in an in vivo stress model of cigarette smoke-exposed mice. This study reveals global circuitry of the Nrf2 stress response emphasizing Nrf2 as a central node in cell survival response.

Nature, 2011

Rare copy number variants (CNVs) play a prominent role in the etiology of schizophrenia and other... more Rare copy number variants (CNVs) play a prominent role in the etiology of schizophrenia and other neuropsychiatric disorders 1 . Substantial risk for schizophrenia is conferred by large (>500 kb) CNVs at several loci, including microdeletions at 1q21.1 2 , 3q29 3 , 15q13.3 2 and 22q11.2 4 and microduplication at 16p11.2 5 . However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia (P= 4.0×10 -5 , OR = 16.14 [3.06, ∞]). Microduplications with variable breakpoints occurred within a 362 kb region and were detected in 29 of 8,290 (0.35%) patients versus two of 7,431 (0.03%) controls in the combined sample (p-value= 5.7×10-7, odds ratio (OR) = 14.1 [3.5, 123.9]). All duplications overlapped or were located within 89 kb upstream of the vasoactive intestinal peptide receptor VIPR2. VIPR2 transcription and cyclic-AMP signaling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered VIP signaling in the pathogenesis of schizophrenia and suggest VIPR2 as a potential target for the development of novel antipsychotic drugs.

Nature Genetics, 2009

1 2 2 3 l e t t e r s Recurrent microdeletions and microduplications of a 600-kb genomic region o... more 1 2 2 3 l e t t e r s Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders 1-3 . We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 × 10 −5 , OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 × 10 −7 ), bipolar disorder (P = 0.017) and autism (P = 1.9 × 10 −7 ). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 × 10 −13 ). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

Fundamental & Clinical Pharmacology, 2010

This study was conducted to determine the number and composition of the various cough and cold fo... more This study was conducted to determine the number and composition of the various cough and cold formulations available in the Indian market and to study their pharmacological rationale over a period of 7 years. Data for the study was collected from an annual Drug Compendium entitled ‘THE DRUG TODAY’ of the years 2001, 2004, and 2007. Medications were assessed for total number, different formulations, and number of constituents present in each formulation, their pharmacological group and amount of each constituent per dose. Rationality of available preparations was assessed on a seven-point scoring criteria. There are over thirteen hundred drug products for cough and cold in the Indian market, which is an increase of 71.2% from the year 2001. More than 90% of the preparations were fixed-dose combinations (FDCs). Majority of the cough and cold preparations had 3–4 constituents. Many preparations contained more than one constituent of the same pharmacological group. Some preparations had constituents with opposing action. A wide variation in the amount of each constituent present per dose in different formulations was observed. The number of banned drug combinations for cough and cold showed an increase from 9 in 2001 to 27 in 2007. Rationality assessment of the FDC preparations revealed that most of the preparations were irrational and had no documented benefit in the treatment of common cold. Availability of such a large number of irrational FDCs for cough and cold requires serious review of the legal provisions in India for drug manufacturing and marketing.

European Journal of Radiology Extra, 2010

Myocardial tuberculosis is a rare but well recognized disease entity. It can either remain clinic... more Myocardial tuberculosis is a rare but well recognized disease entity. It can either remain clinically silent or present in various different forms. The presentation of myocardial tuberculosis depends upon the structures involved by the disease process. We report a case of cardiac tuberculosis with pulmonary venous obstruction presenting with congestive cardiac failure.

India is a developing economy and we are moving ahead compared to other similar economies in rapi... more India is a developing economy and we are moving ahead compared to other similar economies in rapid speed. Communication is the key to growth and a mobile-phone is an essential part of this communication factor. This research paper focuses on the different purposes ...

As evidences have shown that electromagnetic phenomena associated with large earthquakes are cons... more As evidences have shown that electromagnetic phenomena associated with large earthquakes are considered to be most promising tools for earthquake studies.

The Environmentalist, 2007

Studies were carried out to determine the physiological response of few economically important tr... more Studies were carried out to determine the physiological response of few economically important tree species viz., Mango (Mangifera indica), Eucalyptus citriodora, Sagon (Tectona grandis) and Sal (Shorea robusta) to roadside automobile pollution during 2004–2005. By determining some physiological parameters, which included chlorophyll a, and b, total chlorophyll, carotenoids, ascorbic acid, pH and relative water content, impact of automobile exhaust on these species was assessed. The data obtained were further analyzed by using one-way ANOVA and a significant change in all these parameters was found in the leaf samples collected from road side trees, exposed to automobile exhausts in comparison to control. Higher value of air pollution tolerance index (APTI) was recorded for S. robusta (9.02) while the minimum value of APTI was recorded for M. indica (6.76).

Nucleic Acids Research, 2010

The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidat... more The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidative and electrophilic environmental stresses by circumventing repression by Keap1, translocating to the nucleus, and activating cytoprotective genes. Nrf2 responses provide protection against chemical carcinogenesis, chronic inflammation, neurodegeneration, emphysema, asthma and sepsis in murine models. Nrf2 regulates the expression of a plethora of genes that detoxify oxidants and electrophiles and repair or remove damaged macromolecules, such as through proteasomal processing. However, many direct targets of Nrf2 remain undefined. Here, mouse embryonic fibroblasts (MEF) with either constitutive nuclear accumulation (Keap1 À/À ) or depletion (Nrf2 À/À ) of Nrf2 were utilized to perform chromatin-immunoprecipitation with parallel sequencing (ChIP-Seq) and global transcription profiling. This unique Nrf2 ChIP-Seq dataset is highly enriched for Nrf2-binding motifs. Integrating ChIP-Seq and microarray analyses, we identified 645 basal and 654 inducible direct targets of Nrf2, with 244 genes at the intersection. Modulated pathways in stress response and cell proliferation distinguish the inducible and basal programs. Results were confirmed in an in vivo stress model of cigarette smoke-exposed mice. This study reveals global circuitry of the Nrf2 stress response emphasizing Nrf2 as a central node in cell survival response.

Nature, 2011

Rare copy number variants (CNVs) play a prominent role in the etiology of schizophrenia and other... more Rare copy number variants (CNVs) play a prominent role in the etiology of schizophrenia and other neuropsychiatric disorders 1 . Substantial risk for schizophrenia is conferred by large (>500 kb) CNVs at several loci, including microdeletions at 1q21.1 2 , 3q29 3 , 15q13.3 2 and 22q11.2 4 and microduplication at 16p11.2 5 . However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia (P= 4.0×10 -5 , OR = 16.14 [3.06, ∞]). Microduplications with variable breakpoints occurred within a 362 kb region and were detected in 29 of 8,290 (0.35%) patients versus two of 7,431 (0.03%) controls in the combined sample (p-value= 5.7×10-7, odds ratio (OR) = 14.1 [3.5, 123.9]). All duplications overlapped or were located within 89 kb upstream of the vasoactive intestinal peptide receptor VIPR2. VIPR2 transcription and cyclic-AMP signaling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered VIP signaling in the pathogenesis of schizophrenia and suggest VIPR2 as a potential target for the development of novel antipsychotic drugs.

Nature Genetics, 2009

1 2 2 3 l e t t e r s Recurrent microdeletions and microduplications of a 600-kb genomic region o... more 1 2 2 3 l e t t e r s Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders 1-3 . We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 × 10 −5 , OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 × 10 −7 ), bipolar disorder (P = 0.017) and autism (P = 1.9 × 10 −7 ). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 × 10 −13 ). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

Fundamental & Clinical Pharmacology, 2010

This study was conducted to determine the number and composition of the various cough and cold fo... more This study was conducted to determine the number and composition of the various cough and cold formulations available in the Indian market and to study their pharmacological rationale over a period of 7 years. Data for the study was collected from an annual Drug Compendium entitled ‘THE DRUG TODAY’ of the years 2001, 2004, and 2007. Medications were assessed for total number, different formulations, and number of constituents present in each formulation, their pharmacological group and amount of each constituent per dose. Rationality of available preparations was assessed on a seven-point scoring criteria. There are over thirteen hundred drug products for cough and cold in the Indian market, which is an increase of 71.2% from the year 2001. More than 90% of the preparations were fixed-dose combinations (FDCs). Majority of the cough and cold preparations had 3–4 constituents. Many preparations contained more than one constituent of the same pharmacological group. Some preparations had constituents with opposing action. A wide variation in the amount of each constituent present per dose in different formulations was observed. The number of banned drug combinations for cough and cold showed an increase from 9 in 2001 to 27 in 2007. Rationality assessment of the FDC preparations revealed that most of the preparations were irrational and had no documented benefit in the treatment of common cold. Availability of such a large number of irrational FDCs for cough and cold requires serious review of the legal provisions in India for drug manufacturing and marketing.

European Journal of Radiology Extra, 2010

Myocardial tuberculosis is a rare but well recognized disease entity. It can either remain clinic... more Myocardial tuberculosis is a rare but well recognized disease entity. It can either remain clinically silent or present in various different forms. The presentation of myocardial tuberculosis depends upon the structures involved by the disease process. We report a case of cardiac tuberculosis with pulmonary venous obstruction presenting with congestive cardiac failure.

India is a developing economy and we are moving ahead compared to other similar economies in rapi... more India is a developing economy and we are moving ahead compared to other similar economies in rapid speed. Communication is the key to growth and a mobile-phone is an essential part of this communication factor. This research paper focuses on the different purposes ...

As evidences have shown that electromagnetic phenomena associated with large earthquakes are cons... more As evidences have shown that electromagnetic phenomena associated with large earthquakes are considered to be most promising tools for earthquake studies.

The Environmentalist, 2007

Studies were carried out to determine the physiological response of few economically important tr... more Studies were carried out to determine the physiological response of few economically important tree species viz., Mango (Mangifera indica), Eucalyptus citriodora, Sagon (Tectona grandis) and Sal (Shorea robusta) to roadside automobile pollution during 2004–2005. By determining some physiological parameters, which included chlorophyll a, and b, total chlorophyll, carotenoids, ascorbic acid, pH and relative water content, impact of automobile exhaust on these species was assessed. The data obtained were further analyzed by using one-way ANOVA and a significant change in all these parameters was found in the leaf samples collected from road side trees, exposed to automobile exhausts in comparison to control. Higher value of air pollution tolerance index (APTI) was recorded for S. robusta (9.02) while the minimum value of APTI was recorded for M. indica (6.76).