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Article ; Online: Tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] analogues with bactericidal efficacy against Mycobacterium tuberculosis targeting MmpL3.

Remuiñán, Modesto J / Pérez-Herrán, Esther / Rullás, Joaquín / Alemparte, Carlos / Martínez-Hoyos, María / Dow, David J / Afari, Johnson / Mehta, Nalini / Esquivias, Jorge / Jiménez, Elena / Ortega-Muro, Fátima / Fraile-Gabaldón, María Teresa / Spivey, Vickey L / Loman, Nicholas J / Pallen, Mark J / Constantinidou, Chrystala / Minick, Douglas J / Cacho, Mónica / Rebollo-López, María José /

González, Carolina / Sousa, Verónica / Angulo-Barturen, Iñigo / Mendoza-Losana, Alfonso / Barros, David / Besra, Gurdyal S / Ballell, Lluís / Cammack, Nicholas

PloS one

2013 Volume 8, Issue 4, Page(s) e60933

Abstract: ... tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-6' ...

Abstract	Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] (Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This 'genetic phenotype' was further confirmed by a 'chemical phenotype', whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice.
MeSH term(s)	Animals ; Antitubercular Agents/chemistry ; Antitubercular Agents/pharmacokinetics ; Antitubercular Agents/pharmacology ; Antitubercular Agents/therapeutic use ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/metabolism ; Bridged Bicyclo Compounds, Heterocyclic/chemistry ; Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Chromatography, Thin Layer ; Cord Factors ; Disease Models, Animal ; Dogs ; Drug Resistance, Bacterial ; Genotype ; Hep G2 Cells ; Humans ; Kinetics ; Mice ; Microbial Sensitivity Tests ; Microbial Viability/drug effects ; Mutation/genetics ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/isolation & purification ; Pyrazoles/chemistry ; Pyrazoles/pharmacokinetics ; Pyrazoles/pharmacology ; Pyrazoles/therapeutic use ; Rats ; Spiro Compounds/chemistry ; Spiro Compounds/pharmacokinetics ; Spiro Compounds/pharmacology ; Spiro Compounds/therapeutic use ; Treatment Outcome ; Tuberculosis/drug therapy ; Tuberculosis/microbiology
Chemical Substances	Antitubercular Agents ; Bacterial Proteins ; Bridged Bicyclo Compounds, Heterocyclic ; Cord Factors ; Pyrazoles ; Spiro Compounds ; trehalose monomycolate
Language	English
Publishing date	2013-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0060933
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Article ; Online: Mentorship in adolescence and subsequent depression and adiposity among child maltreatment survivors in a United States nationally representative sample.

Cammack, Alison L / Suglia, Shakira F

Preventive medicine

2022 Volume 166, Page(s) 107339

Abstract: ... neglect; N = 3364), we examined associations between mentorship during adolescence and body mass index ...

Abstract	Child maltreatment (CM) is associated with multiple adverse health outcomes. Hence, there is a great need to identify factors that promote resilience in CM survivors. Mentorship may promote positive coping in CM survivors, but this may vary by health outcome and mentor/mentee characteristics. Among participants in a United States nationally representative sample, the National Longitudinal Study of Adolescent to Adult Health, who retrospectively reported any CM before age 18 (sexual, emotional or physical, abuse or neglect; N = 3364), we examined associations between mentorship during adolescence and body mass index (BMI), obesity, and depressive symptoms at ages 24-32 (in 2008-2009). We utilized linear regression and predictive margins with complex sample weighting. Models were stratified by sex and race/ethnicity. Thirty-one percent and 40% of participants' most influential mentor was inside and outside the family, respectively, and 29% reported no mentor. Any mentorship was associated with decreased depressive symptoms in females (adjusted beta for any mentor = -0.78, 95% CI:-1.54,-0.02). By contrast, any mentorship was associated with increased adiposity, namely among Latinas (adjusted beta for BMI = 2.23, 95% CI:0.45,4.02, adjusted risk ratio for obesity = 1.42, 95% CI:1.03,1.97). The influence of mentorship in CM survivors is heterogeneous. While mentorship was associated with reduced psychopathology, it was also linked with worse physical health, underscoring that mentoring does not necessarily promote long-term resilience to physical health outcomes, particularly in minorities. A better understanding of how mentors influence specific mentee behaviors may be important in informing how mentors can promote better physical health and lower obesity risk among CM survivors.
MeSH term(s)	Adolescent ; Adult ; Female ; Humans ; Young Adult ; Adiposity ; Depression/epidemiology ; Longitudinal Studies ; Mentors ; Obesity/epidemiology ; Retrospective Studies ; United States/epidemiology ; Adult Survivors of Child Abuse/psychology ; Adult Survivors of Child Abuse/statistics & numerical data
Language	English
Publishing date	2022-11-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	184600-0
ISSN	1096-0260 ; 0091-7435
ISSN (online)	1096-0260
ISSN	0091-7435
DOI	10.1016/j.ypmed.2022.107339
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Zs.A 878: Show issues

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Article: Activity of the isolated HIV RNase H domain and specific inhibition by N-hydroxyimides.

Hang, Julie Qi / Rajendran, Surendran / Yang, Yanli / Li, Yu / In, Philippe Wong Kai / Overton, Hilary / Parkes, Kevin E B / Cammack, Nick / Martin, Joseph A / Klumpp, Klaus

Biochemical and biophysical research communications

2004 Volume 317, Issue 2, Page(s) 321–329

Abstract: ... functional role of the C-terminal alpha-helix. A prototype N-hydroxyimide (2-hydroxy-4H-isoquinoline-1,3 ... the structurally closely related Escherichia coli RNase HI. Specific binding of N-hydroxyimide compounds ...

Abstract	This report describes a procedure to generate enzymatically active, isolated HIV RNase H domain. In contrast to previously described preparations, the RNA cleavage activity of the untagged RNase H domain was surprisingly similar to that of the full-length HIV-RT protein. Signature cleavages at 18 and 9 nucleotides downstream of a recessed RNA 5'-end were retained with the isolated RNase H domain. Activity was strongly decreased by deletion of 3 amino acids from the C-terminus, consistent with an important structural or functional role of the C-terminal alpha-helix. A prototype N-hydroxyimide (2-hydroxy-4H-isoquinoline-1,3-dione) was found to inhibit the activity of the isolated HIV RNase H domain as well as the RNase H activity of full-length HIV reverse transcriptase. In contrast, the compound did not significantly inhibit the structurally closely related Escherichia coli RNase HI. Specific binding of N-hydroxyimide compounds to the isolated RNase H domain was observed by protein fluorescence quenching.
MeSH term(s)	Amino Acid Substitution ; Binding Sites ; Enzyme Activation ; Enzyme Inhibitors/chemistry ; HIV Reverse Transcriptase/biosynthesis ; HIV Reverse Transcriptase/chemistry ; HIV Reverse Transcriptase/genetics ; HIV-1/enzymology ; HIV-1/genetics ; Hydrolysis ; Imides/chemistry ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry ; Ribonuclease H/biosynthesis ; Ribonuclease H/chemistry ; Ribonuclease H/genetics ; Ribonuclease H/isolation & purification ; Sensitivity and Specificity ; Structure-Activity Relationship ; Substrate Specificity
Chemical Substances	Enzyme Inhibitors ; Imides ; Recombinant Proteins ; HIV Reverse Transcriptase (EC 2.7.7.49) ; Ribonuclease H (EC 3.1.26.4)
Language	English
Publishing date	2004-04-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2004.03.061
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Zs.A 116: Show issues

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Article ; Online: Microbiology. Exploiting malaria drug resistance to our advantage.

Cammack, Nick

Science (New York, N.Y.)

2011 Volume 333, Issue 6043, Page(s) 705–706

MeSH term(s)	Antimalarials/pharmacology ; Biological Evolution ; Drug Combinations ; Drug Resistance/genetics ; Genes, Protozoan ; Genetic Linkage ; Genome, Protozoan ; Genome-Wide Association Study ; High-Throughput Screening Assays ; Parasitic Sensitivity Tests ; Plasmodium falciparum/drug effects ; Plasmodium falciparum/genetics ; Plasmodium falciparum/growth & development ; Plasmodium falciparum/metabolism
Chemical Substances	Antimalarials ; Drug Combinations
Language	English
Publishing date	2011-08-05
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.1210875
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Zs.A 27: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 77: Show issues

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Article: The inhibition of plant mitochondrial respiration by the synthetic analog of ubiquinone, 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole (UHDBT).

Cook, N D / Cammack, R

Archives of biochemistry and biophysics

1985 Volume 240, Issue 1, Page(s) 9–14

Abstract: The quinone analog, 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole (UHDBT), has been shown to inhibit ...

Abstract	The quinone analog, 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole (UHDBT), has been shown to inhibit cyanide-sensitive and cyanide-insensitive respiration in higher plant mitochondria. The inhibition is dependent upon the concentration of mitochondrial protein. The low concentrations of UHDBT required to inhibit the cyanide-sensitive pathway (microM) and the cyanide-insensitive pathway (nM) indicate that UHDBT is acting as a tight-binding inhibitor of ubiquinol oxidation. Inhibition of both pathways was dependent upon pH. It is shown that UHDBT appears to be a less potent inhibitor of cyanide-sensitive NADH oxidation than of cyanide-sensitive succinate oxidation, and that the pH dependence of inhibition of these two pathways differs. The inhibition of NADH and succinate oxidation by the cyanide-insensitive pathway shows similar pH dependences although at a given pH NADH oxidation is more susceptible to inhibition than succinate oxidation.
MeSH term(s)	Cyanides/pharmacology ; Mitochondria/drug effects ; Mitochondria/metabolism ; NAD/metabolism ; Oxygen Consumption/drug effects ; Plants/drug effects ; Plants/metabolism ; Succinates/metabolism ; Succinic Acid ; Thiazoles/pharmacology
Chemical Substances	5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole ; Cyanides ; Succinates ; Thiazoles ; NAD (0U46U6E8UK) ; Succinic Acid (AB6MNQ6J6L)
Language	English
Publishing date	1985-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/0003-9861(85)90002-5
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Uc I Zs.237: Show issues

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Article ; Online: Tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] analogues with bactericidal efficacy against Mycobacterium tuberculosis targeting MmpL3.

Modesto J Remuiñán / Esther Pérez-Herrán / Joaquín Rullás / Carlos Alemparte / María Martínez-Hoyos / David J Dow / Johnson Afari / Nalini Mehta / Jorge Esquivias / Elena Jiménez / Fátima Ortega-Muro / María Teresa Fraile-Gabaldón / Vickey L Spivey / Nicholas J Loman / Mark J Pallen / Chrystala Constantinidou / Douglas J Minick / Mónica Cacho / María José Rebollo-López /

Carolina González / Verónica Sousa / Iñigo Angulo-Barturen / Alfonso Mendoza-Losana / David Barros / Gurdyal S Besra / Lluís Ballell / Nicholas Cammack

PLoS ONE, Vol 8, Iss 4, p e

2013 Volume 60933

Abstract: ... tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-6' ...

Abstract	Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] (Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This 'genetic phenotype' was further confirmed by a 'chemical phenotype', whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Air Embolism Caused by Mesenteric Ischemia.

Ishii, Natsuko / Cammack, Ivor / Matsuzaka, Suguru

Internal medicine (Tokyo, Japan)

2019 Volume 59, Issue 5, Page(s) 749–751

Language	English
Publishing date	2019-11-08
Publishing country	Japan
Document type	Journal Article
ZDB-ID	32371-8
ISSN	1349-7235 ; 0021-5120 ; 0918-2918
ISSN (online)	1349-7235
ISSN	0021-5120 ; 0918-2918
DOI	10.2169/internalmedicine.3396-19
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Zs.A 240: Show issues

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Article: Retrospectively self-reported age of childhood abuse onset in a United States nationally representative sample.

Cammack, Alison L / Hogue, Carol J

Injury epidemiology

2017 Volume 4, Issue 1, Page(s) 7

Abstract: ... Longitudinal Study of Adolescent Health to Adult Health (N = 14,776) to describe distributions of retrospectively ...

Abstract	Background: Child abuse is common and several studies have linked it to health outcomes throughout the lifecourse. Recent information about timing of abuse reported retrospectively is underrepresented in the literature, despite its importance to informing target populations for primary prevention of child abuse and studying effects of child abuse. This study uses data from Wave IV (2008-2009) of The National Longitudinal Study of Adolescent Health to Adult Health (N = 14,776) to describe distributions of retrospectively self-reported age of onset of childhood emotional, physical, and sexual abuse perpetrated by parents/adult caregivers and sexual abuse perpetrated by other individuals. Information on childhood abuse history was collected when participants were between 24 and 32 years old. Findings: Parental/adult caregiver perpetrated abuse frequently started in early childhood, particularly sexual abuse. Non-parental/adult caregiver sexual abuse motivated by physical force also started early in boys (median age = 7.21 years (95% CI: 5.92, 9.05)). Earlier onset of some types of abuse was associated with male sex, not being raised by both biological parents, and low childhood household income. Conclusions: Future studies should further examine timing of childhood abuse onset and include diverse measures of abuse, including those derived from longitudinal studies and validated reports. If these results are replicated, they suggest that abuse, particularly sexual abuse perpetrated by parents/adult caregivers, often starts in early childhood, and preventive interventions should be designed to protect younger children.
Language	English
Publishing date	2017-03-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2764253-7
ISSN	2197-1714
ISSN	2197-1714
DOI	10.1186/s40621-017-0103-1
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Article ; Online: Associations between child maltreatment, cigarette smoking, and nicotine dependence in young adults with a history of regular smoking.

Cammack, Alison L / Haardörfer, Regine / Suglia, Shakira F

Annals of epidemiology

2019 Volume 40, Page(s) 13–20.e4

Abstract: ... adulthood (n = 3581); and lifetime history of nicotine dependence (n = 3594) per the Fagerstrom scale ...

Abstract	Purpose: The purpose of this study was to evaluate whether childhood maltreatment is associated with smoking behaviors and lifetime nicotine dependence and if associations are moderated by sex. We examined these associations among individuals who ever reported being regular smokers. Methods: Using data from the National Longitudinal Study of Adolescent to Adult Health, we examined relationships between retrospectively self-reported child maltreatment (parent/caregiver-perpetrated emotional, physical, sexual abuse, and neglect; and non-parent/caregiver-perpetrated sexual abuse) and self-reported smoking behaviors among individuals with a history of regular smoking. Outcomes were any current smoking in early adulthood (mean age = 28 years), current smoking in adolescent study waves only, adulthood only, and adolescence and adulthood (n = 3581); and lifetime history of nicotine dependence (n = 3594) per the Fagerstrom scale. Results: Poly-maltreatment (aRR for 2+ vs. 0 exposures = 1.20, 95% CI: 1.08, 1.34) was associated with lifetime nicotine dependence; associations between nicotine dependence and neglect and non-parent/caregiver sexual abuse by force were only present in women. Neglect and non-parent/caregiver sexual abuse by nonphysical threat were associated with continued smoking, and an association between non-parent/caregiver sexual abuse by physical force and continued smoking was also noted in women only. Women who experienced poly-maltreatment were less likely to report current smoking in adolescence but not adulthood. Conclusions: These data suggest in a nationally representative sample of ever regular smokers, child maltreatment is associated with outcomes that suggest an inability to quit smoking and some associations may vary by sex.
MeSH term(s)	Adolescent ; Adult ; Adult Survivors of Child Abuse/psychology ; Adult Survivors of Child Abuse/statistics & numerical data ; Behavior, Addictive ; Child ; Child Abuse/psychology ; Child Abuse/statistics & numerical data ; Cigarette Smoking/adverse effects ; Cigarette Smoking/epidemiology ; Cigarette Smoking/psychology ; Female ; Humans ; Longitudinal Studies ; Male ; Risk Factors ; Tobacco Use Disorder/epidemiology ; Tobacco Use Disorder/psychology ; Young Adult
Language	English
Publishing date	2019-10-21
Publishing country	United States
Document type	Evaluation Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1074355-8
ISSN	1873-2585 ; 1047-2797
ISSN (online)	1873-2585
ISSN	1047-2797
DOI	10.1016/j.annepidem.2019.10.003
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Zs.A 3225: Show issues

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Article ; Online: Revealing Population Heterogeneity in Vesicle-Based Nanomedicines Using Automated, Single Particle Raman Analysis.

Saunders, Catherine / Foote, James E J / Wojciechowski, Jonathan P / Cammack, Ana / Pedersen, Simon V / Doutch, James J / Barriga, Hanna M G / Holme, Margaret N / Penders, Jelle / Chami, Mohamed / Najer, Adrian / Stevens, Molly M

ACS nano

2023 Volume 17, Issue 12, Page(s) 11713–11728

Abstract: The intrinsic heterogeneity of many nanoformulations is currently challenging to characterize on both the single particle and population level. Therefore, there is great opportunity to develop advanced techniques to describe and understand nanomedicine ... ...

Abstract	The intrinsic heterogeneity of many nanoformulations is currently challenging to characterize on both the single particle and population level. Therefore, there is great opportunity to develop advanced techniques to describe and understand nanomedicine heterogeneity, which will aid translation to the clinic by informing manufacturing quality control, characterization for regulatory bodies, and connecting nanoformulation properties to clinical outcomes to enable rational design. Here, we present an analytical technique to provide such information, while measuring the nanocarrier and cargo simultaneously with label-free, nondestructive single particle automated Raman trapping analysis (SPARTA). We first synthesized a library of model compounds covering a range of hydrophilicities and providing distinct Raman signals. These compounds were then loaded into model nanovesicles (polymersomes) that can load both hydrophobic and hydrophilic cargo into the membrane or core regions, respectively. Using our analytical framework, we characterized the heterogeneity of the population by correlating the signal per particle from the membrane and cargo. We found that core and membrane loading can be distinguished, and we detected subpopulations of highly loaded particles in certain cases. We then confirmed the suitability of our technique in liposomes, another nanovesicle class, including the commercial formulation Doxil. Our label-free analytical technique precisely determines cargo location alongside loading and release heterogeneity in nanomedicines, which could be instrumental for future quality control, regulatory body protocols, and development of structure-function relationships to bring more nanomedicines to the clinic.
MeSH term(s)	Humans ; Nanomedicine/methods ; Liposomes
Chemical Substances	Liposomes
Language	English
Publishing date	2023-06-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1936-086X
ISSN (online)	1936-086X
DOI	10.1021/acsnano.3c02452
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