Pharmacology and Toxicology

The generation of HepG2 transmitochondrial cybrids to reveal the role of mitochondrial genotype in idiosyncratic drug-induced liver injury

1. Amy Louise Ball
2. Carol E Jolly
3. Mark G Lennon
4. Jonathan J Lyon
5. Ana Alfirevic
6. Amy E Chadwick

• Curated by eLife

  eLife assessment

  This paper is of potential interest to scientists within the field of drug-induced liver injury. The concept of the study is interesting by generating mitochondrial genotype-specific liver cell lines to evaluate idiosyncratic hepatotoxicity. While the proof-of-concept is clearly presented, the current data do not yet allow to draw broad conclusions about the significance of the study in terms of drug effects.

Reviewed by eLife

Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics

1. Ziva Vuckovic
2. Jinan Wang
3. Vi Pham
4. Jesse I Mobbs
5. Matthew J Belousoff
6. Apurba Bhattarai
7. Wessel AC Burger
8. Geoff Thompson
9. Mahmuda Yeasmin
10. Vindhya Nawaratne
11. Katie Leach
12. Emma T van der Westhuizen
13. Elham Khajehali
14. Yi-Lynn Liang
15. Alisa Glukhova
16. Denise Wootten
17. Craig W Lindsley
18. Andrew Tobin
19. Patrick Sexton
20. Radostin Danev
21. Celine Valant
22. Yinglong Miao
23. Arthur Christopoulos
24. David M Thal

• Curated by eLife

  eLife assessment

  This fundamental study is important and carefully executed, providing important insights into the allosteric regulation of GPCRs with exceptional strength of evidence. This work will be of interest to a wide audience in drug discovery and receptor biology. The major strengths are the comprehensive structural and pharmacological characterization with only minor weaknesses, most notably a concern regarding the approach used to quantify efficacy.

Reviewed by eLife

Population dynamics of immunological synapse formation induced by bispecific T cell engagers predict clinical pharmacodynamics and treatment resistance

1. Can Liu
2. Jiawei Zhou
3. Stephan Kudlacek
4. Timothy Qi
5. Tyler Dunlap
6. Yanguang Cao

• Curated by eLife

  eLife assessment

  The authors have developed a useful model for how proteins that mediate a connection between invariant components of the T cell antigen receptor and leukaemic cells antigens, called bispecific engagers (BiTEs), mediate immunological synapse formation and impact T cell search for tumour cells in vivo. The model was compared against the in vitro experiments and in vivo data following a solid approach. The developed framework could provide a direction for employing computational mechanistic models for evaluating various strategies for BiTE treatments.

Reviewed by eLife

A mechanism of uncompetitive inhibition of the serotonin transporter

1. Shreyas Bhat
2. Ali El-Kasaby
3. Ameya Kasture
4. Danila Boytsov
5. Julian B Reichelt
6. Thomas Hummel
7. Sonja Sucic
8. Christian Pifl
9. Michael Freissmuth
10. Walter Sandtner

• Curated by eLife

  eLife assessment

  This study presents the important finding of an unusual uncompetitive inhibitor (ECSI#6) of the serotonin transporter that removes the neurotransmitter serotonin from the synaptic cleft. Through careful and comprehensive analysis, the authors convincingly show that the molecule most likely binds to the inward-facing and K+-bound state and that it assists in folding and targeting the transporter. The work will be of interest to those engaged in biophysical analyses of the serotonin transporter, and colleagues developing pharmacological chaperoning strategies for transporters in general.

Reviewed by eLife

Metformin protects trabecular meshwork against oxidative injury via activating integrin/ROCK signals

1. Lijuan Xu
2. Xinyao Zhang
3. Yin Zhao
4. Xiaorui Gang
5. Tao Zhou
6. Jialing Han
7. Yang Cao
8. Binyan Qi
9. Shuning Song
10. Xiaojie Wang
11. Yuanbo Liang

• Curated by eLife

  eLife assessment

  This manuscript proposes that metformin protects against elevated intraocular pressure and oxidative injury by regulating cytoskeleton remodeling through the integrin/ROCK pathway, thus providing a new direction for further exploration toward the treatment of primary open-angle glaucoma as well as investigation of oxidative injury in multiple settings.

Reviewed by eLife

1. Guang Wang
2. Yong-Feng Wang
3. Jiang-Lan Li
4. Ru-Ji Peng
5. Xin-Yin Liang
6. Xue-Dong Chen
7. Gui-Hua Jiang
8. Jin-Fang Shi
9. Yang-Hu Si-Ma
10. Shi-Qing Xu
11. 苏州大学苏州医学院基础医学与生物科学学院, 江苏 苏州215123, 中国
12. 苏州大学第一附属医院临床检验科, 江苏 苏州215006, 中国
13. School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
14. Department of Clinical Laboratory, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China

• Curated by eLife

  Evaluation Summary:

  The authors present a manuscript addressing an important unmet need, specifically focused on understanding the effects of high protein on hematopoiesis. This information can be of interest to basic biologists and clinicians who specialize in the areas of various diseases associated with elevated protein concentration (e.g. infections, inflammation, multiple myeloma, renal failure, etc). This is in part what makes for the complexity in studying this entity as the consequences of such disparate diseases are difficult to parcel out as causes of which specific disease manifestations. Furthermore, the presented work is done in an invertebrate model without additional confirmation in other model systems. Taken together, the work, which is plentiful in experiments, provides an incomplete understanding of cause and effect, leading to overinterpretation of results and overstating of derived conclusions.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Reviewed by eLife

Robust and Efficient Assessment of Potency (REAP) as a quantitative tool for dose-response curve estimation

1. Shouhao Zhou
2. Xinyi Liu
3. Xinying Fang
4. Vernon M Chinchilli
5. Michael Wang
6. Hong-Gang Wang
7. Nikolay V Dokholyan
8. Chan Shen
9. J Jack Lee

• Curated by eLife

  Evaluation Summary:

  This article proposes methodology and accompanying software for robustly fitting dose-response curves where response is a number between 0 and 1. When response is transformed using the common logistic transformation, values close to 0 or 1 become large in magnitude, unduly influencing the fitted curve after back-transformation and introducing bias in the estimate of certain parameters. The proposed approach, called Robust and Efficient Assessment of Potency, is less perturbed by these extreme measurements.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Reviewed by eLife

Hemin shows antiviral activity in vitro , possibly through suppression of viral entry mediators

1. Mehmet Altay Unal
2. Ceylan Verda Bitirim
3. Julia Somers
4. Gokce Yagmur Summak
5. Omur Besbinar
6. Ebru Kocakaya
7. Cansu Gurcan
8. Hasan Nazir
9. Zeynep Busra Aksoy Ozer
10. Sibel Aysil Ozkan
11. Sidar Bereketoglu
12. Aykut Ozkul
13. Emek Demir
14. Kamil Can Akcali
15. Acelya Yilmazer

Reviewed by ScreenIT

SARS-CoV-2 Subunit Virus-Like Vaccine Demonstrates High Safety Profile and Protective Efficacy: Preclinical Study

1. A.V. Vakhrusheva
2. A.V. Kudriavtsev
3. N.A. Kryuchkov
4. R.V. Deev
5. M.E. Frolova
6. K.A. Blagodatskikh
7. M. Djonovic
8. A.A. Nedorubov
9. E. Odintsova
10. A.V. Ivanov
11. E.A. Romanovskaya-Romanko
12. M.A. Stukova
13. A.A. Isaev
14. I.V. Krasilnikov

Reviewed by ScreenIT

Modeling osteoporosis to design and optimize pharmacological therapies comprising multiple drug types

1. David J Jörg
2. Doris H Fuertinger
3. Alhaji Cherif
4. David A Bushinsky
5. Ariella Mermelstein
6. Jochen G Raimann
7. Peter Kotanko

• Curated by eLife

  Evaluation Summary:

  This paper will be of interest to the pharmacology community with interest in available drug treatments for osteoporosis and how to optimize these. The key findings of the paper are based on in silico results and indicate that combined drug treatments may be more efficient in treatment of osteoporosis. This could have a significant impact on clinical management of osteoporosis patients.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Reviewed by eLife