Experimental Biology and Medicine*

Microbiome in Healthcare and Medicine Editor: Horst von Recum Addressing the presence of unwanted bacteria and fungi following medical procedures has long been a major healthcare concern. Infection applications can range from wounds, to surgical sites to biomedical implants. This Special Issue broadly addresses new knowledge in microbiome-related research, particularly in regards to medicine and healthcare. We hope it can serve as a state-of-the-art review of recent advances, suitable for experts in the field, as well as a primer for the novice to understand what areas are involved and gain a rapid understanding of how these different topics have come together. Read the issue

Cell mimicry and synthetic biology: tools, applications, and emerging conceptual framework Editors: Oscar Ces and Yuval Elani This thematic issue is the first contribution to the journal category, adding to the journal's heritage of exploring cutting edge aspects of the life sciences. The issue contains articles that cover the wide synthetic biology spectrum, including plant synthetic biology, protocell research, artificial cell therapeutic agents, cell-free synthesis and protein reconstitution in cell-mimics, and topography design of synthetic cell membranes. The editors of this issue hope that it will be of value both for experiments in bottom-up and top-down synthetic biology, as well as to general Experimental Biology and Medicine readers. Read the issueExperimental Biology and Medicine*

Pharmacological inhibition of Bax-induced cell death: Bax-inhibiting peptides and small compounds inhibiting Bax
Kelsey Jensen, David Jasen WuWong, Sean Wong, Mieko Matsuyama, Shigemi Matsuyama
First Published March 5, 2019; pp. 621–629
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Bax is an essential mediator of mitochondria-dependent programed cell death. Bax belongs to the Bcl-2 family of proteins and its activities are regulated through interaction with other member proteins in the Bcl-2 family. To date, several apoptosis-inducing drugs activating Bax have been developed, and some of them are already in the market as therapeutics against cancer. However, at present, there are no clinically effective pharmacological Bax inhibitors protecting essential cells. Previously, we developed Bax-Inhibiting Peptides (BIPs) that belong to the peptide group of Cell-Penetrating Peptides (CPPs). CPPs have the ability to deliver cargo molecules into the cell. In this review, we will describe the mechanism of action of BIPs together with the recent applications of BIPs in disease models in vitro and in vivo. However, BIPs have several limitations in their use to treat human diseases, and other types of Bax inhibitors need to be developed for future therapeutics. Recently, several groups reported the successful development of novel small compounds inhibiting Bax. We will review these Bax inhibitors to discuss current strategies to develop pharmacological Bax inhibitors.

Impact statement
Bax induces mitochondria-dependent programed cell death. While cytotoxic drugs activating Bax have been developed for cancer treatment, clinically effective therapeutics suppressing Bax-induced cell death rescuing essential cells have not been developed. This mini-review will summarize previously reported Bax inhibitors including peptides, small compounds, and antibodies. We will discuss potential applications and the future direction of these Bax inhibitors.

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Biomedical Engineering
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Bioengineering approaches to organ preservation ex vivo
Meghan Pinezich, Gordana Vunjak-Novakovic
First Published March 19, 2019; pp. 630–645
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The advent of successful solid organ transplantation is undoubtedly among the most significant medical achievements of the 20th century. Despite advances in the field of transplantation since its inception over 50 years ago, our approach to donor organ preservation outside of the body remains unchanged. Recently, attempts have been made to replace static cold storage with more sophisticated ex vivo machine perfusion. Rather than cooling the organ on ice to slow metabolic processes, machine perfusion aims to support normal metabolic function in a near-physiologic environment and to provide a platform on which the organ can be evaluated, preserved, and recovered. Ex vivo machine perfusion devices have demonstrated early success with respect to transplant outcomes in heart, lung, and liver, with perfusion times limited to several hours. The continued development of more advanced perfusion systems is likely to extend the duration of ex vivo organ support to days or even weeks, and enable recovery of initially unsuitable donor organs. In this review, we discuss recent clinical and pre-clinical studies, state-of-the-art organ preservation technologies, existing limitations, and a perspective on future developments.

Impact statement
Over the past several decades, ex vivo perfusion has emerged as a promising technology for the assessment, preservation, and recovery of donor organs. Many exciting pre-clinical findings have now been translated to clinical use, and successful transplantation following ex vivo perfusion has been achieved for heart, lung, and liver. While machine perfusion provides distinct advantages over traditional cold preservation, many challenges remain, including that of long-term (multi-day) ex vivo support. Here, we provide an overview of the current status of ex vivo machine perfusion in the pre-clinical and clinical setting and share our perspective on the future direction of the field.

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Endocrinology and Nutrition
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Intestinal phosphate absorption: The paracellular pathway predominates?
Matthew Saurette, R Todd Alexander
First Published February 14, 2019; pp. 646–654
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Hyperphosphatemia is nearly universal in patients with advanced chronic kidney disease and end stage renal disease. Given the considerable negative sequelae associated with hyperphosphatemia, i.e. increased cardiovascular disease, hastening of renal failure and death, reducing serum phosphate is a goal of therapy. In the absence of sufficient renal function, intestinal phosphate absorption is the remaining target to reduce plasma phosphate levels. Much work has been done with respect to understanding transcellular phosphate absorption. Both animal studies using inducible or intestinal NaPi-2b knockout mice and specific NaPi-2b inhibitors revealed this transporter as the primary mechanism mediating transcellular phosphate absorption in the intestine. However, this has not translated into effective phosphate lowering therapies in patients with kidney disease. More recently, it was observed that inhibition of the epithelial sodium hydrogen exchanger, sodium–hydrogen exchanger isoform 3 (NHE3), or its genetic deletion, decreases intestinal phosphate absorption. The mechanism mediating this effect is through increased transepithelial resistance and reduced paracellular phosphate permeability. Thus, NHE3 inhibition reduces paracellular phosphate permeability in the intestine. The transepithelial potential difference across intestinal epithelium is lumen negative and phosphate commonly exists as a divalent anion. Further, consumption of the typical Western diet provides a large lumen to blood phosphate concentration gradient. Based on these observations we argue herein that the paracellular phosphate absorption route is the predominant pathway mediating intestinal phosphate absorption in humans.

Impact statement
This review summarizes the work on transcellular intestinal phosphate absorption, arguing why this pathway is not the predominant pathway in humans consuming a "Western" diet. We then highlight the recent evidence which is strongly consistent with paracellular intestinal phosphate absorption mediating the bulk of intestinal phosphate absorption in humans.

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Choline transport for phospholipid synthesis: An emerging role of choline transporter-like protein 1
Vera Hedtke, Marica Bakovic
First Published February 18, 2019; pp. 655–662
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This review provides a summary of recent discoveries in choline transport and the proteins mediating it with a specific focus on the choline transporter-like proteins (CTL)/solute carriers 44 A (SLC44A) and their role in phospholipid metabolism. Since its initial cloning, particularly, the CTL1/SLC44A1 transporter has been investigated further and its ubiquitous expression characterized in various cells and tissues of mouse, rat, and human origin. We describe the role of this choline transporter both in the plasma membrane and in the mitochondria and summarize novel aspects of choline transport regulation in the muscle, nervous system, and cancer.

Impact statement
This review will provide a summary of recent advances in choline transport research and highlight important novel areas of focus in the field.

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Alexandros Sfakianakis
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