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Volume 1 Issue 3 July/August 2016

ISSN 2444-8664


Evidence based Medicine

Page 81


106 A.P.

Faria et al


Ferreira et al

Publishing Services by Elsevier

Porto Biomedical Journal http://www.portobiomedicaljournal.com/

Volume 1.

Number 3.

July/August 2016

CONTENTS Editorial Evidence-based medicine – The case for nutrition V.G.

Larsen .

Review articles Regulation of colonic epithelial butyrate transport: Focus on colorectal cancer P.

Gonçalves and F.

Martel .

Cognitive and emotional impairments in obsessive–compulsive disorder: Evidence from functional brain alterations Ó.F.





Carracedo and A.

Sampaio .

Original articles Association between energy density and diet cost in children A.P.









Moreira and P.

Padrão .



Barros and M.

Severo .


Godinho and J.

Freitas .

Images in Biomedicine A fatal case of upper-extremity deep vein thrombosis P.

Pinto-Lopes and P.

Porto Biomed.

Porto Biomedical Journal http://www.portobiomedicaljournal.com/


Evidence-based medicine – The case for nutrition Vanessa Garcia Larsen ∗ Respiratory Epidemiology,

Occupational Medicine and Public Health Group,

National Heart and Lung Institute,

Imperial College London,

United Kingdom

Diet has been a constant determinant of social,

economic and disease across history.

One of the transformational eras in diet probably started during the Tudor period (1458–1603).

This was a time of great creativity,

political and religious renovation.

This period would also see the discovery and introduction of sugar to the diet (a privilege reserved for the wealthiest),

and its use in preserving fruits.


pottages and wine formed the basis of most diets.

Although fresh fruits and vegetables were available,

it was common for people to avoid eating them uncooked,

believing them to carry disease.


during the plague of 1569 the selling of fresh fruit was banned by law.1 In modern times,

the introduction of evidence-based medicine has been fundamental to improve our understanding of the role of risk factors on disease.

It has also been pivotal to enable the scientific and clinical community to establish recommendations and care plans for patients and populations at high risk of disease.

Blind randomised controlled trials (RCTs) are usually considered the gold standard in evidence-based medicine.

The evidence from such interventions is often used as reference to provide recommendations to patients.

In the case of diet,

there are several limitations inherent to this exposure,

which make evidence-based applications more difficult.

RCTs investigating the effect of diet on disease have often used a single nutrient or a combination of them given as supplements.

Evidence from such trials has led to important public health recommendations in some cases.

For example,

large trials on vitamin A supplementation in Nepal2 have shown a significant decrease in mortality in vulnerable populations of children.

This led to nationwide programmes of supplementation in children,

and until adequate and reliable dietary sources of vitamin A can be made accessible to the target populations,

the supplementation programmes will offer the safest way to deliver this nutrient.

More recently,

Public Health England recommends that all those above age 1 year take a vitamin D'supplement on a regular basis to counteract the health effects caused by the endemic deficiency observed in the general population.

This advice is based on the recommendations of the Scientific Advisory Committee on Nutrition (SACN) following its review of the evidence on vitamin D'and health.3 Studies in vitro and in vivo continue to provide insight into the mechanisms through which diet could modulate disease.

testing the effects of actual diet (not supplements) in RCTs remains difficult due to several issues such as (a) blinding,

which can be better addressed in a pragmatic RCT.

Blinding is a major methodological limitation as patients can rarely be blinded to what food they are eating,

and the intervention might be obvious to the researchers.

This issue is particularly relevant when population-based interventions are planned,

patient and investigator will occur.

To compensate for the lack of blinding,

concealment of randomisation is still important,

as is blinding the assessor of outcomes.4 On the other hand,

estimating the sample size needed for a food intervention may not follow the same rationale as that of a pharmacological or drug-related RCT.


diet can be considered a ‘chronic exposure’ and it is often unclear how long the intervention will need to last until changes in health outcome are measured.

A major challenge remains to improve the adherence of the population to recommendations.

The current recommendation of eating five portions of fruits and vegetables a day is being met by less than 15% of adults in the US5 ,

and by less than half of the adults in Europe.


at a time of increasingly robust evidence from observational studies and high quality systematic review,

suggesting that diet could modulate the risk of disease.

Specific diets (e.g.


natural sources of antioxidants,

or foods with anti-inflammatory properties (e.g.

vegetables) have all been proposed to reduce the severity and burden of several non-communicable chronic diseases,

and inflammatory-mediated illnesses.


as shown by the figures on fruit and vegetable intake,

introducing sustained changes in diet,

Evidence-based medicine will continue to represent a major tool to improve the health of the population.

In particular,

evidence-based nutrition recommendations that can be successfully implemented in the population are urgently needed to tackle the current trends in chronic morbidity.

The Porto Biomedical Journal will welcome studies that help to strengthen the evidence on the role of lifestyle-related risk factors for disease.


E-mail address: [email protected]

British Library.

The food of the 1500s.

Available from: http://www.bl.uk/ learning/langlit/texts/cook/1500s2/1550s2.html [Accessed 02.08.16].

http://dx.doi.org/10.1016/j.pbj.2016.08.004 ˜ S.L.U.

This is an open access article under the CC BY-NC-ND 2444-8664/© 2016 PBJ-Associac¸a˜ o Porto Biomedical/Porto Biomedical Society.

Published by Elsevier Espana,

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Larsen / Porto Biomed.

Bishai D,

Kumar KCS,

Waters H,

The impact of vitamin A supplementation on mortality inequalities among children in Nepal.

Health Policy Plan.


Public Health England.

Available from: https://www.gov.uk/government/news/ phe-publishes-new-advice-on-vitamin-d [Accessed 26.07.16].

Alford L.

On differences between explanatory and pragmatic clinical trials.

New Z J Physiol.


Moore LV,

Thompson FE.

Adults meeting fruit and vegetable intake recommendations — United States,


Centers for Disease Control and Prevention (CDC).

Weekly Report July 10.

Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6426a1.htm [Accessed 02.08.16].

Porto Biomed.

Porto Biomedical Journal http://www.portobiomedicaljournal.com/

Review article

Regulation of colonic epithelial butyrate transport: Focus on colorectal cancer Pedro Gonc¸alves a ,

Fátima Martel b,∗ a b

Innate Immunity Unit,

Institut Pasteur,

and the Institut National de la Santé et de la Recherche Médicale (INSERM) U668,


France Department of Biochemistry,

Faculty of Medicine,

and Institute for Research and Innovation in Health Sciences,

University of Porto,



Keywords: BCRP Butyrate Colorectal cancer MCT1 SMCT1

a b s't r a c't Colorectal cancer (CRC) is one of the most common solid tumors worldwide.

Consumption of dietary fiber is associated with a low risk of developing CRC.

The fermentation of the dietary fiber by intestinal microflora results in production of butyrate (BT).

This short-chain fatty acid is an important metabolic substrate in normal colonic epithelial cells and has important homeostatic functions at the colonic level.

Because the cellular effects of BT (e.g.

inhibition of histone deacetylases) are dependent on its intracellular concentration,

knowledge on the mechanisms involved in BT membrane transport and its regulation seems particularly relevant.

In this review,

we will present the carrier-mediated mechanisms involved in BT membrane transport at the colonic epithelial level and their regulation,

Several xenobiotics known to modulate the risk for developing CRC are able to interfere with BT transport at the intestinal level.


interference with BT transport certainly contributes to the anticarcinogenic or procarcinogenic effect of these compounds and these compounds may interfere with the anticarcinogenic effect of BT.


we suggest that differences in BT transport between normal colonocytes and tumoral cells contribute to the “BT paradox” (the apparent opposing effect of BT in CRC cells and normal colonocytes).

˜ © 2016 PBJ-Associac¸a˜ o Porto Biomedical/Porto Biomedical Society.

Published by Elsevier Espana,


This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Butyrate and colorectal cancer Cancer is the second leading cause of death,

after cardiovascular diseases,

Colorectal cancer (CRC) is one of the most common malignancies and cause of cancer death in developed countries,2 including United States3 and Europe.4 In Europe,

CRC is the third most common type of cancer in both men and women and the second leading cause of cancer related-death.2 The prevalence of CRC has been steadily increasing over the last century,

possibly as a result of industrialization and changes in life style/environmental/dietary factors.2 Both epidemiological and experimental animal studies have shown that dietary fiber possesses a protective role in CRC.5,6 Dietary fiber exerts a protective role against CRC through a variety of mechanisms,

including reduced concentrations of intestinal carcinogens owing to increased stool mass,

and bacterial fermentation of resistant starch to short-chain fatty acids (SCFAs: acetate,

propionate and butyrate) in the colon.6,7 Among

E-mail address: [email protected] (F.



butyrate (BT) plays a key role in colonic epithelium homeostasis,

by having multiple regulatory roles at that level,

namely: (1) it is the main energy source for colonocytes

(2) it promotes growth and proliferation of normal colonic epithelial cells

(3) it inhibits colon carcinogenesis

(4) it inhibits colon inflammation and oxidative stress

(5) it improves the colonic defense barrier function

(6) it stimulates fluid and electrolyte absorption

(7) it stimulates mucus secretion and increases vascular flow and motility

and (8) it reduces visceral perception,

and pain.8,9 Several lines of evidence support an important role of BT in the prevention/inhibition of colon carcinogenesis.10,11 In vitro,

BT suppresses growth of cancer cells,

inducing differentiation and apoptosis and inhibiting cell proliferation.12,13 Also,

several welldesigned animal models have demonstrated a protective effect of BT on colorectal carcinogenesis.14–19 Moreover,

there is an inverse relationship between the levels of BT in the human colon and the incidence of CRC,20 and an increased incidence of tumors in the distal colon,

where the concentration of BT is lower,

suggesting an inverse relationship between BT and CRC.21 The molecular mechanism by which BT inhibits colon carcinogenesis seems to involve various effects on gene expression,

which are mainly attributed to its capacity to act as an histone

http://dx.doi.org/10.1016/j.pbj.2016.04.004 ˜ S.L.U.

This is an open access article under the CC BY-NC-ND 2444-8664/© 2016 PBJ-Associac¸a˜ o Porto Biomedical/Porto Biomedical Society.

Published by Elsevier Espana,

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).


Martel / Porto Biomed.

deacetylases (HDAC) inhibitor,

leading to hyperacetylation of histones.22,23 HDACs can regulate the expression of a large number of genes by direct interaction with transcription factors such as p53,


NF-kB and estrogen receptors8 and histone deacetylase inhibitors (HDACi) are critical epigenetic regulators and a new class of anticancer agents.24 It is likely that BT has also some other intracellular targets,

including DNA methylation,25 histone methylation,26 hyperacetylation of nonhistone proteins,27 inhibition of histone phosphorylation,28 regulation of expression of micro-RNAs (miRNA)29,30 and modulation of intracellular kinase signaling.31–33 More recently,

BT was demonstrated to elicit cellular uptakeindependent biologic effects on colonic epithelial cells.34 Indeed,

BT was found to be a physiologic agonist of GPR109A,

a G-proteincoupled receptor which is abundantly expressed in the apical membrane of mouse and human colonic epithelial cells.34,35 SCFAs were also reported to be GPR41 and GPR43 ligands.36–38 GPR109A and GPR43 appear to act as a colonic tumor suppressors and also to be involved in the anti-inflammatory effect of SCFA.35,36,39,40 Intestinal transport of BT The most important molecular mechanisms involved in the anticarcinogenic effect of BT are dependent on its intracellular concentration (because HDAC expression is overregulated,41,42 while BT membrane receptors (GPR109A and GPR43) are silenced or downregulated in CRC34,38 ).

knowledge on the mechanisms involved in its membrane transport is relevant to both its physiological and pharmacological benefits.


changes in transporter expression or function will have an obvious impact on the effect of BT,

knowledge on the regulation of its membrane transport seems particularly important.

BT is a weak acid (pKa = 4.8) and more than 90% exist in the ionized form under physiological conditions in the colon (pH 5.5–6.7),

thus requiring a transporter for absorption.43,44 BT is preferentially absorbed in the proximal part of colon where the highest luminal concentration occurs.45–47 Several different mechanisms for BT uptake across the apical membrane of colonocytes have been proposed,

including simple diffusion of the undissociated form (in the distal colon),43,44 counter-transport with bicarbonate (BT/HCO3 − exchanger)48,49 and transport by monocarboxylate transporters.50,51 The two major monocarboxylate transporters identified for BT absorption across the luminal membranes of colonocytes are the proton-coupled monocarboxylate transporter 1 (MCT1) and the sodium-coupled monocarboxylate transporter 1 (SMCT1).50–52 These will be next described.

Monocarboxylate transporter 1 (MCT1) The monocarboxylate transporter (MCT) family is composed by 14 members encoded by the SLC16 gene family.53 The MCT1 (SLC16A1) gene was cloned in 199454 and the structural gene organization as well as isolation and characterization of the SLC16A1 promoter were later described.55 MCT1 is composed by 500 amino acids,

is well conserved and is ubiquitously expressed in almost every tissue.56 MCT1 protein levels vary along the human digestive tract: the expression of MCT1 is very low in the small intestine but it increases in the colon with maximal levels in the distal segment,

being confined to the upper regions of colonic crypts.57,58 The precise subcellular localization of MCT1 remains controversial: a predominant basolateral57,59,60 or apical membrane localization58,61 or its presence in both cell membranes62 has been described.

MCT1 translocates a proton through the plasma membrane together with a molecule of BT.63 Physiologically,

MCT1 is probably

more active in the proximal colon,

because its Km for BT is about 2.4–2.8 mM,

and there is a higher concentration of BT (in the mM range after digestion of dietary fiber) and the luminal pH is lower in this region.21 MCT1 transports a variety of natural substrates including monocarboxylates (e.g.

BT) and ketoacids.53 Moreover,

numerous drugs containing a carboxyl group in their chemical structure and/or weak organic acids may be potential substrates for MCT1.

Examples of such drugs are salicylic acid,

nonsteroidal anti-inflammatory drugs (NSAIDS),

cholesterol synthesis inhibitors and some -lactam antibiotics.64–66 MCT1 regulation Transporter regulation includes transcriptional (activators and repressors),

post-transcriptional (splice variants),

chromosomal (epigenetic modifications),

translational (mRNA stability) and posttranslational (alteration of protein) modifications.

MCT1 is known to be regulated at the transcriptional and post-transcriptional level,

and at the level of transporter activity.

MCT1 is known to be regulated at various points during gene expression (transcriptional regulation).

SLC16A1 promoter has putative binding site sequences for the transcription factors upstream stimulatory factor (USF) 1 and 2 (MCT1 repressors),67 NF-B (involved in BT-induced MCT1 upregulation),68 activated protein 1 and 2 (AP1 and AP2) and stimulating protein-1 (Sp1).55 Also,

the co-activators peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1)69 and peroxisome proliferator-activated receptor alpha (PPAR)70,71 upregulate MCT1.

Hormone regulation has also been described.

Somatostatin,72 leptin,73 thyroid-stimulating hormone74 and testosterone75 induce MCT1 expression.

MCT1 is also under post-transcriptional regulation by microRNAs.

The MCT1 untranslated region is a target for three microRNAs (miR-29a,

miR-29a and miR29b have been described to silence MCT1 expression.76 MCT1 activity is modulated by several compounds,

described as classic inhibitors of MCT1: (1) bulky or aromatic monocarboxylates like -cyano-4-hydroxycinnamate

(2) inhibitors of anion transport such as 5-nitro-2-(3-phenylpropylamino)benzoate

such as p-chloromercuribenzene sulphonate (pCMBS),

and amino reagents.53 MCT1 expression is downregulated in the inflamed mucosa of inflammatory bowel disease patients,

in animal models of inflammation,

and in response to the proinflammatory cytokines tumor necrosis factor- (TNF-) and interferon- (IFN-).77 Interestingly,

infliximab (an anti-TNF- monoclonal antibody) markedly increased MCT1 mRNA levels in the inflamed colon of Crohn’s disease patients.57 The reduction in the cellular uptake of BT occurring during inflammation may contribute to the fact that inflammatory bowel disease is associated with an elevated risk of CRC.77,78 Physical activity,

known to reduce CRC risk,79 increases MCT1 protein expression and activity in muscle.80,81 Because MCT1 is substrate-induced by lactate,82 the increased blood lactate levels found after physical activity can affect MCT1 levels in colon.

MCT1 is associated with a plasma accessory protein,

the membrane glycoprotein CD147 (also known as basigin,


OX-47 or HT7),

and this ancillary protein is known to be involved in regulating MCT1 localization and activity.83 MCT1 is also functionally coupled to proteins involved in acid/base regulation.


carbonic anhydrase,84 Na+ /HCO3 − cotransporter and Na+ /H+ exchangers85 enhance MCT1 transport activity.

Several nutrients and xenobiotics present in the diet were also found to affect MCT1 expression and activity.

Intestinal MCT1 gene expression is decreased by the polyphenols EGCG,


Martel / Porto Biomed.

tetrahydrocannabinol and MDMA (ecstasy),86 by high-protein diets (linked to NH3

substrates of MCT1 such as BT increased MCT1 protein expression in colon68,90,91 and its apical localization.92 Recently,

BT)-induced enhancement of MCT1 surface expression and function was found to be mediated by a novel nutrient sensing mechanism involving GPR109A as a SCFA sensor.89 MCT1 activity is also modulated by several exogenous compounds.


MCT1 is inhibited by NSAIDs (e.g.

acetylsalicylic acid and indomethacin),86,93,94 some phytochemicals (e.g.

(−)-epicatechin and (−)-epigallocatechin gallate),12,94–96 xanthines (caffeine and theophylline) and acetaldehyde.86 Chronically,

MCT1 activity is inhibited by tetrahydrocannabinol,

MDMA,86 the bile salt chenodeoxycholic acid,97 enteropathogenic Escherichia coli,98 IFN- and TNF-77 and is increased by caffeine (an effect not related to changes in the expression level of MCT1,

as this agent decreased this parameter

see above),86 some phytochemicals (e.g.


myricetin and catechin)12 and some mineral waters (Melgac¸o® and Vidago® ).99 Of note,

Lactobacillus acidophilus counteracts E.

coli-induced inhibition of BT uptake in intestinal epithelial cells.100 In conclusion,

numerous nutrients and xenobiotics can modulate MCT1 expression and activity,

and competition for the same transport pathway between BT and these compounds can cause a significant change in BT absorption.

MCT1 and CRC The first report on MCT1 protein expression in human tumor samples described a decrease in MCT1 expression in colonic transition from normality to malignancy.61,101 Evidence for MCT1 downregulation was later observed also in other cancer types.61,102 The loss or silencing of MCT1 has been demonstrated to correlate with: (a) transition from normality to malignancy in colonic epithelium,61 (b) dysregulation of BT-responsive genes involved in differentiation and apoptosis101,103 and (c) an important metabolic switch from BT -oxidation to glycolysis.

In relation to this last point,

it should be noted that BT is the main energy source for colonocytes,

accounting to about 70% of total energy utilization.104 However,

CRC cells show a reduction in BT uptake as a result of reduced MCT1 (and SMCT1

see below) expression,104,105 associated with an increase in the rate of glucose uptake (via an upregulation of facilitative glucose transporters (e.g.

GLUT1))106 and glycolytic oxidation (via an increase in the expression levels and activity of glycolytic enzymes).104,107,108 Although MCT1 expression decreases during colonic transition from normality to malignancy,

being downregulated in the early stages of carcinogenesis,61 a later upregulation of MCT1 in advanced metastatic CRC tumors has been described.109,110 Solid tumors are usually exposed to low oxygen environments.

Interestingly enough,

although MCT1 expression is not HIF-1 induced,111 CD147,

the accessory protein that MCT1 requires in order to function,

is upregulated by HIF-1 under hypoxic microenvironment.112 In advanced CRC tumors,

cells are highly glycolytic and convert the majority of glucose into lactate and thus cells must efficiently export lactate,

in order to maintain a permissive intracellular pH,

high glycolytic rates and ATP levels.113 MCTs are bidirectional transporters114 and powerful regulators of intracellular pH by extruding lactate together with a proton.113 Accordingly,

MCT1 inhibition decreases intracellular pH,

resulting in tumoral cell death.108,115,116 So,

isoforms may occur as a means of exporting lactate.

In this context,

lactate transporters (MCTs) are currently seen as potential therapeutic targets in cancer treatment,

with promising results having been obtained.117–119 However,

systemic delivery of MCTs (and more specifically,

MCT1) inhibitors could affect almost every organ of the body,

with the most drastic effects on cardiac and skeletal muscle.120 Also,

both MCT1 and MCT4 appear to play a pivotal role in lactate transport and tumor survival and development.121,122 However,

no specific MCT4 small molecule inhibitor has been identified so far.123 BT was previously approved for clinical use in CRC treatment,124 because BT is a substrate of both MCT1 and MCT4 and is well metabolized,

having no side effects.120 Because BT competes with lactate for MCT1 and is a HDACi,

it is a good compound to test in the context of inhibition of lactate release in CRC.125 So,

although the anticarcinogenic effect of BT is believed to result from HDAC inhibition,23 it is also interesting to speculate that MCT-mediated BT uptake may result in a decrease in the intracellular pH,

originating tumoral cell death.

Sodium-coupled monocarboxylate transporter 1 (SMCT1) SMCT1 is a member of the sodium solute symporter family (SLC5),

first cloned in 2002.126 This transporter is encoded by the SLC5A8 gene127 and the SLC5A8 gene promoter has also been characterized.128 SLC5A8 encodes a protein with 610 amino acids,129 having a restricted distribution (primarily kidney and intestine).130 At the intestinal level,

SLC5A8 is abundantly expressed in the apical membrane of the ileum and colon,131,132 and its levels are highest in distal colon,

followed by proximal colon and ileum.78 SLC5A8 transports a variety of monocarboxylates such as lactate,

pyruvate and -hydroxybutyrate (GHB),132,133 ketone bodies,134 nicotinate structural analogs,135 pyroglutamate (amino acid derivative)136 and benzoate and its derivatives (salicylate and 5-aminosalicylate).135 SLC5A8 has been characterized as a Na+

no studies have characterized SMCT1 function in the native human intestine.

Because SMCT1 has a low Km (50 M) for BT139 and is more expressed in distal colon,78 SMCT1 is probably physiologically more important in the distal colon (where the concentrations of BT are lower).21 SMCT1 regulation Knowledge on the regulation of SMCT1 at the intestinal level is very scarce.

SMCT1 has been found to be inhibited by some NSAIDs (ibuprofen,

naproxen135 and indomethacin94 ),

phytochemicals (resveratrol and quercetin94 ),

TNF-,76 oxidative stress,140 chenodeoxycholic acid97 and by the absence of gut commensal bacteria.141 On the contrary,

SMCT1 was found to be stimulated by some other NSAIDs (diclofenac,

meclofenamate and sulindac142 ),

by activin A143 and by the probiotic Lactobacillus plantarum.76 Obesity and diabetes are risk factors for developing CRC143,144 and it is interesting to verify that ob/ob mice (an animal model of obesity) show a decrease in SMCT1 protein intestinal levels.145 Inflammatory bowel disease is also associated with an increased risk for CRC,9 and SMCT1 is also downregulated during inflammation.78 SMCT1 and CRC Studies have shown that SMCT1 expression is frequently silenced in aberrant crypt foci (the earliest detectable morphologic abnormality of the colonic epithelium),


Martel / Porto Biomed.

colon cancers and colon cancer cell lines,

suggesting that SMCT1 silencing is an early event in colon tumorigenesis.127,130 Interestingly,

CRC patients often have allelic loss of chromosome 12q,

which contains the SLC5A8 gene.146,147 SMCT1 is also silenced in cancers of the thyroid,

pancreas and blood.130,148,149 SMCT1 is silenced by aberrant DNA hypermethylation.148,150 Therefore,

SMCT1 was proposed to function as a tumor suppressor,

the ability of this transporter to mediate the entry of BT into colonocytes underlying its potential tumor suppressor function,52,127,130 and combination of upregulation of matrix metalloproteinases-7 and SMCT1 downregulation is an optimal biomarker for identifying CRC cases.151 Also,

SMCT1 activity is positively correlated with CRC remission and patient survival.152 However,

Smct1-null mice do not reveal a higher incidence of tumors in the colon under optimal dietary fiber conditions,

possibly because BT is transported by Mct1 under these conditions.

under low-fiber dietary conditions,

the incidence of CRC is much higher in Smct1-null mice,