Translational potential of mouse models of human metabolic disease.

Obesity causes significant morbidity and mortality globally. Research in the last three decades has delivered a step-change in our understanding of the fundamental mechanisms that regulate energy homeostasis, building on foundational discoveries in mouse models of metabolic disease. However, not all findings made in rodents have translated to humans, hampering drug discovery in this field. Here, we review how studies in mice and humans have informed our current framework for understanding energy homeostasis, discuss their challenges and limitations, and offer a perspective on how human studies may play an increasingly important role in the discovery of disease mechanisms and identification of therapeutic targets in the future.

IGT/LAZY genes are differentially influenced by light and required for light-induced change to organ angle.

BACKGROUND: Plants adjust their growth orientations primarily in response to light and gravity signals. Considering that the gravity vector is fixed and the angle of light incidence is constantly changing, plants must somehow integrate these signals to establish organ orientation, commonly referred to as gravitropic set-point angle (GSA). The IGT gene family contains known regulators of GSA, including the gene clades LAZY, DEEPER ROOTING (DRO), and TILLER ANGLE CONTROL (TAC). RESULTS: Here, we investigated the influence of light on different aspects of GSA phenotypes in LAZY and DRO mutants, as well as the influence of known light signaling pathways on IGT gene expression. Phenotypic analysis revealed that LAZY and DRO genes are collectively required for changes in the angle of shoot branch tip and root growth in response to light. Single lazy1 mutant branch tips turn upward in the absence of light and in low light, similar to wild-type, and mimic triple and quadruple IGT mutants in constant light and high-light conditions, while triple and quadruple IGT/LAZY mutants show little to no response to changing light regimes. Further, the expression of IGT/LAZY genes is differentially influenced by daylength, circadian clock, and light signaling. CONCLUSIONS: Collectively, the data show that differential expression of LAZY and DRO genes are required to enable plants to alter organ angles in response to light-mediated signals.

Analysis of the relative frequencies of the multipartite BNYVV genomic RNAs in different plants and tissues.

Multipartite virus genomes are composed of two or more segments, each packaged into an independent viral particle. A potential advantage of multipartitism is the regulation of gene expression through changes in the segment copy number. Soil-borne beet necrotic yellow vein virus (BNYVV) is a typical example of multipartism, given its high number of genomic positive-sense RNAs (up to five). Here we analyse the relative frequencies of the four genomic RNAs of BNYVV type B during infection of different host plants (Chenopodium quinoa, Beta macrocarpa and Spinacia oleracea) and organs (leaves and roots). By successfully validating a two-step reverse-transcriptase digital droplet PCR protocol, we show that RNA1 and -2 genomic segments always replicate at low and comparable relative frequencies. In contrast, RNA3 and -4 accumulate with variable relative frequencies, resulting in distinct RNA1 : RNA2 : RNA3 : RNA4 ratios, depending on the infected host species and organ.

Evolution of Antibody Responses in HIV-1 CRF01_AE Acute Infection: Founder Envelope V1V2 Impacts the Timing and Magnitude of Autologous Neutralizing Antibodies.

Understanding the dynamics of early immune responses to HIV-1 infection, including the evolution of initial neutralizing and antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies, will inform HIV vaccine design. In this study, we assess the development of autologous neutralizing antibodies (ANAbs) against founder envelopes (Envs) from 18 participants with HIV-1 CRF01_AE acute infection. The timing of ANAb development directly associated with the magnitude of the longitudinal ANAb response. Participants that developed ANAbs within 6 months of infection had significantly higher ANAb responses at 1 year (50% inhibitory concentration [IC50] geometric mean titer [GMT] = 2,010 versus 184; P = 0.001) and 2 years (GMT = 3,479 versus 340; P = 0.015), compared to participants that developed ANAb responses after 6 months. Participants with later development of ANAb tended to develop an earlier, potent heterologous tier 1 (92TH023) neutralizing antibody (NAb) response (P = 0.049). CRF01_AE founder Env V1V2 loop lengths correlated indirectly with the timing (P = 0.002, r = -0.675) and directly with magnitude (P = 0.005, r = 0.635) of ANAb responses; Envs with longer V1V2 loop lengths elicited earlier and more potent ANAb responses. While ANAb responses did not associate with viral load, the viral load set point correlated directly with neutralization of the heterologous 92TH023 strain (P = 0.007, r = 0.638). In contrast, a striking inverse correlation was observed between viral load set point and peak ADCC against heterologous 92TH023 Env strain (P = 0.0005, r = -0.738). These data indicate that specific antibody functions can be differentially related to viral load set point and may affect HIV-1 pathogenesis. Exploiting Env properties, such as V1V2 length, could facilitate development of subtype-specific vaccines that elicit more effective immune responses and improved protection. IMPORTANCE Development of an effective HIV-1 vaccine will be facilitated by better understanding the dynamics between the founder virus and the early humoral responses. Variations between subtypes may influence the evolution of immune responses and should be considered as we strive to understand these dynamics. In this study, autologous founder envelope neutralization and heterologous functional humoral responses were evaluated after acute infection by HIV-1 CRF01_AE, a subtype that has not been thoroughly characterized. The evolution of these humoral responses was assessed in relation to envelope characteristics, magnitude of elicited immune responses, and viral load. Understanding immune parameters in natural infection will improve our understanding of protective responses and aid in the development of immunogens that elicit protective functional antibodies. Advancing our knowledge of correlates of positive clinical outcomes should lead to the design of more efficacious vaccines.

Per-pathogen virulence of HIV-1 subtypes A, C and D.

HIV-1 subtypes differ in their clinical manifestations and the speed in which they spread. In particular, the frequency of subtype C is increasing relative to subtypes A and D. We investigate whether HIV-1 subtypes A, C and D differ in their per-pathogen virulence and to what extend this explains the difference in spread between these subtypes. We use data from the hormonal contraception and HIV-1 genital shedding and disease progression among women with primary HIV infection study. For each study participant, we determine the set-point viral load value, CD4+ T cell level after primary infection and CD4+ T cell decline. Based on both the CD4+ T cell count after primary infection and CD4+ T cell decline, we estimate the time until AIDS. We then obtain our newly introduced measure of virulence as the inverse of the estimated time until AIDS. After fitting a model to the measured virulence and set-point viral load values, we tested if this relation varies per subtype. We found that subtype C has a significantly higher per-pathogen virulence than subtype A. Based on an evolutionary model, we then hypothesize that differences in the primary length of infection period cause the observed variation in the speed of spread of the subtypes.

Fast Track Treatment of Hypothyroidism with Levothyroxine: Reaching Homeostasis within Four Weeks.

With the current clinical method for the treatment of hypothyroidism the target for the optimum individual values for free thyroxine concentrations [FT4] and thyrotropine concentrations [TSH] of the specific patient are unknown. This situation leads to unnecessary long experimental medication administration that can take a period of sometimes one year. In this article a method will be described where hypothyroid patients are characterized with weekly measured FT4 and TSH concentrations during the first three weeks of synthetic thyroxine or levothyroxine (L-T4) treatment to predict their optimum [FT4] and belonging [TSH] endpoint for a euthyroid homeostatic state. The treatment with levothyroxine will start for all patients with a reference dose of 100 µg, which can be adjusted by the treating physician to a more safe and appropriate dose for the individual which is monitored with weekly thyroid function tests to observe the progress. After three weeks all characteristics of the patient can be inferred from the measured data. The final titration target together with the individual thyroxine half life can be calculated. With the known characteristics and the L-T4 titration target the clinician or treating physician has an instrument to reduce the experimental treatment burden for the patient from one year to a maximum of four weeks.

The Interplay Between Replication Capacity of HIV-1 and Surrogate Markers of Disease.

BACKGROUND: HIV-1 replication capacity (RC) of transmitted/founder viruses may influence the further course of HIV-1 infection. METHODS: RCs of 355 whole-genome primary HIV-1 isolates derived from samples acquired during acute and recent primary HIV-1 infection (PHI) were determined using a novel high-throughput infection assay in primary cells. The RCs were used to elucidate potential factors that could be associated with RC during PHI. RESULTS: Increased RC was found to be associated with increased set point viral load (VL), and significant differences in RCs among 13 different HIV-1 subtypes were discerned. Notably, we observed an increase in RCs for primary HIV-1 isolates of HIV-1 subtype B over a 17-year period. Associations were not observed between RC and CD4 count at sample date of RC measurement, CD4 recovery after initiation of antiretroviral treatment, CD4 decline in untreated individuals, and acute retroviral syndrome severity scores. CONCLUSIONS: These findings highlight that RCs of primary HIV-1 isolates acquired during the acute and recent phase of infection are more associated with viral factors, that is set point VL, than with host factors. Furthermore, we observed a temporal increase in RC for HIV-1 subtype B viruses over a period of 17 years. CLINICAL TRIALS REGISTRATION: NCT00537966.

Influence of NKG2C Genotypes on HIV Susceptibility and Viral Load Set Point.

NKG2C is an activating NK cell receptor encoded by a gene having an unexpressed deletion variant. Cytomegalovirus (CMV) infection expands a population of NKG2C+ NK cells with adaptive-like properties. Previous reports found that carriage of the deleted NKG2C- variant was more frequent in people living with HIV (PLWH) than in HIV- controls unexposed to HIV. The frequency of NKG2C+ NK cells positively correlated with HIV viral load (VL) in some studies and negatively correlated with VL in others. Here, we investigated the link between NKG2C genotype and HIV susceptibility and VL set point in PLWH. NKG2C genotyping was performed on 434 PLWH and 157 HIV-exposed seronegative (HESN) subjects. Comparison of the distributions of the three possible NKG2C genotypes in these populations revealed that the frequencies of NKG2C+/+ and NKG2C+/- carriers did not differ significantly between PLWH and HESN subjects, while that of NKG2C-/- carriers was higher in PLWH than in HESN subjects, in which none were found (P = 0.03, χ2 test). We were unable to replicate that carriage of at least 1 NKG2C- allele was more frequent in PLWH. Information on the pretreatment VL set point was available for 160 NKG2C+/+, 83 NKG2C+/-, and 6 NKG2C-/- PLWH. HIV VL set points were similar between NKG2C genotypes. The frequency of NKG2C+ CD3- CD14- CD19- CD56dim NK cells and the mean fluorescence intensity (MFI) of NKG2C expression on NK cells were higher on cells from CMV+ PLWH who carried 2, versus 1, NKG2C+ alleles. We observed no correlations between VL set point and either the frequency or the MFI of NKG2C expression. IMPORTANCE We compared NKG2C allele and genotype distributions in subjects who remained HIV uninfected despite multiple HIV exposures (HESN subjects) with those in the group PLWH. This allowed us to determine whether NKG2C genotype influenced susceptibility to HIV infection. The absence of the NKG2C-/- genotype among HESN subjects but not PLWH suggested that carriage of this genotype was associated with HIV susceptibility. We calculated the VL set point in a subset of 252 NKG2C-genotyped PLWH. We observed no between-group differences in the VL set point in carriers of the three possible NKG2C genotypes. No significant correlations were seen between the frequency or MFI of NKG2C expression on NK cells and VL set point in cytomegalovirus-coinfected PLWH. These findings suggested that adaptive NK cells played no role in establishing the in VL set point, a parameter that is a predictor of the rate of treatment-naive HIV disease progression.

Oxcarbazepine was associated with risks of newly developed hypothyroxinaemia and impaired central set point of thyroid homeostasis in schizophrenia patients.

AIMS: Hypothyroxinaemia might be easily ignored, because attention is typically paid to individuals with elevated thyroid stimulating hormone (TSH). In this study, we aimed to evaluate the association of oxcarbazepine use as adjuvant for treatment of schizophrenia with hypothyroxinaemia and central set point of thyroid homeostasis. METHODS: This retrospective cohort study was conducted in the Second Affiliated Hospital of Xinxiang Medical University. Inpatients with a diagnosis of schizophrenia admitted between January 2016 and October 2019 with normal thyroid function at admission were included. Oxcarbazepine use was the exposure measure. Newly developed hypothyroxinaemia was the primary outcome measure and parameters of thyroid homeostasis central set point as measured by TSH index and thyroid feedback quantile-based index (TFQI) were the secondary outcome measures. RESULTS: In total, 1207 eligible patients were included. The occurrence of hypothyroxinaemia in patients who received oxcarbazepine was higher (35/107, 32.7%) than in those patients who did not (152/1099, 13.8%), with adjusted relative risk of 2.24 and 95% confidence interval of 1.57 and 3.17. Oxcarbazepine use was associated with greater reduction in TSH index (adjusted ß -0.33 and 95% confidence interval -0.48, -0.19) and TFQI (adjusted ß -0.24 and 95% confidence interval -0.31, -0.16). CONCLUSION: Oxcarbazepine use was independently associated with increased risk of developing hypothyroxinaemia, and greater reduction in TSH index and TFQI, suggesting that impaired central set point of thyroid homeostasis might be involved in the mechanism of oxcarbazepine-induced hypothyroxinaemia.

Is Obesity or Adiposity-Based Chronic Disease Curable: The Set Point Theory, the Environment, and Second-Generation Medications.

Adiposity-based chronic disease (ABCD) requires life-long treatment and follow up. Obesity protects obesity through altered regulation of caloric intake and set point mechanisms, which help maintain a high equilibrium body weight. Lifestyle interventions and obesity medications do not permanently alter the set point, which often makes weight loss achieved using lifestyle changes short-lived and operates to drive weight regain once medications are discontinued. Bariatric surgery procedures can alter appetite and lower the "set point" for the equilibrium body weight via unknown mechanisms. However, few patients attain an ideal body weight following surgery, many regain weight, and all require long-term follow up for the disease. The excess adiposity associated with ABCD gives rise to complications that impair health and confer morbidity and mortality; however, the genetic risks and potential interactions between genes and the environment that give rise to complications cannot be eliminated. The equilibrium body weight around which set point mechanisms operate can be modified by the environment, which underscores the importance of a less obesogenic environment for the prevention and treatment of ABCD on a population basis. Whether ABCD will eventually be curable will depend on a clear understanding of the molecular mechanisms that determine the set point regulation of body weight and the ability to permanently modulate the set point to oscillate around a lean body mass. However, the conceptualization of ABCD as a chronic disease does present us with opportunities for primary, secondary, and tertiary prevention to avert disease progression. For tertiary care, the advent of new, more effective second-generation obesity medications will allow clinicians to treat to target via active management of body weight into a target range that will ameliorate specific complications.

Improving the applicability of the thermo-physiological human simulator by correcting its local set point skin temperatures.

The thermo-physiological human simulator has been used in many regions for estimating thermal behavior of the locals. The applicability of the human simulator to populations from different regions is, however, questioned due to its lack of consideration for the ethnic diversities in thermoregulation. This study checked the potential of improving the applicability of the Newton human simulator, one of the most popular simulators, by correcting its local set point skin temperatures according to the target population (Chinese as an example). First, new set point skin temperatures were obtained by conducting tests with 101 Chinese under a thermal neutral condition. Then, simulator tests using the original and new set point skin temperatures were conducted separately for evaluating thermal responses of the Chinese under non-neutral conditions. The evaluated skin and core temperatures by the simulators were compared with those measured from the real human tests. It demonstrated that the evaluated skin temperatures are positively related with the set point skin temperatures of the simulator. Adjusting set point skin temperatures according to the Chinese improved the prediction performance of the local skin temperatures, with the root-mean-square-deviation being reduced for over 50% of the body segments. The proposed idea of correcting local set point skin temperatures would contribute to evaluating the thermal interaction between human body and its surroundings with a higher accuracy.

Antiobesity drugs before and after bariatric surgery - how to make the best use of them.

Obesity as a chronic, serious, and progressive lifelong disease requires an active approach to treatment. Treatment means necessary adjustment of lifestyle with suitable regular physical activity, including pharmacological or bariatric support. Current pharmacological treatment can be an effective helper in the preparation for the surgical treatment of obesity (bariatric and metabolic operations), and in greater adherence of the patient to the necessary regime changes in life and in preoperative weight reduction. With the lapse of time after surgical treatment, in many cases we indicate the start of pharmacological treatment if the weight increases again. We do not yet know the appropriate types of patients and the exact indications for specific therapeutic modalities - a suitable antiobesity drug or type of bariatric surgery. The best long-term results come from a combination of at least two of these options, along with a lifestyle change. Among modern antiobesity drugs, there are naltrexone-bupropion and liraglutide. Orlistat can be mentioned from older ones.

Trajectories in life satisfaction before and during COVID-19 with respect to perceived valence and self-efficacy.

Actions taken by governments to counteract the spread of the COVID-19 pandemic led to profound restrictions in daily lives, especially for adolescents and young adults, with closed schools and universities, travel restrictions, and reduction in social contacts. The purpose of the current study is to investigate the development of life satisfaction with assessments before and during the pandemic, including separate measurement occasions during a strict lockdown and when the implemented restrictions were relaxed again. Data are based on the German Personality Panel (GePP) with 1,920 young adults, assessed on four measurement occasions over a period of three years. Using latent change score modeling, we investigate the outbreak of the COVID-19 pandemic with respect to its perception as a critical life event over time. Further, we examine the influence of self-efficacy on change in life-satisfaction, as the belief in one's innate abilities has been shown to promote health related behavior and buffers against effects of negatively perceived critical life events. While average life satisfaction remained stable across time, we found a main effect of perceived positive valence and self-efficacy on latent change in life satisfaction at the within person level. Expressions of self-efficacy did not moderate the influence of the perception of the pandemic on self-reported life satisfaction. This study provides an important contribution to the recent COVID-19 literature as well as to the debate on stability and change of self-reported life satisfaction.

Profiling retrospective thyroid function data in complete thyroidectomy patients to investigate the HPT axis set point (PREDICT-IT).

BACKGROUND: The homeostatic euthyroid set point of the hypothalamus-pituitary-thyroid axis of any given individual is unique and oscillates narrowly within substantially broader normal population ranges of circulating free thyroxine (FT4) and thyroid-stimulating hormone (TSH), otherwise termed 'thyroid function test (TFT)'. We developed a mathematical algorithm codenamed Thyroid-SPOT that effectively reconstructs the personalized set point in open-loop situations and evaluated its performance in a retrospective patient sample. METHODS: We computed the set points of 101 patients who underwent total thyroidectomy for non-functioning thyroid disease using Thyroid-SPOT on each patient's own serial post-thyroidectomy TFT. Every predicted set point was compared against its respective healthy pre-operative euthyroid TFT per individual and their separation (i.e. predicted-observed TFT) quantified. RESULTS: Bland-Altman analysis to measure the agreement between each pair of an individual's predicted and actual set points revealed a mean difference in FT4 and TSH of + 3.03 pmol/L (95% CI 2.64, 3.43) and - 0.03 mIU/L (95% CI - 0.25, 0.19), respectively. These differences are small compared to the width of the reference intervals. Thyroid-SPOT can predict the euthyroid set point remarkably well, especially for TSH with a 10-16-fold spread in magnitude between population normal limits. CONCLUSION: Every individual's equilibrium euthyroid set point is unique. Thyroid-SPOT serves as an accurate, precise and reliable targeting system for optimal personalized restoration of euthyroidism. This algorithm can guide clinicians in L-thyroxine dose titrations to resolve persistent dysthyroid symptoms among challenging cases harbouring "normal TFT" within the laboratory ranges but differing significantly from their actual euthyroid set points.

Change and stability: Within-person life satisfaction over a 20-year period using data from the HUNT survey.

Background: The aim of the present study was to investigate within-person life satisfaction (LS) dynamics for two age groups, 20-29 and 30-39 years, from 1984 to 1986 and to follow them over a 20-year period. Methods: Data from 1984 to 2008 were extracted from the large, prospective, longitudinal North-Trøndelag Health Study (HUNT), Norway. This paper includes data from more than 14,500 persons. Data were analysed using logistic regression, and LS dynamics were modelled using gender, time and self-rated health. Results: The analyses revealed that about 20% of people in these age groups had a stable level in LS, also known as set point. Long-term LS change, defined as ⩾2 SDs, was reported for 9% and 6% of people in the youngest and oldest age groups, respectively. A large proportion of more than 70% of people had fluctuations in their LS over a 20-year period. A significant decrease in within-person LS was seen for the age groups from 1984-86 to 1995-97 where a significant increase appeared from 1995-97 to 2006-08. For the initial 20-29 age group, the odds of having a higher score increased by 34%, and for the initial 30-39 age group, the within-person LS increase was 81%. Self-rated health was the most crucial variable influencing within-person LS. Conclusions: These findings suggest that a significant proportion of the responders had a long-term within-person LS change over the 20-year period.

O-GlcNAc cycling mediates energy balance by regulating caloric memory.

Caloric need has long been thought a major driver of appetite. However, it is unclear whether caloric need regulates appetite in environments offered by many societies today where there is no shortage of food. Here we observed that wildtype mice with free access to food did not match calorie intake to calorie expenditure. While the size of a meal affected subsequent intake, there was no compensation for earlier under- or over-consumption. To test how spontaneous eating is subject to caloric control, we manipulated O-linked ß-N-acetylglucosamine (O-GlcNAc), an energy signal inside cells dependent on nutrient access and metabolic hormones. Genetic and pharmacological manipulation in mice increasing or decreasing O-GlcNAcylation regulated daily intake by controlling meal size. Meal size was affected at least in part due to faster eating speed. Without affecting meal frequency, O-GlcNAc disrupted the effect of caloric consumption on future intake. Across days, energy balance was improved upon increased O-GlcNAc levels and impaired upon removal of O-GlcNAcylation. Rather than affecting a perceived need for calories, O-GlcNAc regulates how a meal affects future intake, suggesting that O-GlcNAc mediates a caloric memory and subsequently energy balance.

Extended PKM Fixturing System for Micro-Positioning and Vibration Rejection in Machining Application.

The paper aims to present a mechatronic device able to micro-position the workpiece and to reject disturbances due to machining operation. A decoupling method is proposed for a parallel kinematic machine (PKM) fixturing platform composed by a 3-DoF flexure-based piezo-actuated mechanism. The parallel platform, with a vertical motion and two rotations, is described and its kinematics and dynamics are studied. The coupling undesirable effect is investigated based on a set of poses. To improve the quasi-static regulator model for a set-point following system, a bump less switching controller and a fine-tuning procedure, to estimate the parameter uncertainty and enable the external disturbance containment in an extended broadband frequency range, are presented. The platform and the piezo-actuator controllers are modelled based on a gain scheduling, standard ISA form method, to guarantee the stability. The accuracy is demonstrated through a set of simulations and experimental comparisons. A sensitivity analysis that evaluates the tracking performance and the disturbance rejection based on the number of signal amplitudes, frequencies, and phases is discussed. A validation phase has shown that the developed architecture presents a steady state error lower than 1.2 µm, a vibration reduction of 96% at 1130 Hz with a maximum resolving time of 6.60 ms.

AtDRO1 is nuclear localized in root tips under native conditions and impacts auxin localization.

DEEPER ROOTING 1 (DRO1) contributes to the downward gravitropic growth trajectory of roots upstream of lateral auxin transport in monocots and dicots. Loss of DRO1 function leads to horizontally oriented lateral roots and altered gravitropic set point angle, while loss of all three DRO family members results in upward, vertical root growth. Here, we attempt to dissect the roles of AtDRO1 by analyzing expression, protein localization, auxin gradient formation, and auxin responsiveness in the atdro1 mutant. Current evidence suggests AtDRO1 is predominantly a membrane-localized protein. Here we show that VENUS-tagged AtDRO1 driven by the native AtDRO1 promoter complemented an atdro1 Arabidopsis mutant and the protein was localized in root tips and detectable in nuclei. atdro1 primary and lateral roots showed impairment in establishing an auxin gradient upon gravistimulation as visualized with DII-VENUS, a sensor for auxin signaling and proxy for relative auxin distribution. Additionally, PIN3 domain localization was not significantly altered upon gravistimulation in atdro1 primary and lateral roots. RNA-sequencing revealed differential expression of known root development-related genes in atdro1 mutants. atdro1 lateral roots were able to respond to exogenous auxin and AtDRO1 gene expression levels in root tips were unaffected by the addition of auxin. Collectively, the data suggest that nuclear localization may be important for AtDRO1 function and suggests a more nuanced role for DRO1 in regulating auxin-mediated changes in lateral branch angle. KEY MESSAGE: DEEPER ROOTING 1 (DRO1) when expressed from its native promoter is predominately localized in Arabidopsis root tips, detectable in nuclei, and impacts auxin gradient formation.

What is pH regulation, and why do cancer cells need it?

Metabolism is a continuous source of acids. To keep up with a desired metabolic rate, tumors must establish an adequate means of clearing their acidic end-products. This homeostatic priority is achieved by various buffers, enzymes, and transporters connected through the common denominator of H+ ions. Whilst this complexity is proportionate to the importance of adequate pH control, it is problematic for developing an intuition for tracking the route taken by acids, assessing the relative importance of various acid-handling proteins, and predicting the outcomes of pharmacological inhibition or genetic alteration. Here, with the help of a simplified mathematical framework, the genesis of cancer pH regulation is explained in terms of the obstacles to efficient acid venting and how these are overcome by specific molecules, often associated with cancer. Ultimately, the pH regulatory apparatus in tumors must (i) provide adequate lactic acid permeability through membranes, (ii) facilitate CO2/HCO3-/H+ diffusivity across the interstitium, (iii) invest in a form of active transport that strikes a favorable balance between intracellular pH and intracellular lactate retention under the energetic constraints of a cell, and (iv) enable the necessary feedback to complete the homeostatic loop. A more informed and quantitative approach to understanding acid-handling in cancer is mandatory for identifying vulnerabilities, which could be exploited as therapeutic targets.

CEP receptor signalling controls root system architecture in Arabidopsis and Medicago.

Root system architecture (RSA) influences the effectiveness of resources acquisition from soils but the genetic networks that control RSA remain largely unclear. We used rhizoboxes, X-ray computed tomography, grafting, auxin transport measurements and hormone quantification to demonstrate that Arabidopsis and Medicago CEP (C-TERMINALLY ENCODED PEPTIDE)-CEP RECEPTOR signalling controls RSA, the gravitropic set-point angle (GSA) of lateral roots (LRs), auxin levels and auxin transport. We showed that soil-grown Arabidopsis and Medicago CEP receptor mutants have a narrower RSA, which results from a steeper LR GSA. Grafting showed that CEPR1 in the shoot controls GSA. CEP receptor mutants exhibited an increase in rootward auxin transport and elevated shoot auxin levels. Consistently, the application of auxin to wild-type shoots induced a steeper GSA and auxin transport inhibitors counteracted the CEP receptor mutant's steep GSA phenotype. Concordantly, CEP peptides increased GSA and inhibited rootward auxin transport in wild-type but not in CEP receptor mutants. The results indicated that CEP-CEP receptor-dependent signalling outputs in Arabidopsis and Medicago control overall RSA, LR GSA, shoot auxin levels and rootward auxin transport. We propose that manipulating CEP signalling strength or CEP receptor downstream targets may provide means to alter RSA.