Endogenous Control Mechanisms Research Articles

Experimental Therapeutic Strategies for Severe Sepsis

Severe sepsis is the leading cause of mortality in intensive care units. The limited ability of current therapies to reduce sepsis mortality rates has fueled research efforts for the development of novel treatment strategies. Through the close collaboration between clinicians and scientists, progress can be seen in the struggle to develop effective therapeutic approaches for the treatment of sepsis and other immune and inflammatory disorders. Indeed, significant advances in intensive care, such as lung protective mechanical ventilation, improved antibiotics, and superior monitoring of systemic perfusion, are improving patient survival. Nonetheless, specific strategies that target the pathophysiological disorders in sepsis patients are essential to further improve clinical outcomes. This article reviews current clinical management approaches and experimental interventions that target pleiotropic or late-acting inflammatory mediators like caspases, C5a, MIF, and HMGB1, or the body's endogenous inflammatory control mechanisms such as the cholinergic anti-inflammatory pathway. These inflammatory mediators and anti-inflammatory mechanisms, respectively, show significant potential for the development of new experimental therapies for the treatment of severe sepsis and other infectious and inflammatory disorders.

Imaging pain modulation in health and disease

In this review, we discuss recent advances in pain imaging research. We focus on the involvement of endogenous pain control mechanisms in the healthy central nervous system and the potential contribution of failure within this system for chronic pain states. Nociceptive information processing and related pain perception is subject to substantial pro and antinociceptive modulation. Recent studies demonstrate that this modulation can take place at any stage of ascending information processing. A network of cortical, predominantly mesial and frontal areas, in combination with specific brainstem nuclei, appear to be the key players in the context of endogenous pain modulation. Recent findings from functional and anatomical neuroimaging support the notion that an altered interaction of pro and antinociceptive mechanisms may contribute to the development or maintenance of chronic pain states. The additional use of pharmacological intervention in pain imaging research provides an alternative tool for investigating mechanisms of pain modulation. Top-down pain modulation relies on both cortical and subcortical structures. Research on the involved circuitry, including the implemented mechanisms, is a major focus of contemporary neuroscientific research in the field of pain and will provide new insights into the prevention and treatment of chronic pain states.

Venous responses during exercise in rainbow trout, Oncorhynchus mykiss: α-adrenergic control and the antihypotensive function of the renin–angiotensin system

The role of the α-adrenergic system in the control of cardiac preload (central venous blood pressure; P ven) and venous capacitance during exercise was investigated in rainbow trout ( Oncorhynchus mykiss). In addition, the antihypotensive effect of the renin–angiotesin system (RAS) was investigated during exercise after α-adrenoceptor blockade. Fish were subjected to a 20-min exercise challenge at 0.66 body lengths s −1 (BL s −1) while P ven, dorsal aortic blood pressure ( P da) and relative cardiac output ( Q) was recorded continuously. Heart rate ( f H), cardiac stroke volume (SV) and total systemic resistance ( R sys) were derived from these variables. The mean circulatory filling pressure (MCFP) was measured at rest and at the end of the exercise challenge, to investigate potential exercise-mediated changes in venous capacitance. The protocol was repeated after α-adrenoceptor blockade with prazosin (1 mg kg −1 M b) and again after additional blockade of angiotensin converting enzyme (ACE) with enalapril (1 mg kg −1 M b). In untreated fish, exercise was associated with a rapid (within approx. 1–2 min) and sustained increase in Q and P ven associated with a significant increase in MCFP (0.17 ± 0.02 kPa at rest to 0.27 ± 0.02 kPa at the end of exercise). Prazosin treatment did not block the exercise-mediated increase in MCFP (0.25 ± 0.04 kPa to 0.33 ± 0.04 kPa at the end of exercise), but delayed the other cardiovascular responses to swimming such that Q and P ven did not increase significantly until around 10–13 min of exercise, suggesting that an endogenous humoral control mechanism had been activated. Subsequent enalapril treatment revealed that these delayed responses were in fact due to activation of the RAS, because resting P da and R sys were decreased further and essentially all cardiovascular changes during exercise were abolished. This study shows that the α-adrenergic system normally plays an important role in the control of venous function during exercise in rainbow trout. It is also the first study to suggest that the RAS may be an important modulator of venous pressure and capacitance in fish.

Distribution of GABAergic neurons in the striatum of amygdala-kindled rats: An immunohistochemical and in situ hybridization study

A large body of experimental evidence suggests that the basal ganglia circuitry may be part of a remote control system modulating the spread of epileptic seizures. In the kindling model of temporal lobe epilepsy, this endogenous inhibitory control mechanism seems to be impaired. Neurochemical and neurophysiological studies have indicated that the activity of the GABAergic projection from the striatum to the substantia nigra pars reticulata is reduced in kindled rats, but the exact mechanisms involved in this observation are not known. Possible explanations include a kindling-induced loss of striatal GABAergic projection neurons to the substantia nigra or enhanced inhibition of these neurons by GABAergic interneurons. In the present experiments, the GABAergic system of the striatum (caudate–putamen) of amygdala-kindled rats and controls was studied immunohistochemically with a monoclonal antibody to GABA and with nonisotopic in situ hybridization with cRNA probes selective for glutamic acid decarboxylase 65 (GAD65) and GAD67, respectively. Compared to sham controls, an increased density of neurons heavily labeled for GAD67 mRNA was observed in the anterior striatum of kindled rats when cells were counted 6 weeks after the last kindled seizure. This subgroup of striatal GABAergic neurons has been suggested previously to correspond to the medium-sized aspiny interneurons in the striatum, indicating that kindling is associated with an increased activity of these neurons. Our previous finding of reduced GAD and GABA levels in synaptosomes isolated from the substantia nigra of kindled rats together with the present observation of increased density of GABAergic striatal interneurons in such rats suggest that kindling affects the regulation of the GABAergic projections from the striatum to the substantia nigra rather than directly damaging GABAergic neurons in the striatum.

Common scale-invariant patterns of sleep-wake transitions across mammalian species.

Although mammals of different species have different sleep patterns, brief sleep-wake transitions commonly are observed across species and appear to occur randomly throughout the sleeping period. The dynamical patterns and functions of these brief awakenings from sleep are not well understood, and they often are viewed as disruptions (random or pathologic) of the sleep process. In this article, we hypothesize that brief awakenings from sleep may reflect aspects of the endogenous sleep control mechanism and thus may exhibit certain robust dynamical patterns across species. We analyze sleep recordings from mice, rats, cats, and humans, and we compare the distributions of sleep and wake episode durations. For all four species, we find that durations of brief wake episodes during the sleep period exhibit a scale-free power-law behavior with an exponent alpha that remains the same for all species (alpha approximately equal to 2.2). In contrast, sleep episode durations for all four species follow exponential distributions with characteristic time scales, which change across species in relation to body mass and metabolic rate. Our findings suggest common dynamical features of brief awakenings and sleep durations across species and may provide insights into the dynamics of the neural circuits controlling sleep.

Oncogenic Kinase Signaling in Human Neoplasms

Oncogenic proteins participate in cellular functions that involve transduction of signals from the extracellular environment, through the membrane, into the cytoplasm towards the nucleus, where transcription is initiated to generate proteins that will eventually contribute to the oncogenic phenotype. The wild-type homologues of cellular oncoproteins (proto-oncoproteins) frequently participate in signal transduction mechanisms that regulate cell and tissue homeostasis. Deregulation of proto-oncoprotein expression or function results in altered cellular signaling, oncogenic transformation, and inhibition of apoptosis. Oncogenic signals initiated from mutant proteins can override endogenous homeostasis control mechanisms such as anoikis and apoptosis and result in anchorage-independent growth, uncontrolled proliferation, and metastasis.

Peptides that fine-tune the serotonin system

The dorsal raphe nucleus (DR) contains serotonin (5-HT) neurons that innervate the cortex and limbic system and through these projections is thought to regulate cognition and behavior. Clinical and pharmacological findings implicate dysfunctions in the DR-5-HT system in affective disorders, including anxiety, depression and suicide. Although the DR is often considered in light of its 5-HT neurons, recent studies underscore the complexity of this nucleus and its heterogeneous nature. Of particular interest, are peptides that are either present within neurons in the DR, innervate DR-5-HT neurons or act upon local circuitry within the DR to indirectly impact on this 5-HT system. These peptides are positioned to fine-tune the activity of selective groups of serotonergic neurons within the DR and thereby 5-HT release in different terminal fields. This review will focus on substance P and corticotropin-releasing factor as two peptides that act independently and interdependently to influence DR-5-HT function. The role of non-serotonergic components of the DR in translating the effect of each of these peptides is discussed. This synthesis refines our views on the regulation of the DR-5-HT system and importantly, gives insight into mechanisms of endogenous control of DR function, the dysregulation of which may contribute to pathophysiology.

Naloxone Fails to Antagonize Initial Hypoalgesic Effect of a Manual Therapy Treatment for Lateral Epicondylalgia

Background Recent research has shown that Mulligan’s Mobilization With Movement treatment technique for the elbow (MWM), a peripheral joint mobilization technique, produces a substantial and immediate pain relief in chronic lateral epicondylalgia (48% increase in pain-free grip strength). [1] This hypoalgesic effect is far greater than that previously reported with spinal manual therapy treatments, prompting speculation that peripheral manual therapy treatments may differ in mechanism of action to spinal manual therapy techniques. Naloxone antagonism and tolerance studies, which employ widely accepted tests for the identification of endogenous opioid-mediated pain control mechanisms, have shown that spinal manual therapy-induced hypoalgesia does not involve an opioid mechanism. Objective The aim of this study was to evaluate the effect of naloxone administration on the hypoalgesic effect of MWM. Methods A randomized, controlled trial evaluated the effect of administering naloxone, saline, or no-substance control injection on the MWM-induced hypoalgesia in 18 participants with lateral epicondylalgia. Pain-free grip strength, pressure pain threshold, thermal pain threshold, and upper limb neural tissue provocation test 2b were the outcome measures. Results The results demonstrated that the initial hypoalgesic effect of the MWM was not antagonized by naloxone, suggesting a nonopioid mechanism of action. Conclusions The studied peripheral mobilization treatment technique appears to have a similar effect profile to previously studied spinal manual therapy techniques, suggesting a nonopioid-mediated hypoalgesia following manual therapy.

Circadian Clock-Controlled Regulation of cGMP-Protein Kinase G in the Nocturnal Domain

The suprachiasmatic nucleus (SCN) circadian clock exhibits a recurrent series of dynamic cellular states, characterized by the ability of exogenous signals to activate defined kinases that alter clock time. To explore potential relationships between kinase activation by exogenous signals and endogenous control mechanisms, we examined clock-controlled protein kinase G (PKG) regulation in the mammalian SCN. Signaling via the cGMP-PKG pathway is required for light- or glutamate (GLU)-induced phase advance in late night. Spontaneous cGMP-PKG activation occurred at the end of subjective night in free-running SCN in vitro. Phasing of the SCN rhythm in vitro was delayed by approximately 3 hr after treatment with guanylyl cyclase (GC) inhibitors, PKG inhibition, or antisense oligodeoxynucleotide (alphaODN) specific for PKG, but not PKA inhibitor or mismatched ODN. This sensitivity to GC-PKG inhibition was limited to the same 2 hr time window demarcated by clock-controlled activation of cGMP-PKG. Inhibition of the cGMP-PKG pathway at this time caused delays in the phasing of four endogenous rhythms: wheel-running activity, neuronal activity, cGMP, and Per1. Timing of the cGMP-PKG-necessary window in both rat and mouse depended on clock phase, established by the antecedent light/dark cycle rather than solar time. Because behavioral, neurophysiological, biochemical, and molecular rhythms showed the same temporal sensitivities and qualitative responses, we predict that clock-regulated GC-cGMP-PKG activation may provide a necessary cue as to clock state at the end of the nocturnal domain. Because sensitivity to phase advance by light-GLU-activated GC-cGMP-PKG occurs in juxtaposition, these signals may induce a premature shift to this PKG-necessary clock state.

The mechanisms of endogenous control of hepatocyte proliferation are different in mice of two inbred strains (BALB/c and AKR).

The mechanisms of endogenous control of hepatocyte proliferation are different in mice of two inbred strains (BALB/c and AKR).

Specific deletion of autoreactive T cells by adenovirus-transfected, Fas ligand-producing antigen-presenting cells.

Immune privilege is a unique strategy developed in several internal organs that can prevent the development of immune attack against these vital organs. One critical mechanism of immune privilege is utilization of Fas/FasL-mediated apoptosis to delete the invading T cells at the immune privilege sites. In this article, we describe the development and application of a unique cell-gene therapy to correct defective FasL-mediated apoptosis and autoimmune disease in autoimmune mice. This cell-gene therapy strategy using antigen-presenting cells (APCs) to express FasL is not only a therapeutic tool, but also has allowed us to understand the complexity of T cell regulation and the concept of eliminating T cells in the spleen, lymph node, or elsewhere in vivo to regulate the homeostasis of the peripheral T cell response. In this regard, the FasL-expressing APCs can be considered as circulating and regulatable immune privilege sites. Our studies provide substantial evidence that FasL-expressing APCs can be introduced exogenously without liver toxicity to eliminate infiltrating T cells and prevent the development of immune attack in lung, liver, kidney, joint, and salivary gland. Therefore, given the hazardous potential of persistent T cell invasion at the local inflammatory site, it is tempting to speculate that such an endogenous control mechanism occurs normally in vivo to limit a chronic T cell inflammatory response.

Photosynthesis controls of rhizosphere respiration and organic matter decomposition

The effects of shading wheat plants on rhizosphere respiration and rhizosphere priming of soil organic matter decomposition were investigated by using a natural abundance 13C tracer method and 14C pulse labeling simultaneously. Seven days with strongly reduced photosynthesis (12/60 h day/night period) resulted in only half of the total CO 2 efflux from soil compared to the treatment with a 12/12 h day/night period. The CO 2 efflux from unplanted soil amounted to only 12 and 20% of the total CO 2 efflux from the soil with non-shaded and shaded plants, respectively. On average 75% of total CO 2 efflux from the planted soil with prolonged night periods was root-derived. Rhizosphere respiration was tightly coupled with plant photosynthetic activity. Any factor affecting photosynthesis, or substrate supply to roots and rhizosphere microorganisms, is an important determinant of root-derived CO 2 efflux, and thereby, total CO 2 efflux from soils. Clear diurnal dynamics of the total CO 2 efflux intensity indicate the existence of an endogenous control mechanism of rhizosphere respiration. The light-on events after prolonged dark periods lead to strong increases of root-derived and therefore of total CO 2 efflux from soil. After 14C pulse labeling, two maxima of the root-derived 14CO 2 efflux were measured (6 and 24 h). This result demonstrated the diurnal dynamics of the rhizosphere respiration of recently-assimilated C in both the normal light conditions and shaded plants as well. The total amount of root-derived C respired in the rhizosphere was 17.3 and 20.6% of the total assimilated C for non-shaded and shaded plants, respectively. Both methods used, 13C natural abundance and 14C pulse labeling, gave similar estimates of root-derived CO 2 during the whole observation period: 1.80±0.27 and 1.67±0.37 mg C kg −1 h −1 (±SD), respectively. Both tracer methods show that the cultivation of wheat led to the increasing decomposition intensity of soil organic matter (priming effect). Additionally, 13C natural abundance allows tracing of the dynamics of the priming effect depending on the light-on events.

The NK1 Receptor Is Essential for the Full Expression of Noxious Inhibitory Controls in the Mouse

Behavioral analysis of the NK1 receptor gene knock-out (NK1-/-) mouse indicated that substance P was closely involved in orchestrating the physiological and behavioral response of the animal to major environmental stressors. In particular, endogenous pain control mechanisms, such as stress-induced analgesia were substantially impaired in mutant mice, suggesting a reduction in descending inhibitory controls to the spinal cord from the brainstem. To directly test the integrity of descending controls in NK1-/- mice, we have analyzed c-Fos expression in laminae I-II of the lumbar and cervical cord and in the rostral ventromedial medulla in an experimental paradigm known to require recruitment of descending inhibitory controls. Anesthetized mice were stimulated with water at 50 degrees C either on their forepaw, hindpaw, or on both the hindpaw plus forepaw concurrently. Wild-type mice, naive or treated with an NK1 antagonist (RP67580) or its inactive isomer (RP68651), were compared with NK1-/- mice. C-Fos expression at the lumbar laminae I-II level was significantly reduced, whereas it was significantly greater in the raphe magnus and pallidus nuclei in the double stimulation situation in wild-type compared with NK1-/- mice. Blocking the NK1 receptor pharmacologically reproduced, in an enantiomere-selective manner, the data from NK1-/- mice, with no evidence for recruitment of descending inhibition at the lumbar cord level after forepaw stimulation. The present study demonstrates that the NK1 receptor is essential for the full development of noxiously evoked descending inhibition.

Cell cycle-dependent expression of cyclooxygenase-2 in human fibroblasts.

The purpose of this investigation is to determine whether the levels of cyclooxygenase-2 (COX-2) expression are cell cycle dependent. We used a serum-starved human foreskin fibroblast model to determine changes in COX-2 mRNA, protein, and promoter activity in response to stimulation with interleukin-1b (IL-1b) and phorbol 12-myristate 13-acetate (PMA) at G0, G1, S and G2/M phases of the cell cycle. IL-1b (1 ng/ml) and PMA (100 nM) induced robust COX-2 expression in the G0 cells, and the level of COX-2 expression declined progressively after the cells had entered the cell cycle. The COX-2 mRNA level at G1, S and G2/M phases of the cell cycle was 76%, 46%, and 30% of that at G0, respectively. A 5-flanking promoter fragment of COX-2 constructed into a luciferase expression vector was transfected into cells. The promoter activity in response to PMA stimulation was significantly higher in G0 than in S phase cells. These results imply that G0 cells are the key players in inflammation and other COX-2-dependent pathophysiological processes. When the cells are in the proliferative phase, COX-2 inducibility becomes restrained probably by an endogenous control mechanism to avoid COX-2 mediated oxidative DNA damage.

Textbook of Pain

Part 1 Basic aspects: peripheral - peripheral neural mechnaisms of nociception, the course and termination of primary afferent fibres, teh pathophysiology of damaged peripheral nerves, functional chemistry of primary afferent neurons central - the dorsal horn, the origin and destination of pathways involved in pain transmission, visceral versus somatic mechanisms, experimental data related to nociception and pain at the supraspinal level, deafferentation and central pain, the central pharmacology of pain transmission, endogenous pain control mechanism psychological - emotional aspects of pain, cognitive aspects of pain, acute versus chronic pain, methods of assessing pain in animals, methods of testing pain mechanisms in normal man, testing pain mechanisms in persons in pain. Part 2 Clinical aspects of disease in which pain predominates: soft tissue, joints and bone - acute and postoperative pain, osteoarthritis, rheumatoid arthritis, orthopaedic pain after trauma, back pain, the failed back, evaluation of the patient presenting with upper-extremity pain, myosascial pain syndromes, headache, the pain of burns deep and visceral pain - heart, muscle, eye, orofacial, abdominal, gynaecologica, labour and genitourinary pain nerve and root damage - phantom pain and related phenomena after amputation, peripheral neuropathies, tic douloureux and atypical face pain, nerve root damage and arachnoiditis pain in children carcinoma - cancer pain, carcinoma invading nerve, psychological and social aspects of cancer pain, pain and impending death central nervous system - central pain due to spinal cord and brain stem damage, pain and psychological medicine. Part 3 Therapeutic aspects: pharmacology - non-narcotic analgesics, opioids, psychotropic drugs local blockade - local anaesthesia and regional blocks, epidural and anaesthetics and narcotics, pharmacological target blocks in painful dystrophic limbs lesions - peripheral nerve and root chemical lesions, sympathetic ganglion lesions, root, disc and orthopaedic surgery, operations in the brain stem and spinal canal, percutaneous cordotomy, stereotactic surgery, pituitary destruction, psychosurgery for pain stimulation - segmental afferent fiber-induced analgesia, folk medicine and the sensory modualation of pain, acupuncture analgesia and therpy, spinal cord stimulation, brain stimulation physiotherapy - ultrasound, shortwave, microwave, superficial heat and cold in the treatment of pain, manipulation and massage, movement education radiotherapy and chemotherapy pysychotherapy - pain and illness behaviour relaxation and biofeedback, a cognitive-behavioural approach to pain management, a collaborative model of care, behaviour therapy, hypnosis, pain and litigation.

Coagulation inhibitor replacement in sepsis is a potentially useful clinical approach

In sepsis, levels of the endogenous coagulation inhibitors antithrombin III and protein C are lowered as a result of complex formation with multiple activated clotting factors. In addition, their activity can further be curtailed by proteolytic inactivation. Loss of antithrombin III and protein C activity blocks the endogenous control mechanism for thrombin generation resulting in a state of systemic activation of coagulation and inflammatory processes. Levels of tissue factor pathway inhibitor, a third endogenous coagulation inhibitor, are increased in sepsis rather than decreased, probably reflecting a depletion of the endothelial cell bound tissue factor pathway inhibitor pool with loss of its endothelial protective function. Administration of any of these three inhibitors in various animal species and sepsis models reduces morbidity and mortality. In addition to their anticoagulant effects, these inhibitors also have various anti-inflammatory activities that may contribute to their protective effects. Phase II studies in patients with severe sepsis using coagulation inhibitors have indicated that this therapeutic approach may be useful. Large-scale phase III trials will ultimately decide whether adjunctive coagulation inhibitor replacement will have a place in the treatment of patients with severe sepsis.

Physiology and pathophysiology of pain

Pain is described as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. A painful stimulus elicits an activation of receptors in the periphery which transduce the stimulus into an electrical impulse. This electrical impulse is transmitted to the dorsal horn of the spinal cord and subsequently to the brain. Here the stimulus is perceived as a painful experience in the context of the specific situation and earlier experiences. In its physiological function, pain serves the prevention of tissue injury. If tissue injury occurs, pain becomes persistent leading to changes in the neuroplasticity of the periphery, spinal cord and the brain. This results in an enhanced sensitivity of the nervous system against both noxious and unnoxious stimuli. In parallel, endogenous control mechanisms, in which predominantly the opioid but also other systems are involved, counteract these pathological changes. Both the initiation of pain and its control can be regarded as the body's response to prevent further injury, to support wound healing, and to return to a normal function as quickly as possible. The transition from acute to chronic pain may critically depend on disturbances of the intrinsic pain control mechanisms as well as on effective therapeutic measures, initiated at the earliest possible time.

Programmed cell death in rat microglia is controlled by extracellular adenosine

The induction of programmed cell death by adenosine was investigated in cultured rat microglial cells using the enzyme-linked immunosorbent assay (ELISA) for determining DNA fragmentation. Twelve hours exposure to micromolar levels of the unselective adenosine receptor agonist 2-chloro-adenosine led to the appearance of DNA fragments in the cytosolic fraction preceding damage of the plasma membrane. This effect was still seen in the presence of an adenosine uptake blocker. Conventional A 1, A 2 or A 3 agonists and antagonists were rather ineffective, suggesting mediation via an atypical adenosine receptor subtype. Microglial DNA fragmentation was inhibited by H-7 and staurosporine but not by dibutyryl-cyclic AMP, pointing to a protein kinase C linked mechanism. Such an induction of programmed cell death by an elevation of the extracellular adenosine concentration may provide an endogenous control mechanism to limit the function of activated microglial cells.

Control of rod retinomotor movements in teleost retinae: the role of dopamine in mediating light-dependent and circadian signals.

In the retinae of lower vertebrates, several morphological changes, including photomechanical movements of rods, cones and pigment epithelium, occur during light and dark adaptation. We studied the contribution of exogenous and endogenous circadian control mechanisms to rod retinomotor movements in the teleost retina and their dependence on an intact dopaminergic system. Blue acara (Aequidens pulcher) were kept under a 12:12 h light/dark cycle. One population of fish remained untreated; another population was treated with 6-hydroxy-dopamine, selectively to destroy dopaminergic cells. Rod positions were determined in semi-thin radial sections. During the normal light/dark cycle, rods were elongated during the day and contracted at night. Rod retinomotor movements persisted during two cycles of continuous darkness. Expected light levels of rod positions were reduced by about 40% in comparison with normal light phases. Adaptation-dependent retinomotor movements and movements driven by an endogenous circadian clock also occurred in dopamine-depleted retinae. No statistically significant differences were observed between dopamine-containing and dopamine-depleted retinae. We conclude that rod retinomotor movements in teleost retinae are controlled by light and by an endogenous circadian clock. Dopamine plays no essential role in the light-dependent and endogenous control of rod retinomotor movements.

Plasmodesmal companion cell-mesophyll communication in the control over carbon metabolism and phloem transport: insights gained from viral movement proteins

Many plant viruses encode for a protein(s) that is essential for movement from the site of replication to surrounding, uninfected cells. These proteins have the ability to interact with endogenous plasmodesmal proteins to increase the plasmodesmal size exclusion limit (SEL). When expressed in transgenic tobacco plants, the movement protein of tobacco mosaic virus (TMV-MP), in addition to increasing the SEL, also alters the biomass partitioning and carbon allocation within these plants. During the day, source leaves of transgenic plants that express the TMV-MP accumulate sugars and starch and biomass partitioning into root tissue is reduced when compared with vector control plants. However, studies with transgenic tobacco plants expressing various mutant forms of the TMV-MP, as well as plants expressing the MP of cucumber mosaic virus, established that the effect on biomass partitioning and carbon allocation is independent of its effect on plasmodesmal SEL. Graft experiments and analysis of transgenic tobacco and potato plants expressing the TMV-MP under tissue-specific promoters indicated that mesophyll cells may be the site of TMV-MP action. In the light of these results and evidence that plasmodesmata are capable of trafficking macromolecules, it is proposed that plasmodesmata within the leaf establish a special communication network between the companion cells (CC) and the mesophyll. In this model, output signals from the CC to the mesophyll and input signals from the mesophyll to the CC are involved in regulating photosynthesis occurring within the mesophyll and loading/export that takes place in the CC-SE complex. It is proposed that the TMV-MP-mediated influence on plasmodesmal trafficking of these signal molecules alters this endogenous control mechanism resulting in a shift in biomass partitioning and carbon allocation.