Modulation of central synapse remodeling after remote peripheral injuries by the CCL2-CCR2 axis and microglia.

Microglia-mediated synaptic plasticity after CNS injury varies depending on injury severity, but the mechanisms that adjust synaptic plasticity according to injury differences are largely unknown. This study investigates differential actions of microglia on essential spinal motor synaptic circuits following different kinds of nerve injuries. Following nerve transection, microglia and C-C chemokine receptor type 2 signaling permanently remove Ia axons and synapses from the ventral horn, degrading proprioceptive feedback during motor actions and abolishing stretch reflexes. However, Ia synapses and reflexes recover after milder injuries (nerve crush). These different outcomes are related to the length of microglia activation, being longer after nerve cuts, with slower motor-axon regeneration and extended expression of colony-stimulating factor type 1 in injured motoneurons. Prolonged microglia activation induces CCL2 expression, and Ia synapses recover after ccl2 is deleted from microglia. Thus, microglia Ia synapse removal requires the induction of specific microglia phenotypes modulated by nerve regeneration efficiencies. However, synapse preservation was not sufficient to restore the stretch-reflex function.

Air-stepping in the neonatal mouse: a powerful tool for analyzing early stages of rhythmic limb movement development.

There is a lack of experimental methods in genetically tractable mouse models to analyze the developmental period at which newborns mature weight-bearing locomotion. To overcome this deficit, we introduce methods to study l-3,4-dihydroxyphenylalanine (l-DOPA)-induced air-stepping in mice at postnatal day (P)7 and P10. Air-stepping is a stereotypic rhythmic behavior that resembles mouse walking overground locomotion but without constraints imposed by weight bearing, postural adjustments, or sensory feedback. We propose that air-stepping represents the functional organization of early spinal circuits coordinating limb movements. After subcutaneous injection of l-DOPA (0.5 mg/g), we recorded air-stepping movements in all four limbs and electromyographic (EMG) activity from ankle flexor (tibialis anterior, TA) and extensor (lateral gastrocnemius, LG) muscles. Using DeepLabCut pose estimation, we analyzed rhythmicity and limb coordination. We demonstrate steady rhythmic stepping of similar duration from P7 to P10 but with some fine-tuning of interlimb coordination with age. Hindlimb joints undergo a greater range of flexion at older ages, indicating maturation of flexion-extension cycles as the animal starts to walk. EMG recordings of TA and LG show alternation but with more focused activation particularly in the LG from P7 to P10. We discuss similarities to neonatal rat l-DOPA-induced air-stepping and infant assisted walking. We conclude that limb coordination and muscle activations recorded with this method represent basic spinal cord circuitry for limb control in neonates and pave the way for future investigations on the development of rhythmic limb control in genetic or disease models with correctly or erroneously developing motor circuitry.NEW & NOTEWORTHY We present novel methods to study neonatal air-stepping in newborn mice. These methods allow analyses at the onset of limb coordination during the period in which altricial species like rats, mice, and humans "learn" to walk. The methods will be useful to test a large variety of mutations that serve as models of motor disease in newborns or that are used to probe for specific circuit mechanisms that generate coordinated limb motor output.

SPINAL V1 INHIBITORY INTERNEURON CLADES DIFFER IN BIRTHDATE, PROJECTIONS TO MOTONEURONS AND HETEROGENEITY.

Spinal cord interneurons play a crucial role in shaping motor output, but their precise identity and circuit connectivity remain unclear. Focusing on the cardinal class of inhibitory V1 interneurons, we define the diversity of four major V1 subsets according to timing of neurogenesis, genetic lineage-tracing, synaptic output to motoneurons, and synaptic inputs from muscle afferents. Birthdating delineates two early-born (Renshaw and Pou6f2) and two late-born V1 clades (Foxp2 and Sp8) suggesting sequential neurogenesis gives rise to different V1 clades. Neurogenesis did not correlate with motoneuron targeting. Early-born Renshaw cells and late-born Foxp2-V1 interneurons both tightly coupled to motoneurons, while early-born Pou6f2-V1 and late-born Sp8-V1 interneurons did not. V1-clades also greatly differ in cell numbers and diversity. Lineage labeling of the Foxp2-V1 clade shows it contains over half of all V1 interneurons and provides the largest inhibitory input to motoneuron cell bodies. Foxp2-V1 subgroups differ in neurogenesis and proprioceptive input. Notably, one subgroup defined by Otp expression and located adjacent to the lateral motor column exhibits substantial input from proprioceptors, consistent with some Foxp2-V1 cells at this location forming part of reciprocal inhibitory pathways. This was confirmed with viral tracing methods for ankle flexors and extensors. The results validate the previous V1 clade classification as representing unique interneuron subtypes that differ in circuit placement with Foxp2-V1s forming the more complex subgroup. We discuss how V1 organizational diversity enables understanding of their roles in motor control, with implications for the ontogenetic and phylogenetic origins of their diversity. SIGNIFICANCE STATEMENT: Spinal interneuron diversity and circuit organization represents a key challenge to understand the neural control of movement in normal adults and also during motor development and in disease. Inhibitory interneurons are a core element of these spinal circuits, acting on motoneurons either directly or via premotor networks. V1 interneurons comprise the largest group of inhibitory interneurons in the ventral horn and their organization remains unclear. Here we present a comprehensive examination of V1 subtypes according to neurogenesis, placement in spinal motor circuits and motoneuron synaptic targeting. V1 diversity increases during evolution from axial-swimming fishes to limb-based mammalian terrestrial locomotion and this is reflected in the size and heterogeneity of the Foxp2-V1 clade which is closely associated to limb motor pools. We show Foxp2-V1 interneurons establish the densest and more direct inhibitory synaptic input to motoneurons, especially on cell bodies. This is of further importance because deficits on motoneuron cell body inhibitory V1 synapses and on Foxp2-V1 interneurons themselves have recently been shown to be affected at early stages of pathology in motor neurodegenerative diseases like amyotrophic lateral sclerosis.

Correction: Iridium-(κ2-NSi) catalyzed dehydrogenation of formic acid: effect of auxiliary ligands on the catalytic performance.

Correction for 'Iridium-(κ2-NSi) catalyzed dehydrogenation of formic acid: effect of auxiliary ligands on the catalytic performance' by Alejandra Gomez-España et al., Dalton Trans., 2023, 52, 6722-6729, https://doi.org/10.1039/d3dt00744h.

Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe.

The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological ecosystem. Most of the diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in the variable domain of antibodies, mostly in the regions that form the paratope, yielding antibodies with higher antigen binding affinity. However, antigen recognition is only possible if the antibody folds into a stable functional conformation. Therefore, a key force determining the survival of B cell clones undergoing somatic hypermutation is the ability of the mutated heavy and light chains to efficiently fold and assemble into a functional antibody. The antibody is the structural context where the selection of the somatic mutations occurs, and where both the heavy and light chains benefit from protective mechanisms that counteract the potentially deleterious impact of the changes. However, in patients with monoclonal gammopathies, the proliferating plasma cell clone may overproduce the light chain, which is then secreted into the bloodstream. This places the light chain out of the protective context provided by the quaternary structure of the antibody, increasing the risk of misfolding and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma (cast) nephropathy are a diverse group of diseases derived from the pathologic aggregation of light chains, in which somatic mutations are recognized to play a role. In this review, we address the mechanisms by which somatic mutations promote the misfolding and pathological aggregation of the light chains, with an emphasis on AL amyloidosis. We also analyze the contribution of the variable domain (VL) gene segments and somatic mutations on light chain cytotoxicity, organ tropism, and structure of the AL fibrils. Finally, we analyze the most recent advances in the development of computational algorithms to predict the role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and discuss the challenges and perspectives that this approach faces.

Iridium-(κ2-NSi) catalyzed dehydrogenation of formic acid: effect of auxiliary ligands on the catalytic performance.

The iridium(III) complexes [Ir(H)(Cl)(κ2-NSitBu2)(κ2-bipyMe2)] (2) and [Ir(H)(OTf)(κ2-NSitBu2)(κ2-bipyMe2)] (3) (NSitBu2 = {4-methylpyridine-2-yloxy}ditertbutylsilyl) have been synthesized and characterized including X-ray studies of 3. A comparative study of the catalytic activity of complexes 2, 3, [Ir(H)(OTf)(κ2-NSitBu2)(coe)] (4), and [Ir(H)(OTf)(κ2-NSitBu2)(PCy3)] (5) (0.1 mol%) as catalysts precursors for the solventless formic acid dehydrogenation (FADH) in the presence of Et3N (40 mol%) at 353 K has been performed. The highest activity (TOF5 min ≈ 3260 h-1) has been obtained with 3 at 373 K. However, at that temperature the FTIR spectra show traces of CO together with the desired products (H2 and CO2). Thus, the best performance was achieved at 353 K (TOF5 min ≈ 1210 h-1 and no observable CO). Kinetic studies at variable temperature show that the activation energy of the 3-catalyzed FADH process is 16.76 kcal mol-1. Kinetic isotopic effect (5 min) values of 1.6, 4.5, and 4.2 were obtained for the 3-catalyzed dehydrogenation of HCOOD, DCOOH, and DCOOD, respectively, at 353 K. The strong KIE found for DCOOH and DCOOD evidenced that the hydride transfer from the C-H bond of formic acid to the metal is the rate-determining step of the process.

Correction: Iridium-(κ2-NSi) catalyzed dehydrogenation of formic acid: effect of auxiliary ligands on the catalytic performance.

Correction for 'Iridium-(κ2-NSi) catalyzed dehydrogenation of formic acid: effect of auxiliary ligands on the catalytic performance' by Alejandra Gomez-España et al., Dalton Trans., 2023, https://doi.org/10.1039/d3dt00744h.

Exploring the perception of barriers to a dual career by student-athletes with/out disabilities.

In recent years, there has been an increase in knowledge about the barriers experienced by people with disabilities in the education system or sports. However, no studies have analyzed the barriers for those who try to succeed in both disciplines (dual career). The purpose of this study was to examine the barriers faced by student-athletes with/out disability to a dual career combining studies and sport. Two groups were involved in the study (n = 162): student-athletes with disabilities (n = 79) and student-athletes without disabilities (n = 83). Data collected included: (a) socio-demographic aspects; and (b) barriers towards achieving a good balance between sport and academics during the dual career, through the "Perceptions of dual career student-athletes" (ESTPORT) questionnaire. The results showed that student-athletes with disabilities were more likely to perceive in a greater extent the barriers, the university is far from my home (p = 0.007) and the university is far from my training site (p = 0.006), I find myself unable to balance study and training time (p = 0.030), I have to take care of my family (p<0.001), and my current job does not allow me to study enough (p<0.001). The MANOVA analysis showed that the factors gender, competitive level, and employment status had an influence on the perception of some barriers between groups. In conclusion, student-athletes with disabilities perceived barriers more strongly than those without disabilities, and measures are needed to ensure their inclusion in the education system.

Effects of Cannabidiol, Hypothermia, and Their Combination in Newborn Rats with Hypoxic-Ischemic Encephalopathy.

Therapeutic hypothermia is well established as a standard treatment for infants with hypoxic-ischemic (HI) encephalopathy but it is only partially effective. The potential for combination treatments to augment hypothermic neuroprotection has major relevance. Our aim was to assess the effects of treating newborn rats following HI injury with cannabidiol (CBD) at 0.1 or 1 mg/kg, i.p., in normothermic (37.5°C) and hypothermic (32.0°C) conditions, from 7 d of age (neonatal phase) to 37 d of age (juvenile phase). Placebo or CBD was administered at 0.5, 24, and 48 h after HI injury. Two sensorimotor (rotarod and cylinder rearing) and two cognitive (novel object recognition and T-maze) tests were conducted 30 d after HI. The extent of brain damage was determined by magnetic resonance imaging, histologic evaluation, magnetic resonance spectroscopy, amplitude-integrated electroencephalography, and Western blotting. At 37 d, the HI insult produced impairments in all neurobehavioral scores (cognitive and sensorimotor tests), brain activity (electroencephalography), neuropathological score (temporoparietal cortexes and CA1 layer of hippocampus), lesion volume, magnetic resonance biomarkers of brain injury (metabolic dysfunction, excitotoxicity, neural damage, and mitochondrial impairment), oxidative stress, and inflammation (TNFα). We observed that CBD or hypothermia (to a lesser extent than CBD) alone improved cognitive and motor functions, as well as brain activity. When used together, CBD and hypothermia ameliorated brain excitotoxicity, oxidative stress, and inflammation, reduced brain infarct volume, lessened the extent of histologic damage, and demonstrated additivity in some parameters. Thus, coadministration of CBD and hypothermia could complement each other in their specific mechanisms to provide neuroprotection.

Preservation of KCC2 expression in axotomized abducens motoneurons and its enhancement by VEGF.

The potassium chloride cotransporter 2 (KCC2) is the main Cl- extruder in neurons. Any alteration in KCC2 levels leads to changes in Cl- homeostasis and, consequently, in the polarity and amplitude of inhibitory synaptic potentials mediated by GABA or glycine. Axotomy downregulates KCC2 in many different motoneurons and it is suspected that interruption of muscle-derived factors maintaining motoneuron KCC2 expression is in part responsible. In here, we demonstrate that KCC2 is expressed in all oculomotor nuclei of cat and rat, but while trochlear and oculomotor motoneurons downregulate KCC2 after axotomy, expression is unaltered in abducens motoneurons. Exogenous application of vascular endothelial growth factor (VEGF), a neurotrophic factor expressed in muscle, upregulated KCC2 in axotomized abducens motoneurons above control levels. In parallel, a physiological study using cats chronically implanted with electrodes for recording abducens motoneurons in awake animals, demonstrated that inhibitory inputs related to off-fixations and off-directed saccades in VEGF-treated axotomized abducens motoneurons were significantly higher than in control, but eye-related excitatory signals in the on direction were unchanged. This is the first report of lack of KCC2 regulation in a motoneuron type after injury, proposing a role for VEGF in KCC2 regulation and demonstrating the link between KCC2 and synaptic inhibition in awake, behaving animals.

Massive Loss of Proprioceptive Ia Synapses in Rat Spinal Motoneurons after Nerve Crush Injuries in the Postnatal Period.

Peripheral nerve injuries (PNIs) induce the retraction from the ventral horn of the synaptic collaterals of Ia afferents injured in the nerve, effectively removing Ia synapses from α-motoneurons. The loss of Ia input impairs functional recovery and could explain, in part, better recovery after PNIs with better Ia synaptic preservation. Synaptic losses correlate with injury severity, speed, and efficiency of muscle reinnervation and requires ventral microglia activation. It is unknown whether this plasticity is age dependent. In neonates, axotomized motoneurons and sensory neurons undergo apoptosis, but after postnatal day 10 most survive. The goal of this study was to analyze vesicular glutamate transporter 1 (VGluT1)-labeled Ia synapses (which also include II afferents) after nerve crush in 10 day old rats, a PNI causing little Ia/II synapse loss in adult rats. We confirmed fast and efficient reinnervation of leg muscles; however, a massive number of VGluT1/Ia/II synapses were permanently lost. This synapse loss was similar to that after more severe nerve injuries involving full transection in adults. In adults, disappearance of ventrally directed Ia/II collaterals targeting α-motoneurons was associated with a prolonged microglia reaction and a CCR2 mechanism that included infiltration of CCR2 blood immune cells. By contrast, microgliosis after P10 injuries was fast, resolved in about a week, and there was no evidence of peripheral immune cell infiltration. We conclude that VGluT1/Ia/II synapse loss in young animals differs in mechanism, perhaps associated with higher microglia synaptic pruning activity at this age and results in larger losses after milder nerve injuries.

Endothelin Receptor Antagonists in Kidney Disease.

Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines. In this context, ET, via the endothelin receptor type A (ETA) activation, causes sustained vasoconstriction of the afferent arterioles that produces deleterious effects such as hyperfiltration, podocyte damage, proteinuria and, eventually, GFR decline. Therefore, endothelin receptor antagonists (ERAs) have been proposed as a therapeutic strategy to reduce proteinuria and slow the progression of kidney disease. Preclinical and clinical evidence has revealed that the administration of ERAs reduces kidney fibrosis, inflammation and proteinuria. Currently, the efficacy of many ERAs to treat kidney disease is being tested in randomized controlled trials; however, some of these, such as avosentan and atrasentan, were not commercialized due to the adverse events related to their use. Therefore, to take advantage of the protective properties of the ERAs, the use of ETA receptor-specific antagonists and/or combining them with sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been proposed to prevent oedemas, the main ERAs-related deleterious effect. The use of a dual angiotensin-II type 1/endothelin receptor blocker (sparsentan) is also being evaluated to treat kidney disease. Here, we reviewed the main ERAs developed and the preclinical and clinical evidence of their kidney-protective effects. Additionally, we provided an overview of new strategies that have been proposed to integrate ERAs in kidney disease treatment.

Mechanism Insights into the Iridium(III)- and B(C6F5)3-Catalyzed Reduction of CO2 to the Formaldehyde Level with Tertiary Silanes.

The catalytic system [Ir(CF3CO2)(κ2-NSiMe)2] [1; NSiMe = (4-methylpyridin-2-yloxy)dimethylsilyl]/B(C6F5)3 promotes the selective reduction of CO2 with tertiary silanes to the corresponding bis(silyl)acetal. Stoichiometric and catalytic studies evidenced that species [Ir(CF3COO-B(C6F5)3)(κ2-NSiMe)2] (3), [Ir(κ2-NSiMe)2][HB(C6F5)3] (4), and [Ir(HCOO-B(C6F5)3)(κ2-NSiMe)2] (5) are intermediates of the catalytic process. The structure of 3 has been determined by X-ray diffraction methods. Theoretical calculations show that the rate-limiting step for the 1/B(C6F5)3-catalyzed hydrosilylation of CO2 to bis(silyl)acetal is a boron-promoted Si-H bond cleavage via an iridium silylacetal borane adduct.

Synthesis and Characterization of Ir-(κ2-NSi) Species Active toward the Solventless Hydrolysis of HSiMe(OSiMe3)2.

The reaction of [IrH(Cl)(κ2-NSitBu2)(coe)] (1) with 1 equiv of PCy3 (or PHtBu2) gives the species [IrH(Cl)(κ2-NSitBu2)(L)] (L = PCy3, 2a; PHtBu2, 2b), which reacts with 1 equiv of AgOTf to afford [IrH(OTf)(κ2-NSitBu2)(L)] (L = PCy3, 3a and PHtBu2, 3b). Complexes 2a, 2b, 3a, and 3b have been characterized by means of NMR spectroscopy and HR-MS. The solid-state structures of complexes 2a, 2b, and 3a have been determined by X-ray diffraction studies. The reversible coordination of water to 3a, 3b, and 4 to afford the corresponding adduct [IrH(OTf)(κ2-NSitBu2)(L)(H2O)] (L = PCy3, 3a-H2O; PHtBu2, 3b-H2O; coe, 4-H2O) has been demonstrated spectroscopically by NMR studies. The structure of complexes 3b-H2O and 4-H2O have been determined by X-ray diffraction studies. Computational analyses of the interaction between neutral [NSitBu2]• and [Ir(H)L(X)]• fragments in Ir-NSitBu2 species confirm the electron-sharing nature of the Ir-Si bond and the significant role of electrostatics in the interaction between the transition metal fragment and the κ2-NSitBu2 ligand. The activity of Ir-(κ2-NSitBu2) species as catalysts for the hydrolysis of HSiMe(OSiMe3)2 depends on the nature of the ancillary ligands. Thus, while the triflate derivatives are active, the related chloride species show no activity. The best catalytic performance has been obtained when using complexes 3a, with triflate and PCy3 ligands, as a catalyst precursor, which allows the selective obtention of the corresponding silanol.

The Role of Microglia in Neuroinflammation of the Spinal Cord after Peripheral Nerve Injury.

Peripheral nerve injuries induce a pronounced immune reaction within the spinal cord, largely governed by microglia activation in both the dorsal and ventral horns. The mechanisms of activation and response of microglia are diverse depending on the location within the spinal cord, type, severity, and proximity of injury, as well as the age and species of the organism. Thanks to recent advancements in neuro-immune research techniques, such as single-cell transcriptomics, novel genetic mouse models, and live imaging, a vast amount of literature has come to light regarding the mechanisms of microglial activation and alluding to the function of microgliosis around injured motoneurons and sensory afferents. Herein, we provide a comparative analysis of the dorsal and ventral horns in relation to mechanisms of microglia activation (CSF1, DAP12, CCR2, Fractalkine signaling, Toll-like receptors, and purinergic signaling), and functionality in neuroprotection, degeneration, regeneration, synaptic plasticity, and spinal circuit reorganization following peripheral nerve injury. This review aims to shed new light on unsettled controversies regarding the diversity of spinal microglial-neuronal interactions following injury.

Dehydrogenation of formic acid using iridium-NSi species as catalyst precursors.

Using a low loading of the iridium(III) complexes [Ir(CF3SO3)(κ2-NSiiPr)2] (1) (NSiiPr = (4-methylpyridin-2-yloxy)diisopropylsilyl) and [{Ir(κ2-NSiMe)2}2(µ-CF3SO3)2] (2) (NSiMe = (4-methylpyridin-2-yloxy)dimethylsilyl) in the presence of Et3N, it has been possible to achieve the solventless selective dehydrogenation of formic acid. The best catalytic performance (TOF5 min ≈ 2900 h-1) has been achieved with 2 (0.1 mol%) and Et3N (40 mol% to FA) at 373 K. Kinetic studies at variable temperatures show that the activation energy of the 2-catalyzed process at 353 K is 22.8 ± 0.8 kcal mol-1. KIE values of 1.33, 2.86, and 3.33 were obtained for the 2-catalyzed dehydrogenation of HCOOD, DCOOH, and DCOOD, respectively, in the presence of 10 mol% of Et3N at 353 K. These data show that the activation of the C-H bond of FA is the rate-determining step of the process. A DFT mechanistic study for the catalytic cycle involving hydride abstraction from the formate anion by the metal, assisted by a molecule of formic acid, and heterolytic H2 formation has been performed. Moreover, the presence of Ir-formate intermediates was identified by means of NMR studies of the catalytic reactions in thf-d8 at 323 K. In all the cases, the decomposition of the catalyst to give unactive crystalline iridium NPs was observed.

Genetic targeting of adult Renshaw cells using a Calbindin 1 destabilized Cre allele for intersection with Parvalbumin or Engrailed1.

Renshaw cells (RCs) are one of the most studied spinal interneurons; however, their roles in motor control remain enigmatic in part due to the lack of experimental models to interfere with RC function, specifically in adults. To overcome this limitation, we leveraged the distinct temporal regulation of Calbindin (Calb1) expression in RCs to create genetic models for timed RC manipulation. We used a Calb1 allele expressing a destabilized Cre (dgCre) theoretically active only upon trimethoprim (TMP) administration. TMP timing and dose influenced RC targeting efficiency, which was highest within the first three postnatal weeks, but specificity was low with many other spinal neurons also targeted. In addition, dgCre showed TMP-independent activity resulting in spontaneous recombination events that accumulated with age. Combining Calb1-dgCre with Parvalbumin (Pvalb) or Engrailed1 (En1) Flpo alleles in dual conditional systems increased cellular and timing specificity. Under optimal conditions, Calb1-dgCre/Pvalb-Flpo mice targeted 90% of RCs and few dorsal horn neurons; Calb1-dgCre/En1-Flpo mice showed higher specificity, but only a maximum of 70% of RCs targeted. Both models targeted neurons throughout the brain. Restricted spinal expression was obtained by injecting intraspinally AAVs carrying dual conditional genes. These results describe the first models to genetically target RCs bypassing development.

Origin of the Ir-Si bond shortening in Ir-NSiN complexes.

The Ir-Si bond distances reported for Ir-(fac-κ3-NSiNOPy) and Ir-(fac-κ3-NSiN4MeOPy) species (NSiNOPy = bis(pyridine-2-yloxy)methylsilyl and NSiN4MeOPy = bis(4-methyl-pyridine-2-yloxy)methylsily) are in the range of 2.220-2.235 Å. These values are in the lowest limit of the Ir-Si bond distances found in the Cambridge Structural Database (CSD). To understand the origin of such remarkable shortening, a computational study of the bonding situation of representative examples of Ir-(fac-κ3-NSiN) species has been carried out. It is found that the Ir-Si bond can be described as an electron-sharing (i.e. covalent) bond. Despite that, this bond is highly polarized and as a result, the contribution of the electrostatic attractions to the bonding is rather significant. Indeed, there exists a linear relationship (R2 = 0.97) between the Ir-Si bond distance and the extent of the computed electrostatic interactions, which indicates that the ionic contribution to the bonding is mainly responsible for the observed Ir-Si bond shortening.