Foxm1 regulates cardiomyocyte proliferation in adult zebrafish after cardiac injury.

The regenerative capacity of the mammalian heart is poor, with one potential reason being that adult cardiomyocytes cannot proliferate at sufficient levels to replace lost tissue. During development and neonatal stages, cardiomyocytes can successfully divide under injury conditions; however, as these cells mature their ability to proliferate is lost. Therefore, understanding the regulatory programs that can induce post-mitotic cardiomyocytes into a proliferative state is essential to enhance cardiac regeneration. Here, we report that the forkhead transcription factor Foxm1 is required for cardiomyocyte proliferation after injury through transcriptional regulation of cell cycle genes. Transcriptomic analysis of injured zebrafish hearts revealed that foxm1 expression is increased in border zone cardiomyocytes. Decreased cardiomyocyte proliferation and expression of cell cycle genes in foxm1 mutant hearts was observed, suggesting it is required for cell cycle checkpoints. Subsequent analysis of a candidate Foxm1 target gene, cenpf, revealed that this microtubule and kinetochore binding protein is also required for cardiac regeneration. Moreover, cenpf mutants show increased cardiomyocyte binucleation. Thus, foxm1 and cenpf are required for cardiomyocytes to complete mitosis during zebrafish cardiac regeneration.

Stabilization of Diborynes versus Destabilization of Diborenes by Coordination of Lewis Bases: Unravelling the Dichotomy.

We have quantum chemically investigated the boron-boron bonds in B2 , diborynes B2 L2 , and diborenes B2 H2 L2 (L=none, OH2 , NH3 ) using dispersion-corrected relativistic density functional theory at ZORA-BLYP-D3(BJ)/TZ2P. B2 has effectively a single B-B bond provided by two half π bonds, whereas B2 H2 has effectively a double B=B bond provided by two half π bonds and one σ 2p-2p bond. This different electronic structure causes B2 and B2 H2 to react differently to the addition of ligands. Thus, in B2 L2 , electron-donating ligands shorten and strengthen the boron-boron bond whereas, in B2 H2 L2 , they lengthen and weaken the boron-boron bond. The aforementioned variations in boron-boron bond length and strength become more pronounced as the Lewis basicity of the ligands L increases.

Blueshift in Trifurcated Hydrogen Bonds: A Tradeoff between Tetrel Bonding and Steric Repulsion.

We have quantum chemically investigated the origin of the atypical blueshift of the H-C bond stretching frequency in the hydrogen-bonded complex X- •••H3 C-Y (X, Y=F, Cl, Br, I), as compared to the corresponding redshift occurring in Cl- •••H3 N and Cl- •••H3 C-H, using relativistic density functional theory (DFT) at ZORA-BLYP-D3(BJ)/QZ4P. Previously, this blueshift was attributed, among others, to the contraction of the H-C bonds as the H3 C moiety becomes less pyramidal. Herein, we provide quantitative evidence that, instead, the blueshift arises from a direct and strong X- •••C interaction of the HOMO of A- with the backside lobe on carbon of the low-lying C-Y antibonding σ* LUMO of the H3 C-Y fragment. This X- •••C bond, in essence a tetrel bond, pushes the H atoms towards a shorter H-C distance and makes the H3 C moiety more planar. The blueshift may, therefore, serve as a diagnostic for tetrel bonding.

Blueshift in Trifurcated Hydrogen Bonds: A Tradeoff between Tetrel Bonding and Steric Repulsion.

The front cover artwork is provided by the TheoCheM group at the Vrije Universiteit Amsterdam. The image shows how, in X- •••H3 C-Y complexes, the Lewis base X- tetrel-binds to the central C while sterically pushing the H atoms towards C; hence, the compression and blueshift of the H-C bonds. Read the full text of the Research Article at 10.1002/cphc.202300480.

Clinical implications of additional chromosomal abnormalities in adult acute myeloid leukemia with inv (16)/t(16;16)/CBFB::MYH11.

OBJECTIVES: This study assesses the clinical significance of additional cytogenetic abnormalities (ACAs) and/or the deletion of 3'CBFB (3'CBFBdel) resulting in unbalanced CBFB::MYH11 fusion in acute myeloid leukemia (AML) with inv (16)/t(16;16)/CBFB::MYH11. METHODS: We retrospectively evaluated the clinicopathologic features of 47 adult de novo AML with inv (16)/t(16;16)/CBFB::MYH11 fusion. There were 44 balanced and 3 unbalanced CBFB::MYH11 fusions. Given the low frequency of unbalanced cases, the latter group was combined with 19 published cases (N = 22) for statistic and meta-analysis. RESULTS: Both balanced and unbalanced cases were characterized by frequent ACAs (56.5% and 72.7%, respectively), with +8, +22, and del(7q) as the most frequent abnormalities. The unbalanced group tends to be younger individuals (p = .04) and is associated with a lower remission rate (p = .02), although the median overall survival (OS) was not statistically different (p = .2868). In the balanced group, "ACA" subgroup had higher mortality (p = .013) and shorter OS (p = .011), and patients with relapsed disease had a significantly shorter OS (p = .0011). Cox multivariate regression analysis confirmed that ACAs and history of disease relapse are independent risk factors, irrespective of disease relapse status. In the combined cohort, cases with ACAs had shorter OS than those with "Sole" abnormality (p = .0109). CONCLUSIONS: ACAs are independent high-risk factors in adult AML with inv (16)/t(16;16)/CBFB::MYH11 fusion and should be integrated for risk stratification in this disease. Larger studies are needed to assess the clinical significance of the unbalanced CBFB::MYH11 fusion resulting from the 3'CBFBdel.

Multiple hydrogen-bonded dimers: are only the frontier atoms relevant?

Non-frontier atom exchanges in hydrogen-bonded aromatic dimers can induce significant interaction energy changes (up to 6.5 kcal mol-1). Our quantum-chemical analyses reveal that the relative hydrogen-bond strengths of N-edited guanine-cytosine base pair isosteres, which cannot be explained from the frontier atoms, follow from the charge accumulation in the monomers.

Brain morphometry and estimation of aging brain in subjects with congenital untreated isolated GH deficiency.

PURPOSE: Individuals with isolated GH deficiency (IGHD) due to a mutation in the GHRH receptor gene have a normal life expectancy and above 50 years of age, similar total cognitive performance, with better attention and executive function than controls. Our objectives were to evaluate their brain morphometry and brain aging using MRI. METHODS: Thirteen IGHD and 14 controls matched by age, sex, and education, were enrolled. Quantitative volumetric data and cortical thickness were obtained by automatic segmentation using Freesurfer software. The volume of each brain region was normalized by the intracranial volume. The difference between the predicted brain age estimated by MRI using a trained neuronal network, and the chronological age, was obtained. p < 0.005 was considered significant and 0.005 < p < 0.05 as a suggestive evidence of difference. RESULTS: In IGHD, most absolute values of cortical thickness and regional brain volumes were similar to controls, but normalized volumes were greater in the white matter in the frontal pole and in the insula bilaterally, and in the gray matter, in the right insula and in left Caudate (p < 0.005 for all comparisons) We also noticed suggestive evidence of a larger volume in IGHD in left thalamus (p = 0.006), right thalamus (p = 0.025), right caudate (p = 0.046) and right putamen (p = 0.013). Predicted brain ages were similar between groups. CONCLUSION: IGHD is primarily associated with similar absolute brain measurements, and a set of larger normalized volumes, and does not appear to alter the process of brain aging.

Excess of body weight is associated with accelerated T-cell senescence in hospitalized COVID-19 patients.

BACKGROUND: Several risk factors have been involved in the poor clinical progression of coronavirus disease-19 (COVID-19), including ageing, and obesity. SARS-CoV-2 may compromise lung function through cell damage and paracrine inflammation; and obesity has been associated with premature immunosenescence, microbial translocation, and dysfunctional innate immune responses leading to poor immune response against a range of viruses and bacterial infections. Here, we have comprehensively characterized the immunosenescence, microbial translocation, and immune dysregulation established in hospitalized COVID-19 patients with different degrees of body weight. RESULTS: Hospitalised COVID-19 patients with overweight and obesity had similarly higher plasma LPS and sCD14 levels than controls (all p < 0.01). Patients with obesity had higher leptin levels than controls. Obesity and overweight patients had similarly higher expansions of classical monocytes and immature natural killer (NK) cells (CD56+CD16-) than controls. In contrast, reduced proportions of intermediate monocytes, mature NK cells (CD56+CD16+), and NKT were found in both groups of patients than controls. As expected, COVID-19 patients had a robust expansion of plasmablasts, contrasting to lower proportions of major T-cell subsets (CD4 + and CD8+) than controls. Concerning T-cell activation, overweight and obese patients had lower proportions of CD4+CD38+ cells than controls. Contrasting changes were reported in CD25+CD127low/neg regulatory T cells, with increased and decreased proportions found in CD4+ and CD8+ T cells, respectively. There were similar proportions of T cells expressing checkpoint inhibitors across all groups. We also investigated distinct stages of T-cell differentiation (early, intermediate, and late-differentiated - TEMRA). The intermediate-differentiated CD4 + T cells and TEMRA cells (CD4+ and CD8+) were expanded in patients compared to controls. Senescent T cells can also express NK receptors (NKG2A/D), and patients had a robust expansion of CD8+CD57+NKG2A+ cells than controls. Unbiased immune profiling further confirmed the expansions of senescent T cells in COVID-19. CONCLUSIONS: These findings suggest that dysregulated immune cells, microbial translocation, and T-cell senescence may partially explain the increased vulnerability to COVID-19 in subjects with excess of body weight.

Anatomy of the posterior Fossa: a comprehensive description for pediatric brain tumors.

Posterior fossa tumors are the most common pediatric brain tumors, and present unique challenges in terms of their location and surgical management. The posterior fossa comprehends complex anatomy and represents the smallest and deepest of the three cranial base fossae. An in-depth understanding of posterior fossa anatomy is crucial when it comes to the surgical resection of pediatric brain tumors. Mastering the knowledge of posterior fossa anatomy helps the neurosurgeon in achieving a maximal and safe volumetric resection, that impacts in both overall and progression free survival. With the advancements in microsurgery, the telovelar approach has emerged as the workhorse technique for the resection of posterior fossa tumors in pediatric patients. This approach involves meticulously dissecting of the natural clefts present in the cerebellomedullary fissure, making a comprehensive understanding of the underlying anatomy key for its success.

Impacts of bycatch from beach seining: a case study of a shrimp fishery in Brazil.

It is commonly assumed that beach seining (BS) is more sustainable than bottom trawling because it involves non-motorized operations and limited fishing power. However, no scientific evidence supports this assumption. To address this gap, we evaluated the impact of beach seining, taking a small-scale shrimp fishery in northeast Brazil. Data collected monthly from December 2016 to November 2017 and in literature, were assessed (BS 31,001 individuals, 119 species, 37 families, and 19 orders; BT 6,031 individuals, 58 species, 20 families, and 14 orders). Beach seining demonstrated a lower proportion of bycatch (BS 1:2.3; BT 1:3.2), higher total shrimp catch (BS 87.2 t; BT 65 t), and greater species diversity than bottom trawling catches (BS 119; BT 58). Other aspects were closer associated with bottom trawling, such as the composition of dominant families (Sciaenidae and Pristigasteridae), the proportion of rare species (BS 30%; BT 24%) juveniles (BS 11g; BT 13g), the risk of species extinction, and the composition of ecological guilds. Despite their social significance, both fishing gears showed similar ecological indicators and adverse effects. The findings establish that the ecological concerns related to the impact of bottom trawling are also applicable to beach seine.

Unveiling the reproductive and migrative behavior of Trichiurus lepturus in a tropical environment: Insights and implications.

This study aimed to understand the reproductive biology and migrative behavior of the largehead hairtail Trichiurus lepturus in a tropical area, specifically off Pernambuco coast, northeastern Brazil. Commercial catches from fish corrals provided samples for analysis, including measurements, weight recording, and examination of gonads to determine its maturation stage. Reproductive analyses were performed, such as sex ratio, gonado-somatic index, and sizes at first maturity. There was a slightly higher proportion of females among the 141 largehead hairtail specimens analysed. No significant differences were observed in length distributions between males and females. However, during the winter, significant differences were observed in length distributions for grouped sexes. The species exhibited a seasonal migratory pattern, with a higher presence on the continental shelf during the winter. The study identified strategic allocation of energy in feeding activities and temporal spacing of reproductive cycles, as indicated by the sex ratio and abundance of individuals during different seasons. Fish corrals probably do not harm largehead hairtail population off the southwestern Atlantic tropical coast, with minimal capture of individuals below the size of first maturity. The insights of the study into reproductive and migration patterns contribute to future assessments and management strategies for this species and corral fisheries.

An equatorial mid-Atlantic Ocean archipelago as nursery area for the cookiecutter shark: Investigating foraging strategies of neonates through bite mark inferences.

This study delves into the foraging ecology of the cookiecutter shark (Isistius brasiliensis) in the Saint Peter and Saint Paul Archipelago (SPSPA), assessing bite marks on pelagic fishes collected between March and September 2018. Examination of 200 individuals from five species revealed the shark's predilection for targeting adult fish, ensuring efficient removal of energy-rich tissue layers. However, a notable exception is Thunnus albacares, preyed on predominantly during its juvenile stage, possibly due to vertical spatial segregation. Recent bites were pervasive across species, with wahoo displaying a distinctive pattern. Cookiecutter shark bites predominantly targeted the lateral body portion (>55%) except for yellowfin tuna, which exhibited a preference for the ventral region (95%). The estimated length distribution suggests the SPSPA as a potential nursery area for cookiecutter sharks. Bite mark positions and frequencies may be linked to fish behavior, swimming velocity, and fishing gear strategy, highlighting the complex interplay in pelagic ecosystems.

Experimental and Computational Analysis of Synthesis Conditions of Hybrid Nanoflowers for Lipase Immobilization.

This work presents a framework for evaluating hybrid nanoflowers using Burkholderia cepacia lipase. It was expanded on previous findings by testing lipase hybrid nanoflowers (hNF-lipase) formation over a wide range of pH values (5-9) and buffer concentrations (10-100 mM). The free enzyme activity was compared with that of hNF-lipase. The analysis, performed by molecular docking, described the effect of lipase interaction with copper ions. The morphological characterization of hNF-lipase was performed using scanning electron microscopy. Fourier Transform Infrared Spectroscopy performed the physical-chemical characterization. The results show that all hNF-lipase activity presented values higher than that of the free enzyme. Activity is higher at pH 7.4 and has the highest buffer concentration of 100 mM. Molecular docking analysis has been used to understand the effect of enzyme protonation on hNF-lipase formation and identify the main the main binding sites of the enzyme with copper ions. The hNF-lipase nanostructures show the shape of flowers in their micrographs from pH 6 to 8. The spectra of the nanoflowers present peaks typical of the amide regions I and II, current in lipase, and areas with P-O vibrations, confirming the presence of the phosphate group. Therefore, hNF-lipase is an efficient biocatalyst with increased catalytic activity, good nanostructure formation, and improved stability.

Emergence of carbapenem-resistant Klebsiella pneumoniae species complex from agrifood systems: detection of ST6326 co-producing KPC-2 and NDM-1.

BACKGROUND: Klebsiella pneumoniae species complex (KpSC) is an important disseminator of carbapenemase-encoding genes, mainly blaKPC-2 and blaNDM-1, from hospitals to the environment. Consequently, carbapenem-resistant strains can be spread through the agrifood system, raising concerns about food safety. This study therefore aimed to isolate carbapenem-resistant KpSC strains from the agricultural and environmental sectors and characterize them using phenotypic, molecular, and genomic analyses. RESULTS: Klebsiella pneumoniae and Klebsiella quasipneumoniae strains isolated from soils used for lemon, guava, and fig cultivation, and from surface waters, displayed an extensive drug-resistance profile and carried blaKPC-2, blaNDM-1, or both. In addition to carbapenemase-encoding genes, KpSC strains harbor a broad resistome (antimicrobial resistance and metal tolerance) and present putative hypervirulence. Soil-derived K. pneumoniae strains were assigned as high-risk clones (ST11 and ST307) and harbored the blaKPC-2 gene associated with Tn4401b and Tn3-like elements on IncN-pST15 and IncX5 plasmids. In surface waters, the coexistence of blaKPC-2 and blaNDM-1 genes was identified in K. pneumoniae ST6326, a new carbapenem-resistant regional Brazilian clone. In this case, blaKPC-2 with Tn4401a isoform and blaNDM-1 associated with a Tn125-like transposon were located on different plasmids. Klebsiella quasipneumoniae ST526 also presented the blaNDM-1 gene associated with a Tn3000 transposon on an IncX3 plasmid. CONCLUSION: These findings provide a warning regarding the transmission of carbapenemase-positive KpSC across the agricultural and environmental sectors, raising critical food safety and environmental issues. © 2024 Society of Chemical Industry.

Genetic diversity of KPC-2-producing Klebsiella pneumoniae complex from aquatic ecosystems.

During the COVID-19 pandemic, the occurrence of carbapenem-resistant Klebsiella pneumoniae increased in human clinical settings worldwide. Impacted by this increase, international high-risk clones harboring carbapenemase-encoding genes have been circulating in different sources, including the environment. The blaKPC gene is the most commonly disseminated carbapenemase-encoding gene worldwide, whose transmission is carried out by different mobile genetic elements. In this study, blaKPC-2-positive Klebsiella pneumoniae complex strains were isolated from different anthropogenically affected aquatic ecosystems and characterized using phenotypic, molecular, and genomic methods. K. pneumoniae complex strains exhibited multidrug-resistant and extensively drug-resistant profiles, spotlighting the resistance to carbapenems, ceftazidime-avibactam, colistin, and tigecycline, which are recognized as last-line antimicrobial treatment options. Molecular analysis showed the presence of several antimicrobial resistance, virulence, and metal tolerance genes. In-depth analysis showed that the blaKPC-2 gene was associated with three different Tn4401 isoforms (i.e., Tn4401a, Tn4401b, and Tn4401i) and NTEKPC elements. Different plasmid replicons were detected and a conjugative IncN-pST15 plasmid harboring the blaKPC-2 gene associated with Tn4401i was highlighted. K. pneumoniae complex strains belonging to international high-risk (e.g., ST11 and ST340) and unusual clones (e.g., ST323, ST526, and ST4216) previously linked to clinical settings. In this context, some clones were reported for the first time in the environmental sector. Therefore, these findings evidence the occurrence of carbapenemase-producing K. pneumoniae complex strains in aquatic ecosystems and contribute to the monitoring of carbapenem resistance worldwide.

Colonization With Antibiotic-Resistant Bacteria in a Hospital and Associated Communities in Guatemala: An Antibiotic Resistance in Communities and Hospitals (ARCH) Study.

BACKGROUND: We estimated the prevalence of colonization with extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE) and carbapenem-resistant Enterobacterales (CRE) from a hospital and associated communities in western Guatemala. METHODS: Randomly selected infants, children, and adults (<1, 1-17, and ≥18 years, respectively) were enrolled from the hospital (n = 641) during the coronavirus disease 2019 (COVID-19) pandemic, March to September 2021. Community participants were enrolled using a 3-stage cluster design between November 2019 and March 2020 (phase 1, n = 381) and between July 2020 and May 2021 (phase 2, with COVID-19 pandemic restrictions, n = 538). Stool samples were streaked onto selective chromogenic agar, and a Vitek 2 instrument was used to verify ESCrE or CRE classification. Prevalence estimates were weighted to account for sampling design. RESULTS: The prevalence of colonization with ESCrE and CRE was higher among hospital patients compared to community participants (ESCrE: 67% vs 46%, P < .01; CRE: 37% vs 1%, P < .01). Hospital ESCrE colonization was higher for adults (72%) compared with children (65%) and infants (60%) (P < .05). Colonization was higher for adults (50%) than children (40%) in the community (P < .05). There was no difference in ESCrE colonization between phase 1 and 2 (45% and 47%, respectively, P > .05), although reported use of antibiotics among households declined (23% and 7%, respectively, P < .001). CONCLUSIONS: While hospitals remain foci for ESCrE and CRE colonization, consistent with the need for infection control programs, community prevalence of ESCrE in this study was high, potentially adding to colonization pressure and transmission in healthcare settings. Better understanding of transmission dynamics and age-related factors is needed.

Bexarotene drives the self-renewing proliferation of adult neural stem cells, promotes neuron-glial fate shift, and regulates late neuronal differentiation.

Treatment with bexarotene, a selective retinoid X receptor (RXR) agonist, significantly improves behavioral dysfunctions in various neurodegenerative animal models. Additionally, it activates neurodevelopmental and plasticity pathways in the brains of adult mice. Our objective was to investigate the impact of RXR activation by bexarotene on adult neural stem cells (aNSC) and their cell lineages. To achieve this, we treated NSCs isolated from the subventricular zone (SVZ) of adult rat brains from the proliferative stage to the differentiated status. The results showed that bexarotene-treated aNSC exhibited increased BrdU incorporation, SOX2+ dividing cell pairs, and cell migration from neurospheres, revealing that the treatment promotes self-renewing proliferation and cell motility in SVZ-aNCS. Furthermore, bexarotene induced a cell fate shift characterized by a significant increase in GFAP+/S100B+ differentiated astrocytes, which uncovers the participation of activated-RXR in astrogenesis. In the neuronal lineage, the fate shift was counteracted by bexarotene-induced enhancement of NeuN+ nuclei together with neurite network outgrowth, indicating that the RXR agonist stimulates SVZ-aNCS neuronal differentiation at later stages. These findings establish new connections between RXR activation, astro- and neurogenesis in the adult brain, and contribute to the development of therapeutic strategies targeting nuclear receptors for neural repair.

Promoter deletion in the soybean Compact mutant leads to overexpression of a gene with homology to the C20-gibberellin 2-oxidase family.

Height is a critical component of plant architecture, significantly affecting crop yield. The genetic basis of this trait in soybean remains unclear. In this study, we report the characterization of the Compact mutant of soybean, which has short internodes. The candidate gene was mapped to chromosome 17, and the interval containing the causative mutation was further delineated using biparental mapping. Whole-genome sequencing of the mutant revealed an 8.7 kb deletion in the promoter of the Glyma.17g145200 gene, which encodes a member of the class III gibberellin (GA) 2-oxidases. The mutation has a dominant effect, likely via increased expression of the GA 2-oxidase transcript observed in green tissue, as a result of the deletion in the promoter of Glyma.17g145200. We further demonstrate that levels of GA precursors are altered in the Compact mutant, supporting a role in GA metabolism, and that the mutant phenotype can be rescued with exogenous GA3. We also determined that overexpression of Glyma.17g145200 in Arabidopsis results in dwarfed plants. Thus, gain of promoter activity in the Compact mutant leads to a short internode phenotype in soybean through altered metabolism of gibberellin precursors. These results provide an example of how structural variation can control an important crop trait and a role for Glyma.17g145200 in soybean architecture, with potential implications for increasing crop yield.

d-Limonene complexed with cyclodextrin attenuates cardiac arrhythmias in an experimental model of doxorubicin-induced cardiotoxicity: Possible involvement of calcium/calmodulin-dependent protein kinase type II.

BACKGROUND: Arrhythmias are one manifestation of the cardiotoxicity that results from doxorubicin (Doxo) administration. Although cardiotoxicity is an anticipated outcome in anticancer therapies, there is still a lack of treatment options available for its effective management. This study sought to evaluate the possible cardioprotective effect of complex d-limonene (DL) plus hydroxypropyl-ß-cyclodextrin (HßDL) during treatment with Doxo, focusing on the arrhythmic feature. METHODS: Cardiotoxicity was induced in Swiss mice with Doxo 20 mg/kg, with 10 mg/kg of HßDL being administered 30 min before the Doxo. Plasma CK-MB and LDH levels were analyzed. Cellular excitability and susceptibility to cardiac and cardiomyocyte arrhythmias were evaluated using in vivo (pharmacological cardiac stress) and in vitro (burst pacing) ECG protocols. Ca2+ dynamics were also investigated. The expression of CaMKII and its activation by phosphorylation and oxidation were evaluated by western blot, and molecular docking was used to analyze the possible interaction between DL and CaMKII. RESULTS: Electrocardiograms showed that administration of 10 mg/kg of HßDL prevented Doxo-induced widening of the QRS complex and QT interval. HßDL also prevented cardiomyocyte electrophysiological changes that trigger cellular arrhythmias, such as increases in action potential duration and variability; decreased the occurrence of delayed afterdepolarizations (DADs) and triggered activities (TAs), and reduced the incidence of arrhythmia in vivo. Ca2+ waves and CaMKII overactivation caused by phosphorylation and oxidation were also decreased. In the in silico study, DL showed potential inhibitory interaction with CaMKII. CONCLUSION: Our results show that 10 mg/kg of ßDL protects the heart against Doxo-induced cardiotoxicity arrhythmias, and that this is probably due to its inhibitory effect on CaMKII hyperactivation.

Intermolecular Covalent Interactions: Nature and Directionality.

Quantum chemical methods were employed to analyze the nature and the origin of the directionality of pnictogen (PnB), chalcogen (ChB), and halogen bonds (XB) in archetypal Fm Z⋅⋅⋅F- complexes (Z=Pn, Ch, X), using relativistic density functional theory (DFT) at ZORA-M06/QZ4P. Quantitative Kohn-Sham MO and energy decomposition analyses (EDA) show that all these intermolecular interactions have in common that covalence, that is, HOMO-LUMO interactions, provide a crucial contribution to the bond energy, besides electrostatic attraction. Strikingly, all these bonds are directional (i.e., F-Z⋅⋅⋅F- is approximately linear) despite, and not because of, the electrostatic interactions which, in fact, favor bending. This constitutes a breakdown of the σ-hole model. It was shown how the σ-hole model fails by neglecting both, the essential physics behind the electrostatic interaction and that behind the directionality of electron-rich intermolecular interactions. Our findings are general and extend to the neutral, weaker ClI⋅⋅⋅NH3 , HClTe⋅⋅⋅NH3 , and H2 ClSb⋅⋅⋅NH3 complexes.