Metformin alters dendrite development and synaptic plasticity in rat cortical neurons.

Synaptic plasticity is crucial as it dynamically molds the strength and connectivity of neural circuits, influencing learning, memory, and the development of neurological disorders. Metformin, a widely prescribed anti-diabetic medication, has been shown to readily cross the blood-brain barrier (BBB) and the placenta. However, its prolonged impact on neuronal morphology and functions remains underexplored. In this study, we investigated the influence of metformin on dendrite development and synaptic plasticity in embryonic brains and primary rat cortical neurons. Our findings reveal a negative modulation of dendrite development by metformin, as evidenced by altered dendritic arborization, impaired dendritic spine morphology and disruptions in synaptic plasticity, suggesting a potential link between metformin exposure and aberrations in neuronal connectivity. In addition, we extend our insights to the impact of maternal metformin exposure on embryonic brains, revealing a significant inhibition of dendrite development in E18.5 rat brains. In conclusion, this study adds to the expanding knowledge base on the non-metabolic effects of metformin, emphasizing the significance of assessing its potential influence on both neuronal structure and function. There is an urgent need for further investigations into the enduring impact of prolonged metformin administration on the structural and functional aspects of neurons.

The effect of antifibrotic agents on acute respiratory failure in COVID-19 patients: a retrospective cohort study from TriNetX US collaborative networks.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on global health and economies, resulting in millions of infections and deaths. This retrospective cohort study aimed to investigate the effect of antifibrotic agents (nintedanib and pirfenidone) on 1-year mortality in COVID-19 patients with acute respiratory failure. METHODS: Data from 61 healthcare organizations in the TriNetX database were analyzed. Adult patients with COVID-19 and acute respiratory failure were included. Patients with a pre-existing diagnosis of idiopathic pulmonary fibrosis before their COVID-19 diagnosis were excluded. The study population was divided into an antifibrotic group and a control group. Propensity score matching was used to compare outcomes, and hazard ratios (HR) for 1-year mortality were calculated. RESULTS: The antifibrotic group exhibited a significantly lower 1-year mortality rate compared to the control group. The survival probability at the end of the study was 84.42% in the antifibrotic group and 69.87% in the control group. The Log-Rank test yielded a p-value of less than 0.001. The hazard ratio was 0.434 (95% CI: 0.264-0.712), indicating a significant reduction in 1-year mortality in the antifibrotic group. Subgroup analysis demonstrated significantly improved 1-year survival in patients receiving nintedanib treatment and during periods when the Wuhan strain was predominant. DISCUSSION: This study is the first to demonstrate a survival benefit of antifibrotic agents in COVID-19 patients with acute respiratory failure. Further research and clinical trials are needed to confirm the efficacy of these antifibrotic agents in the context of COVID-19 and acute respiratory failure.

Anterior mid-portion capsular tear with Bankart lesion in recurrent anterior shoulder dislocation: outcome report and bone defect evaluation.

INTRODUCTION: This study aimed to report the incidence of anterior mid-portion capsular tears identified during arthroscopic Bankart repair (ABR), the clinical outcomes of repairing this combined lesion, and to evaluate the associated bone defects. METHODS: We retrospectively reviewed the records of patients undergoing ABR between January 2014 and December 2017. Data from patients with capsular tears identified during ABR were included and analyzed. Age, number of dislocations, repair technique, follow-up results, and X-rays were reviewed. The size of the glenoid defect and Hill-Sachs lesion were reviewed via magnetic resonance imaging or magnetic resonance arthrography (MRA). RESULTS: Records of 95 patients undergoing ABR during the study period were reviewed, and nine were included. The overall incidence of capsular tears was 9.5% and the mean age at surgery was 45.3 ± 14.3 years. All cases had > 3 dislocations before treatment. All patients had labral lesions, and one had a glenoid defect. Hill-Sachs lesions were observed in eight patients. Seven patients underwent MRA examination, and all seven showed axillary pouch disruption. Over 3.9 ± 1.1 years of follow-up, there was no instability recurrence, and Rowe scores improved from 42.2 to 96.7 (p < 0.001). CONCLUSIONS: There was no recurrent shoulder instability after combined arthroscopic repair of capsular and Bankart lesions. There were Rowe score improvements over at least three years of follow-up. Although our case number was small, we found that mid-portion capsular tear occurred in patients over 30 years with multiple recurrent dislocations, with or without small glenoid bone defects, and with axillary pouch disruption on MRA images.

Operando Observation of Oxygenated Intermediates during CO Hydrogenation on Rh Single Crystals.

The CO hydrogenation reaction over the Rh(111) and (211) surfaces has been investigated operando by X-ray photoelectron spectroscopy at a pressure of 150 mbar. Observations of the resting state of the catalyst give mechanistic insight into the selectivity of Rh for generating ethanol from CO hydrogenation. This study shows that the Rh(111) surface does not dissociate all CO molecules before hydrogenation of the O and C atoms, which allows methoxy and other both oxygenated and hydrogenated species to be visible in the photoelectron spectra.

Atom-Specific Probing of Electron Dynamics in an Atomic Adsorbate by Time-Resolved X-Ray Spectroscopy.

The electronic excitation occurring on adsorbates at ultrafast timescales from optical lasers that initiate surface chemical reactions is still an open question. Here, we report the ultrafast temporal evolution of x-ray absorption spectroscopy (XAS) and x-ray emission spectroscopy (XES) of a simple well-known adsorbate prototype system, namely carbon (C) atoms adsorbed on a nickel [Ni(100)] surface, following intense laser optical pumping at 400 nm. We observe ultrafast (∼100 fs) changes in both XAS and XES showing clear signatures of the formation of a hot electron-hole pair distribution on the adsorbate. This is followed by slower changes on a few picoseconds timescale, shown to be consistent with thermalization of the complete C/Ni system. Density functional theory spectrum simulations support this interpretation.

Symmetry-resolved CO desorption and oxidation dynamics on O/Ru(0001) probed at the C K-edge by ultrafast x-ray spectroscopy.

We report on carbon monoxide desorption and oxidation induced by 400 nm femtosecond laser excitation on the O/Ru(0001) surface probed by time-resolved x-ray absorption spectroscopy (TR-XAS) at the carbon K-edge. The experiments were performed under constant background pressures of CO (6 × 10-8 Torr) and O2 (3 × 10-8 Torr). Under these conditions, we detect two transient CO species with narrow 2π* peaks, suggesting little 2π* interaction with the surface. Based on polarization measurements, we find that these two species have opposing orientations: (1) CO favoring a more perpendicular orientation and (2) CO favoring a more parallel orientation with respect to the surface. We also directly detect gas-phase CO2 using a mass spectrometer and observe weak signatures of bent adsorbed CO2 at slightly higher x-ray energies than the 2π* region. These results are compared to previously reported TR-XAS results at the O K-edge, where the CO background pressure was three times lower (2 × 10-8 Torr) while maintaining the same O2 pressure. At the lower CO pressure, in the CO 2π* region, we observed adsorbed CO and a distribution of OC-O bond lengths close to the CO oxidation transition state, with little indication of gas-like CO. The shift toward "gas-like" CO species may be explained by the higher CO exposure, which blocks O adsorption, decreasing O coverage and increasing CO coverage. These effects decrease the CO desorption barrier through dipole-dipole interaction while simultaneously increasing the CO oxidation barrier.

Antrodia salmonea extract inhibits cell proliferation through regulating cell cycle arrest and apoptosis in prostate cancer cell lines.

Antrodia salmonea (AS) is a fungus, which belongs to a fungal family of Taiwanofungus salmoneus with the features of anti-oxidant, anti-inflammatory, and anticancer. Recent studies have shown that AS has anti-cancer functions in ovarian and breast cancer. However, the effects of AS on prostate cancer (PCa) proliferation remain unknown. Therefore, we investigated the role of AS in PCa proliferation through apoptosis, and cell cycle regulation in PCa cell lines. Our results showed that Antrodia salmonea extract (ASE) inhibited PCa cells growth with a dose-dependent manner. In addition, ASE decreased the anchorage-independent growth formation ability in PC3 cells. Moreover, ASE-induced cell growth inhibition in PCa cells (DU145, PC3) was correlated to decreased cell cycle-related proteins such as cyclin A/B and cyclin-dependent kinase CDK1/2/4, and increased cell cycle inhibitor proteins p21. Besides, ASE decreased the total protein level of epidermal growth factor receptor and its downstream signaling pathways Akt and Erk in both PCa cells. We found that apoptotic markers such as cleaved-PARP protein levels increased significantly in DU145 cells indicating ASE might induce apoptosis. In conclusion, our results suggest that ASE may have the ability to induce PCa cell death through regulating cell cycle arrest and apoptosis pathways.

Improvement in vocal-cord visualization with Trachway video intubating stylet using direct oxygen flow and effective analysis of the fraction of inspired oxygen: a bench study.

The Trachway video intubating stylet device facilitates the visualization of the airways of patients from the tip of an endotracheal tube (ETT) during intubation. The major limitations of Trachway are the restricted view due to secretions and the risk of a prolonged apnea during intubation. We conducted a bench study to verify the performance of an alternative, easily applicable airway device that allows better visualization of trackways during Trachway-assisted intubation and prevents the detrimental effects of apnea-related hypoxia. We conducted a bench study to thoroughly evaluate the oral-secretion-elimination ability of a newly designed oxygen delivery device (ODD) to improve vocal-cord visualization using the three commonly used ETT sizes (i.e., 7, 7.5, and 8 mm). Moreover, we measured the fraction of inspired oxygen (FiO2) under different, continuous oxygen-flow supplies (1-10 L/min) during intubation. Each condition was analyzed for a 2 min video-stylet-intubation period. The supplemental oxygen flow and FiO2 fraction achieved using our ODD were higher, and smaller ETTs exhibited better secretion elimination. The ODD, which can be easily coupled with Trachway stylets, enabled high-quality visualization during oxygen flows of 6-8 L/min, and higher FiO2 fractions were achieved at higher oxygen flow rates. The use of the ODD improved the visualization of the airways during video stylet-assisted intubations using the additional FiO2 supply. The ODD developed in this study improves the visualization of airways with Trachway stylets and enhances the safety of intubation.

Direct Evidence of Subsurface Oxygen Formation in Oxide-Derived Cu by X-ray Photoelectron Spectroscopy.

Subsurface oxygen has been proposed to be crucial in oxide-derived copper (OD-Cu) electrocatalysts for enhancing the binding of CO intermediates during CO2 reduction reaction (CO2 RR). However, the presence of such oxygen species under reductive conditions still remains debated. In this work, the existence of subsurface oxygen is validated by grazing incident hard X-ray photoelectron spectroscopy, where OD-Cu was prepared by reduction of Cu oxide with H2 without exposing to air. The results suggest two types of subsurface oxygen embedded between the fully reduced metallic surface and the Cu2 O buried beneath: (i) oxygen staying at lattice defects and/or vacancies in the surface-most region and (ii) interstitial oxygen intercalated in metal structure. This study adds convincing support to the presence of subsurface oxygen in OD-Cu, which previously has been suggested to play an important role to mitigate the σ-repulsion of Cu for CO intermediates in CO2 RR.

Role of the frontal eye field in human pupil and saccade orienting responses.

The appearance of a salient stimulus evokes a series of orienting responses including saccades and pupil size to prepare the body for appropriate action. The midbrain superior colliculus (SC) that receives critical control signals from the frontal eye field (FEF) is hypothesized to coordinate all components of orienting. It has shown recently that the FEF, together with the SC, is also importantly involved in the control of pupil size, in addition to its well-documented role in eye movements. Although the role of the FEF in pupil size is demonstrated in monkeys, its role in human pupil responses and the coordination between pupil size and saccades remains to be established. Through applying continuous theta-burst stimulation over the right FEF and vertex, we investigated the role of the FEF in human pupil and saccade responses evoked by a salient stimulus, and the coordination between pupil size and saccades. Our results showed that neither saccade reaction times (SRT) nor pupil responses evoked by salient stimuli were modulated by FEF stimulation. In contrast, the correlation between pupil size and SRTs in the contralateral stimulus condition was diminished with FEF stimulation, but intact with vertex stimulation. Moreover, FEF stimulation effects between saccade and pupil responses associated with salient stimuli correlated across participants. This is the first transcranial magnetic stimulation (TMS) study on the pupil orienting response, and our findings suggest that human FEF was involved in coordinating pupil size and saccades, but not involved in the control of pupil orienting responses.

Ultrafast Adsorbate Excitation Probed with Subpicosecond-Resolution X-Ray Absorption Spectroscopy.

We use a pump-probe scheme to measure the time evolution of the C K-edge x-ray absorption spectrum from CO/Ru(0001) after excitation by an ultrashort high-intensity optical laser pulse. Because of the short duration of the x-ray probe pulse and precise control of the pulse delay, the excitation-induced dynamics during the first picosecond after the pump can be resolved with unprecedented time resolution. By comparing with density functional theory spectrum calculations, we find high excitation of the internal stretch and frustrated rotation modes occurring within 200 fs of laser excitation, as well as thermalization of the system in the picosecond regime. The ∼100 fs initial excitation of these CO vibrational modes is not readily rationalized by traditional theories of nonadiabatic coupling of adsorbates to metal surfaces, e.g., electronic frictions based on first order electron-phonon coupling or transient population of adsorbate resonances. We suggest that coupling of the adsorbate to nonthermalized electron-hole pairs is responsible for the ultrafast initial excitation of the modes.

The Hill-Sachs interval to glenoid track width ratio is comparable to the instability severity index score for predicting risk of recurrent instability after arthroscopic Bankart repair.

PURPOSE: The purpose of this study was to clinically validate the Hill-Sachs interval to glenoid track width ratio (H/G ratio) compared with the instability severity index (ISI) score for predicting an increased risk of recurrent instability after arthroscopic Bankart repair. METHODS: A retrospective evaluation was performed using data from patients with anteroinferior shoulder instability who underwent arthroscopic Bankart repair with a follow-up period of at least 24 months. A receiver operating characteristic (ROC) curve was used to determine the optimal cut-off values for the H/G ratio and the ISI score to predict an increased risk of recurrent instability. The area under the ROC curve (AUC) of the two methods and the sensitivity and specificity of their optimal cut-off values were compared. RESULTS: A total of 222 patients were included, among whom 31 (14.0%) experienced recurrent instability during the follow-up period. The optimal cut-off values for predicting an increased risk of recurrent instability were an H/G ratio of ≥ 0.7 and ISI score of ≥ 4. There were no significant differences between the AUC of the two methods (H/G ratio AUC = 0.821, standard error = 0.035 and ISI score AUC = 0.792, standard error = 0.04; n.s.) nor between the sensitivity and specificity of the optimal cut-off values (n.s. and n.s., respectively). CONCLUSIONS: The H/G ratio is comparable to the ISI score for predicting an increased risk of recurrent instability after arthroscopic Bankart repair. Surgeons are recommended to consider other strategies to treat anterior shoulder instability if H/G ratio is ≥ 0.7. LEVEL OF EVIDENCE: III.

Amorphous versus Crystalline in Water Oxidation Catalysis: A Case Study of NiFe Alloy.

Catalytic water splitting driven by renewable electricity offers a promising strategy to produce molecular hydrogen, but its efficiency is severely restricted by the sluggish kinetics of the anodic water oxidation reaction. Amorphous catalysts are reported to show better activities of water oxidation than their crystalline counterparts, but little is known about the underlying origin, which retards the development of high-performance amorphous oxygen evolution reaction catalysts. Herein, on the basis of cyclic voltammetry, electrochemical impedance spectroscopy, isotope labeling, and in situ X-ray absorption spectroscopy studies, we demonstrate that an amorphous catalyst can be electrochemically activated to expose active sites in the bulk thanks to the short-range order of the amorphous structure, which greatly increases the number of active sites and thus improves the electrocatalytic activity of the amorphous catalyst in water oxidation.

Intrinsic activity temporal structure reactivity to behavioural state change is correlated with depressive symptoms.

The brain's intrinsic activity plays a fundamental role in its function. In normal conditions this activity is responsive to behavioural context, changing as an individual switches between directed tasks and task-free conditions. A key feature of such changes is the movement of the brain between corresponding critical and sub-critical states, with these dynamics supporting efficient cognitive processing. Breakdowns in processing efficiency can occur, however, in brain disorders such as depression. It was therefore hypothesised that depressive symptoms would be related to reduced intrinsic activity responsiveness to changes in behavioural state. This was tested in a mixed group of major depressive disorder patients (n = 26) and healthy participants (n = 37) by measuring intrinsic EEG activity temporal structure, quantified with detrended fluctuation analysis (DFA), in eyes-closed (EC) and eyes-open task-free states and contrasting between the conditions. The degree to which DFA values changed between the states was found to correlate negatively with depressive symptoms. DFA values did not differ between states in those with higher symptom levels, meaning that the brain remained in a less flexible sub-critical condition. This sub-critical condition in the EC state was further found to correlate with levels of maladaptive rumination. This may reflect a general cognitive inflexibility resulting from a lack in neural activity reactivity that may predispose people to overly engage in self-directed attention. These results provide an initial link between intrinsic activity reactivity and psychological features found in psychiatric disorders.

Time-resolved observation of transient precursor state of CO on Ru(0001) using carbon K-edge spectroscopy.

The transient dynamics of carbon monoxide (CO) molecules on a Ru(0001) surface following femtosecond optical laser pump excitation has been studied by monitoring changes in the unoccupied electronic structure using an ultrafast X-ray free-electron laser (FEL) probe. The particular symmetry of perpendicularly chemisorbed CO on the surface is exploited to investigate how the molecular orientation changes with time by varying the polarization of the FEL pulses. The time evolution of spectral features corresponding to the desorption precursor state was well distinguished due to the narrow line-width of the C K-edge in the X-ray absorption (XA) spectrum, illustrating that CO molecules in the precursor state rotated freely and resided on the surface for several picoseconds. Most of the CO molecules trapped in the precursor state ultimately cooled back down to the chemisorbed state, while we estimate that ∼14.5 ± 4.9% of the molecules in the precursor state desorbed into the gas phase. It was also observed that chemisorbed CO molecules diffused over the metal surface from on-top sites toward highly coordinated sites. In addition, a new "vibrationally hot precursor" state was identified in the polarization-dependent XA spectra.

Enhanced recovery after surgery: Prediction for early extubation in video-assisted thoracic surgery using a response surface model in anesthesia.

BACKGROUND/PURPOSE: Enhanced recovery after surgery (ERAS) is a growing tendency in modern perioperative period management, but no protocol has been established for a strategy that optimally facilitates rapid recovery from anesthesia. We hypothesized that applying a total intravenous anesthesia (TIVA) method to the response surface model (RSM) would allow prediction of the emergence and endotracheal tube extubation in cases undergoing video-assisted thoracotomy surgery (VATS). METHODS: Thirty patients who were scheduled to undergo VATs under TIVA were enrolled. Pharmacokinetic profiles were calculated using a Tivatrainer. Emergence from anesthesia was observed and the exact time point of the regained response (RR) was recorded. The effect of concentration was analyzed and applied to a response surface model. RESULTS: The cumulative prediction curve of the RR was closer to the 50% probability as set by the OAA/S ≥ 4 than by the OAA/S ≥ 2 model. The median, averages, and standard deviations of the time differences were 14.5, 22.05 ± 19.23 min for the OAA/S ≥2 model and 10.4, 14.26 ± 10.40 min for the OAA/S ≥ 4 model. CONCLUSION: The OAA/S ≥ 4 model could identify the target concentration in propofol-remifentanil pairs that predicted the time of emergence from VATS in 10 min. Our results indicate that RSM can be used to derive an ERAS protocol for VATS under TIVA. Further studies should investigate application of RSM to predict ERAS for various types of procedures.

Future Aspects of CDK5 in Prostate Cancer: From Pathogenesis to Therapeutic Implications.

Cyclin-dependent kinase 5 (CDK5) is a unique member of the cyclin-dependent kinase family. CDK5 is activated by binding with its regulatory proteins, mainly p35, and its activation is essential in the development of the central nervous system (CNS) and neurodegeneration. Recently, it has been reported that CDK5 plays important roles in regulating various biological and pathological processes, including cancer progression. Concerning prostate cancer, the androgen receptor (AR) is majorly involved in tumorigenesis, while CDK5 can phosphorylate AR and promotes the proliferation of prostate cancer cells. Clinical evidence has also shown that the level of CDK5 is associated with the progression of prostate cancer. Interestingly, inhibition of CDK5 prevents prostate cancer cell growth, while drug-triggered CDK5 hyperactivation leads to apoptosis. The blocking of CDK5 activity by its small interfering RNAs (siRNA) or Roscovitine, a pan-CDK inhibitor, reduces the cellular AR protein level and triggers the death of prostate cancer cells. Thus, CDK5 plays a crucial role in the growth of prostate cancer cells, and AR regulation is one of the important pathways. In this review paper, we summarize the significant studies on CDK5-mediated regulation of prostate cancer cells. We propose that the CDK5-p35 complex might be an outstanding candidate as a diagnostic marker and potential target for prostate cancer treatment in the near future.

Arthroscopic Partial Repair of Irreparable Rotator Cuff Tears: Factors Related to Greater Degree of Clinical Improvement at 2 Years of Follow-Up.

PURPOSE: This study aimed to evaluate the clinical outcomes of irreparable rotator cuff tears (RCT) treated with an arthroscopic partial repair, as well as the preoperative factors that may be related to greater improvement of clinical outcomes at short-term follow-up. METHODS: We retrospectively reviewed patients with irreparable RCT who underwent arthroscopic partial rotator cuff repair between January 2011 and April 2014. Minimal follow-up of 24 months was required. Partial repair was defined as repairing the less retracted posterosuperior rotator cuff with a residual defect of the tendon-footprint junction. Tearing involving the subscapularis tendon was excluded. Factors collected included age, sex, diabetes, smoking, night pain, duration of symptoms, pain visual analog scale (VAS) score, acromiohumeral distance (AHD), and American Shoulder and Elbow Surgeons (ASES) score. Magnetic resonance images without intra-articular contrast were assessed for healing 6 months after surgery for all patients. Functional outcome was evaluated with ASES score. Degree of functional improvement was defined as the difference of ASES scores pre- and postoperatively (d-ASES). Paired t-test and simple linear analysis were used for statistical analysis. RESULTS: Thirty-seven patients were included with a mean follow-up period of 29.6 ± 6.6 months. VAS score improved from 5.22 to 1.51 (P < .001). ASES score improved from 46.0 to 78.6 (P < .001). The incidence of night pain improved from 70.3% to 8.1% (P < .001). Only a preoperative lower ASES score, higher VAS score, and night pain were related to the higher d-ASES score (P < .001, P = .005, P = .017, respectively). The rate of repair failure was 41.6% at a mean follow-up of 6.4 months. CONCLUSIONS: Arthroscopic partial repair of irreparable RCTs is an effective treatment to improve the shoulder function and decrease the pain, despite the high repair failure rate of 41.6%. Patients with preoperative lower functional score, higher VAS score, or night pain experienced a greater degree of functional improvement from the surgery. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Partial component-retained two-stage reconstruction for chronic infection after uncemented total hip arthroplasty: results of sixteen cases after five years of follow-up.

PURPOSE: Two-stage reconstruction with total implant removal and re-implantation after infection control is considered the gold standard treatment for infection after hip arthroplasty. However, removal of the well-fixed stem or cup may cause substantial bone loss and other complications, thereby making reconstruction difficult. We evaluated whether an infection post total hip arthroplasty can be treated without removal of the radiographically and clinically well-fixed femoral stem or acetabular cup. METHODS: Patients with a chronic infection after total hip arthroplasty, with a radiographically well-fixed, cementless stem or cup, were selected. During the first surgical stage, we retained the stem or cup if we were unable to remove these with a stem or cup extractor. An antibiotic-impregnated cement spacer was then implanted. After control of infection (C-reactive protein level within normal value), we performed the second stage of re-implantation surgery. Treatment failure was defined as uncontrolled infection requiring removal of the retained implant. RESULTS: From January 2004 to December 2013, 16 patients underwent partial component-retained two stage reconstruction. Thirteen patients (81.3%) were free of infection, with a mean follow-up time of five years. The remaining three patients, who had high-risk comorbidities and, of whom, two were infected by high-virulence organisms, had uncontrolled infection and required further surgery to remove the retained implant. CONCLUSIONS: Partial component-retained two-stage reconstruction could be an alternative treatment option for chronic infection after an uncemented total hip arthroplasty with a radiographically and clinically well-fixed component in selected patients, who are not immunocompromised and are infected by a low-virulence organism.

In Operando Identification of Geometrical-Site-Dependent Water Oxidation Activity of Spinel Co3O4.

Spinel Co3O4, comprising two types of cobalt ions: one Co(2+) in the tetrahedral site (Co(2+)(Td)) and the other two Co(3+) in the octahedral site (Co(3+)(Oh)), has been widely explored as a promising oxygen evolution reaction (OER) catalyst for water electrolysis. However, the roles of two geometrical cobalt ions toward the OER have remained elusive. Here, we investigated the geometrical-site-dependent OER activity of Co3O4 catalyst by substituting Co(2+)(Td) and Co(3+)(Oh) with inactive Zn(2+) and Al(3+), respectively. Following a thorough in operando analysis by electrochemical impedance spectroscopy and X-ray absorption spectroscopy, it was revealed that Co(2+)Td site is responsible for the formation of cobalt oxyhydroxide (CoOOH), which acted as the active site for water oxidation.