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The excitation-inhibition (E/I) imbalance is an important molecular pathological feature of major depressive disorder (MDD) as altered GABA and glutamate levels have been found in multiple brain regions in patients. Healthy subjects show topographic organization of the E/I balance (EIB) across various brain regions. We here raise the question of whether such EIB topography is altered in MDD. Therefore, we systematically review the gene and protein expressions of inhibitory GABAergic and excitatory glutamatergic signaling-related molecules in postmortem MDD brain studies as proxies for EIB topography. Searches were conducted through PubMed and 45 research articles were finally included. We found: i) brain-wide GABA- and glutamatergic alterations; ii) attenuated GABAergic with enhanced glutamatergic signaling in the cortical-subcortical limbic system; iii) that GABAergic signaling is decreased in regions comprising the default mode network (DMN) while it is increased in lateral prefrontal cortex (LPFC). These together demonstrate abnormal GABA- and glutamatergic signaling-based EIB topographies in MDD. This enhances our pathophysiological understanding of MDD and carries important therapeutic implications for stimulation treatment.

Major depressive disorder (MDD) is a complex state-dependent psychiatric illness for which biomarkers linking psychophysical, biochemical, and psychopathological changes remain yet elusive, though. Earlier studies demonstrate reduced GABA in lower-order occipital cortex in acute MDD leaving open its validity and significance for higher-order visual perception, though. The goal of our study is to fill that gap by combining psychophysical investigation of visual perception with measurement of GABA concentration in middle temporal visual area (hMT+) in acute depressed MDD. Psychophysically, we observe a highly specific deficit in visual surround motion suppression in a large sample of acute MDD subjects which, importantly, correlates with symptom severity. Both visual deficit and its relation to symptom severity are replicated in the smaller MDD sample that received MRS. Using high-field 7T proton Magnetic resonance spectroscopy (1H-MRS), acute MDD subjects exhibit decreased GABA concentration in visual MT+ which, unlike in healthy subjects, no longer correlates with their visual motion performance, i.e., impaired SI. In sum, our combined psychophysical-biochemical study demonstrates an important role of reduced occipital GABA for altered visual perception and psychopathological symptoms in acute MDD. Bridging the gap from the biochemical level of occipital GABA over visual-perceptual changes to psychopathological symptoms, our findings point to the importance of the occipital cortex in acute depressed MDD including its role as candidate biomarker.

Major depressive disorder (MDD) is characterized by psychomotor retardation whose underlying neural source remains unclear. Psychomotor retardation may either be related to a motor source like the motor cortex or, alternatively, to a psychomotor source with neural changes outside motor regions, like input regions such as visual cortex. These two alternative hypotheses in main (n = 41) and replication (n = 18) MDD samples using 7 Tesla MRI are investigated. Analyzing both global and local connectivity in primary motor cortex (BA4), motor network and middle temporal visual cortex complex (MT+), the main findings in MDD are: 1) Reduced local and global synchronization and increased local‐to‐global output in motor regions, which do not correlate with psychomotor retardation, though. 2) Reduced local‐to‐local BA4 – MT+ functional connectivity (FC) which correlates with psychomotor retardation. 3) Reduced global synchronization and increased local‐to‐global output in MT+ which relate to psychomotor retardation. 4) Reduced variability in the psychophysical measures of MT+ based motion perception which relates to psychomotor retardation. Together, it is shown that visual cortex MT+ and its relation to motor cortex play a key role in mediating psychomotor retardation. This supports psychomotor over motor hypothesis about the neural source of psychomotor retardation in MDD. Using 7 Tesla MRI and analyzing both global and local synchronization in motor and visual cortex, this work finds psychomotor retardation relates to visual cortex on both neural and perceptual levels which, through globally mediated synchronization, down modulates neural activity in motor cortex. This supports psychomotor over motor model of psychomotor retardation in depression which carries diagnostic and therapeutic implications.

Previous studies showed abnormalities in both visual motion perception (VMP) and occipital cortex activity in subjects suffering from major depressive disorder (MDD). Can the psychophysical and/or neural markers of visual perception serve for clinical identification of MDD subgroups? To address this yet unresolved issue, we develope a novel analytical framework combining visual perceptual measurement with machine learning clustering to identify MDD subgroups. Within a cohort of 272 individuals with acute MDD, this approach reveals a VMP‐positive (VMP‐P) biotype characterized by impaired VMP. Clinically, this biotype exhibits significant cognitive deficits. We validate the robustness of this biotype through cross‐validation and confirm its generalizability in an independent sample (n = 63). Furthermore, 7T MRI implicate aberrant neural activity in the occipital cortex as a mechanism underlying the VMP‐P biotype. Our findings establish a novel, clinically translatable path for stratifying MDD, which can guide treatment development and advance precision medicine. In a discover dataset (272 acute MDD patients), this work identifies a novel depression biotype characterized by impaired visual motion perception, using machine learning clustering. An independent dataset confirms the robustness of this biotype through cross‐validation and demonstrates its generalizability. 7T MRI study further reveals the underlying neural mechanisms, highlighting a specific alteration in occipital cortex function within this biotype.

Childhood trauma is one of the most prominent risk factors in developing major depressive disorder (MDD) and may lead to unfavorable outcomes of pharmacotherapy and psychotherapy in MDD. While how it modulates the treatment outcome of the repetitive transcranial magnetic stimulation (rTMS) and how sex difference may play a role in mediating this relationship remain unknown. To evaluate this question, 51 (37 women) MDD patients were treated with 10 Hz rTMS to the left dorsolateral prefrontal cortex (lDLPFC). The experience of childhood trauma was quantified by the Childhood Traumatic Questionnaire (CTQ). The depressive severity was assessed by Hamilton Depression Scale (HAMD) and Beck Depression Inventory (BDI) as the primary and secondary assessments. Beck Hopelessness Scale (BHS) and Hamilton Anxiety Scale (HAMA) were also assessed for further confirmation. Thirty-six (70.6%) participants showed a response including 17 (33.3%) achieving remission to the rTMS treatment. The alleviation of depressive symptoms was negatively correlated with the CTQ scores, specifically in women but not men, in subjective BDI and BHS, but not objective HAMD or HAMA. We demonstrate that childhood trauma negatively affects the subjective perception of rTMS-lDLPFC treatment outcomes in female MDD patients. This highlights the importance of measuring childhood trauma-related symptoms in routine clinical rTMS treatment, as they may impact perceived efficacy.

Toludesvenlafaxine hydrochloride sustained‐release tablets, as China’s first independently developed chemical Class 1 innovative drug with independent intellectual property rights for the treatment of depression and a new molecular entity, represent a novel triple reuptake inhibitor (TRI) with specific target selectivity for serotonin (5‐HT), norepinephrine (NE), and dopamine (DA). This single‐arm, multicenter clinical study aimed to evaluate the efficacy and safety of toludesvenlafaxine in alleviating anhedonia symptoms in patients with major depressive disorder (MDD). A total of 123 patients aged 18–65 years were enrolled between April 2023 and April 2024 and received an 8‐week treatment with toludesvenlafaxine sustained‐release tablets (80–160 mg/day). The primary efficacy endpoint was the change in the total score of the Dimensional Anhedonia Rating Scale (DARS) at weeks 2, 4, and 8. Significant improvements in DARS scores were observed, with mean changes from baseline of 8.4 (95% CI [6.4, 10.4], p < 0.0001), 14.1 (95% CI [12.0, 16.2], p < 0.0001), and 20.4 (95% CI [18.0, 22.9], p < 0.0001), respectively. Additionally, after 8 weeks of treatment, plasma levels of neurotrophic factors, including mature brain‐derived neurotrophic factor (mBDNF) ( t = 28.78, p < 0.0001), pro‐BDNF ( t = 27.71, p < 0.0001), and vascular endothelial growth factor (VEGF) ( t = 31.07, p < 0.0001), were significantly increased, and the plasma level of IGF‐1 was not significantly changed ( t = 0.35, p = 0.7269). No association was found between the percentage of changes in neurotrophic factors and the percentage of symptom improvements. Toludesvenlafaxine was generally well‐tolerated, with treatment‐emergent adverse events (AEs) (TEAEs) reported in 83.7% of participants and treatment‐related AEs (TRAEs) in 76.4%. These findings indicate that toludesvenlafaxine hydrochloride sustained‐release tablets are safe, well‐tolerated, and effective in alleviating anhedonia symptoms in patients with depression. Trial Registration: http://www.chictr.org.cn (No.: ChiCTR2300070331).

Metabolic enzymes have an indispensable role in metabolic reprogramming, and their aberrant expression or activity has been associated with chemosensitivity. Hence, targeting metabolic enzymes remains an attractive approach for treating tumors. However, the influence and regulation of cysteine desulfurase (NFS1), a rate-limiting enzyme in iron–sulfur (Fe–S) cluster biogenesis, in colorectal cancer (CRC) remain elusive. Here, using an in vivo metabolic enzyme gene-based clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 library screen, we revealed that loss of NFS1 significantly enhanced the sensitivity of CRC cells to oxaliplatin. In vitro and in vivo results showed that NFS1 deficiency synergizing with oxaliplatin triggered PANoptosis (apoptosis, necroptosis, pyroptosis, and ferroptosis) by increasing the intracellular levels of reactive oxygen species (ROS). Furthermore, oxaliplatin-based oxidative stress enhanced the phosphorylation level of serine residues of NFS1, which prevented PANoptosis in an S293 phosphorylation-dependent manner during oxaliplatin treatment. In addition, high expression of NFS1, transcriptionally regulated by MYC, was found in tumor tissues and was associated with poor survival and hyposensitivity to chemotherapy in patients with CRC. Overall, the findings of this study provided insights into the underlying mechanisms of NFS1 in oxaliplatin sensitivity and identified NFS1 inhibition as a promising strategy for improving the outcome of platinum-based chemotherapy in the treatment of CRC.

Soft wearable electronics for underwater applications are of interest, but depend on the development of a waterproof, long-term sustainable power source. In this work, we report a bionic stretchable nanogenerator for underwater energy harvesting that mimics the structure of ion channels on the cytomembrane of electrocyte in an electric eel. Combining the effects of triboelectrification caused by flowing liquid and principles of electrostatic induction, the bionic stretchable nanogenerator can harvest mechanical energy from human motion underwater and output an open-circuit voltage over 10 V. Underwater applications of a bionic stretchable nanogenerator have also been demonstrated, such as human body multi-position motion monitoring and an undersea rescue system. The advantages of excellent flexibility, stretchability, outstanding tensile fatigue resistance (over 50,000 times) and underwater performance make the bionic stretchable nanogenerator a promising sustainable power source for the soft wearable electronics used underwater. Flexible devices such as solar cells and nanogenerators are attractive for powering wearable electronics, but waterproof capabilities would extend applications. Here the authors report a bionic stretchable nanogenerator that is capable of harvesting energy and multi-position motion monitoring underwater.

Consider a discrete-time insurance risk model. Within period i, i ≥ 1, Xi and Yi denote the net insurance loss and the stochastic discount factor of an insurer, respectively. Assume that (Xi, Yi), i ≥ 1 form a sequence of independent and identically distributed random vectors following a common bivariate Sarmanov distribution. In the presence of heavy-tailed net insurance losses, an asymptotic formula is derived for the finite-time ruin probability.