Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases.A prominent feature of neurodegenerative diseases, including Parkinson disease (PD) 3 and Alzheimer disease, is the accumulation of undigested protein aggregates (1, 2). Although the underlying mechanisms are complex, several cellular alterations can cause aggregate accumulation, including impaired quality control pathways and the generation of reactive oxygen species (ROS) as a consequence of mitochondrial damage (1, 3).In healthy cells, protein aggregates and damaged cellular components are delivered to lysosomes to be degraded through a process termed autophagy (1, 2, 4, 5). As such, autophagy plays an important neuroprotective role. Nevertheless, the defects in degradation pathways observed in neurodegenerative diseases extend well beyond alterations in autophagy. Specifically, disruption of lysosomal function has been linked to neuronal loss in several neurodegenerative diseases. For example, mutations in the lysosomal ATPase ATP13A2 cause PD, whereas lysosomal dysfunction in Gaucher disease leads to Parkinsonism and the appearance of Lewy bodies (6, 7). In addition, the ␣-synuclein-containing Lewy bodies found in PD are positive for lysosomal markers, suggesting that they represent lysosomes that failed to degrade their content (8). In fact, lysosomal alterations are a common feature of PD (8 -11). Nevertheless, the pathological consequences of a loss of lysosomal function extend well beyond PD, because a wide variety of mutations that impair lysosomes and cause the accumulation of intracellular material (lysosomal storage diseases) show features of neurodegeneration (12).A second key metabolic pathway required for neuronal survival is mitochondrial activity. In fact, mitochondrial dysfunction is a common feature of neurodegenerative diseases. For example, decreased activity of complex I of the electron transport chain (ETC) is present in a number of PD cases (13, 14), whereas amyloid ␤, Tau tangles, and Htt aggregates all cause mitochondrial dysfunction (15-17). In addition, several genes mutated in PD (including PINK1, Parkin, and DJ-1) affect mitochondrial function and turnover (18 -21), whereas deregulation of mitochon...

Apoptosis has an important role during development to regulate cell number. In differentiated cells, however, activation of autophagy has a critical role by enabling cells to remain functional following stress. In this study, we show that the antiapoptotic BCL-2 homologue MCL-1 has a key role in controlling both processes in a developmentally regulated manner. Specifically, MCL-1 degradation is an early event not only following induction of apoptosis, but also under nutrient deprivation conditions where MCL-1 levels regulate activation of autophagy. Furthermore, deletion of MCL-1 in cortical neurons of transgenic mice activates a robust autophagic response. This autophagic response can, however, be converted to apoptosis by either reducing the levels of the autophagy regulator Beclin-1, or by a concomitant activation of BAX. Our results define a pathway whereby MCL-1 has a key role in determining cell fate, by coordinately regulating apoptosis and autophagy.

Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during Coronavirus Disease 2019 (COVID-19) ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin signaling. Dexamethasone during severe COVID-19 affected circulating neutrophils, altered IFNactive neutrophils, downregulated interferon-stimulated genes and activated IL-1R2+ neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFNactive neutrophils and preferential steroid-induced immature neutrophil expansion, potentially affecting outcomes. Our single-cell atlas (see ‘Data availability’ section) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.

The ectostriatum is a large visual structure in the avian telencephalon. Part of the tectofugal pathway, the ectostriatum receives a large ascending thalamic input from the nucleus rotundus, the homolog of the mammalian pulvinar complex. We investigated the effects of bilateral lesions of the ectostriatum in pigeons on visual motion and spatial-pattern perception tasks. To test motion perception, we measured performance on a task requiring detection of coherently moving random dots embedded in dynamic noise. To test spatialpattern perception, we measured performance on the detection of a square wave grating embedded in static noise. A double dissociation was revealed. Pigeons with lesions to the caudal ectostriatum showed a performance deficit on the motion task but not the grating task. In contrast, pigeons with lesions to the rostral ectostriatum showed a performance deficit on the grating task but not the motion task. Thus, in the avian telencephalon, there is a separation of visual motion and spatial-pattern perception as there is in the mammalian telencephalon. However, this separation of function is in the targets of the tectofugal pathway in pigeons rather than in the thalamofugal pathway as described in mammals. The implications of these findings with respect to the evolution of the visual system are discussed. Specifically, we suggest that the principle of parallel visual streams originated in the tectofugal pathway rather than the thalamofugal pathway.

Objective To estimate whether postpartum visit attendance was improved in women exposed to a postpartum patient navigation program compared with those who received care immediately prior to the program's initiation, and to assess whether other postpartum health behaviors improved during the intervention period. Methods This is a prospective observational study of women enrolled in a patient navigation program compared to women receiving care prior to the program. Navigating New Motherhood was a postpartum patient navigation program for adult, English-speaking women receiving prenatal care at a Medicaid-based university clinic. In 2015, Navigating New Motherhood introduced a clinic-level change in which a navigator was hired and assumed supportive and logistical responsibilities for enrolled patients between delivery and postpartum visit completion. We compared medical record data from women who enrolled in Navigating New Motherhood to those of women receiving care in the same clinic for one year immediately prior to Navigating New Motherhood. The primary outcome was postpartum visit attendance. Secondary outcomes included WHO Tier 1 or 2 contraception uptake and other health services measures. We conducted bivariable and multivariable analyses. Results Of the 225 women approached for Navigating New Motherhood participation after program initiation, 96.9% (N=218) enrolled; these women were compared to 256 women in the historical cohort. Most women on both groups were racial or ethnic minorities and all had Medicaid insurance. There were no important differences in demographic, clinical, or health services characteristics between groups, though women in Navigating New Motherhood were more likely to transfer into the clinic for prenatal care and to deliver babies admitted to the NICU. The primary outcome, return for postpartum care, was more common among women in Navigating New Motherhood (88.1% vs. 70.3%, p<0.001), a difference that persisted after adjustment for potential confounding factors (aOR 3.57, 95% CI 2.11-6.04). Women in Navigating New Motherhood also were more likely to receive a WHO Tier 1 or 2 contraceptive method (aOR 1.56, 95% 1.02-2.38), postpartum depression screening (aOR 2.82, 95% CI 1.79-4.43), and influenza (aOR 2.10, 95% CI 1.38-3.19) and HPV vaccination (aOR 2.33, 95% CI 1.25-4.33). Conclusions Implementation of a postpartum navigation program was associated with improved retention in routine postpartum care and frequency of contraception uptake, depression screening, and vaccination.