Summary Selective degeneration of midbrain dopaminergic (mDA) neurons is associated with Parkinson’s disease (PD), and thus an in-depth understanding of molecular pathways underlying mDA development will be crucial for optimal bioassays and cell replacement therapy for PD. In this study, we identified a novel Wnt1-Lmx1a autoregulatory loop during mDA differentiation of ES cells, and confirmed its in vivo presence during embryonic development. We found that the Wnt1-Lmx1a autoregulatory loop directly regulates Otx2 through the β-catenin complex and Nurr1 and Pitx3 through Lmx1a. We also found that Lmx1a and Lmx1b co-operatively regulate mDA differentiation with overlapping and cross-regulatory functions. Furthermore, co-activation of both Wnt1 and SHH pathways by exogenous expression of Lmx1a, Otx2 and FoxA2 synergistically enhanced the differentiation of ES cells to mDA neurons. Together with previous works, this study shows that two regulatory loops (Wnt1-Lmx1a and SHH-FoxA2) critically link extrinsic signals to cell-intrinsic factors and cooperatively regulate mDA neuron development.

Summary Seizure disorders debilitate more than 65,000,000 people worldwide, with temporal lobe epilepsy (TLE) being the most common form. Previous studies have shown that transplantation of GABA-releasing cells results in suppression of seizures in epileptic mice. Derivation of interneurons from human PSC has been reported, pointing to clinical translation of quality-controlled human cell sources that can enhance inhibitory drive and restore host circuitry. In this study, we demonstrate that human PSC-derived maturing GABAergic interneurons (mGIN) migrate extensively and integrate into dysfunctional circuitry of the epileptic mouse brain. Using optogenetic approaches, we find that grafted mGINs generate inhibitory postsynaptic responses in host hippocampal neurons. Importantly, even before acquiring full electrophysiological maturation, grafted neurons were capable of suppressing seizures and ameliorating behavioral abnormalities such as cognitive deficits, aggressiveness and hyperactivity. These results provide support for the potential of human PSC-derived mGIN for restorative cell therapy for epilepsy.

BACKGROUND:The COVID-19 pandemic resulted in a statewide stay-at-home (SAH) order in California beginning March 19, 2020, forcing large-scale behavioral changes and taking an emotional and economic toll. The effects of SAH orders on the trauma population remain unknown. We hypothesized an increase in rates of penetrating trauma, gunshot wounds, suicide attempts, and domestic violence in the Southern California trauma population after the SAH order. METHODS:A multicenter retrospective analysis of all trauma patients presenting to 11 American College of Surgeons levels I and II trauma centers spanning seven counties in California was performed. Demographic data, injury characteristics, clinical data, and outcomes were collected. Patients were divided into three groups based on injury date: before SAH from

During early development, midbrain dopaminergic (mDA) neuronal progenitors (NPs) arise from the ventral mesencephalic area by the combined actions of secreted factors and their downstream transcription factors. These mDA NPs proliferate, migrate to their final destinations, and develop into mature mDA neurons in the substantia nigra and the ventral tegmental area. Here, we show that such authentic mDA NPs can be efficiently isolated from differentiated ES cells (ESCs) using a FACS method combining two markers, Otx2 and Corin. Purified Otx2 + Corin + cells coexpressed other mDA NP markers, including FoxA2, Lmx1b, and Glast. Using optimized culture conditions, these mDA NPs continuously proliferated up to 4 wk with almost 1,000-fold expansion without significant changes in their phenotype. Furthermore, upon differentiation, Otx2 + Corin + cells efficiently generated mDA neurons, as evidenced by coexpression of mDA neuronal markers (e.g., TH, Pitx3, Nurr1, and Lmx1b) and physiological functions (e.g., efficient DA secretion and uptake). Notably, these mDA NPs differentiated into a relatively homogenous DA population with few serotonergic neurons. When transplanted into PD model animals, aphakia mice, and 6-OHDA-lesioned rats, mDA NPs differentiated into mDA neurons in vivo and generated well-integrated DA grafts, resulting in significant improvement in motor dysfunctions without tumor formation. Furthermore, grafted Otx2 + Corin + cells exhibited significant migratory function in the host striatum, reaching >3.3 mm length in the entire striatum. We propose that functional and expandable mDA NPs can be efficiently isolated by this unique strategy and will serve as useful tools in regenerative medicine, bioassay, and drug screening.neural precursors | dopaminergic neurons | transplantation

The training program can be used for preparing generalist nurses of their nursing competencies in disaster preparedness, response and post-disaster recovery and rehabilitation.

We analyzed data from two ongoing COVID-19 longitudinal serological surveys in Orange County, CA., between April 2020 and March 2021. A total of 8476 finger stick blood specimens were collected before and after a vaccination campaign. IgG levels were determined using a multiplex antigen microarray containing antigens from SARS-CoV-2, SARS, MERS, Common CoV, and Influenza. Twenty-six percent of specimens from unvaccinated Orange County residents in December 2020 were SARS-CoV-2 seropositive; out of 852 seropositive individuals 77 had symptoms and 9 sought medical care. The antibody response was predominantly against nucleocapsid (NP), full length, and S2 domain of spike. Anti-receptor binding domain (RBD) reactivity was low and not cross-reactive against SARS S1 or SARS RBD. A vaccination campaign at the University of California Irvine Medical Center (UCIMC) started on December, 2020 and 6724 healthcare workers were vaccinated within 3 weeks. Seroprevalence increased from 13% pre-vaccination to 79% post-vaccination in January, 93% in February, and 99% in March. mRNA vaccination induced higher antibody levels than natural exposure, especially against the RBD domain and cross-reactivity against SARS RBD and S1 was observed. Nucleocapsid protein antibodies can be used to distinguish vaccinees to classify pre-exposure to SARS-CoV-2 Previously infected individuals developed higher antibody titers to the vaccine than non pre-exposed individuals. Hospitalized patients in intensive care with severe disease reach significantly higher antibody levels than mild cases, but lower antibody levels compared to the vaccine. These results indicate that mRNA vaccination rapidly induces a much stronger and broader antibody response than SARS-CoV-2 infection.

Given the limitations of existing health-related quality-of-life (QOL) measures in capturing the end-of-life experience of patients with advanced chronic diseases, an empirically grounded instrument, the quality-of-life concerns in the end of life questionnaire (QOLC-E), was developed. Though it was built on the McGill quality of life questionnaire (MQOL), its sphere is more holistic and culturally specific for the Chinese patients in Hong Kong. One hundred and forty-nine patients with advanced chronic obstructive pulmonary disease (COPD) or metastatic cancer completed the questionnaire. Seven factors (28 items) which emerged from the factor analysis were grouped into four positive (support, value of life, food-related concerns, and healthcare concerns) and four negative (physical discomfort, negative emotions, sense of alienation, and existential distress) subscales. Good internal consistency and concurrent validity were shown. The results also revealed that these two groups of patients had similar QOL concerns. The validity of applying QOLC-E as an outcome measure to evaluate the effectiveness of palliative and psychoexistential interventions has yet to be tested.

Implantation of left ventricular assist devices (LVAD) has increased because of improved safety profile and limited availability of heart transplantation. Although supervised exercise training (ET) programs are known to improve exercise capacity and quality of life (QoL) in heart failure (HF) patients, similar data is inconclusive in LVAD patients. Thus, we performed a systematic review on studies that incorporated supervised ET and measured peak oxygen uptake in LVAD patients. A total of 150 patients in exercise and 55 patients in control groups were included from 8 studies selected from our predefined criteria. Our systematic review suggests supervised ET has an inconsistent effect on exercise capacity and QoL when compared to control groups undergoing usual care. A quantitative sub-analysis was performed with 4 studies that provided enough data to compare peak oxygen uptake and QoL at baseline and at follow-up. After at least 6 weeks of training, LVAD patients undergoing supervised ET demonstrated significant improvement in exercise capacity (standardized mean difference [SMD] = 0.735, 95% Confidence Interval-[CI], 0.31–1.15 units of the standard deviation, P = 0.001) and QoL scores (SMD = 1.58, 95% CI 0.97–2.20 units of the standard deviation, P <0.001) when compared to the usual care group, with no serious adverse events with exercise. These results suggest that supervised ET is safe and can improve patient outcomes in LVAD patients when compared to the usual care.