The Discounted Labor of BIPOC Students and Faculty

Black Law Students experienced a different COVID-19 pandemic than their majority counterparts due in part to the emotional and physical toll caused by the violent, public mistreatment of Black persons at the hands of law enforcement. While some law faculty at some institutions were proactive in identifying the struggles that their Black students were facing, most law faculty and administrators did nothing—prompting Black students to take time away from their studies to organize, draft letters, gather signatures, and have very uncomfortable conversations with university administrators and faculty about the need for change. Meanwhile, Black faculty and faculty of color, who were experiencing their own trials with pandemic teaching, childcare, increased service obligations and mental fatigue from the political and racial unrest, were often called upon to contribute substantial time to the design and implementation of the “diversity” or “anti-racism” initiatives necessary to increase diversity and to create inclusive environments for their BIPOC students and faculty. Most of this labor discounted, if acknowledged at all. We offer recommendations for how law schools can help shift some of these burdens

A Microfluidic Platform for High-Throughput Screening of Aquaporin Performance

Aquaporins are a family of small integral membrane proteins that transport water across cell membranes in response to osmotic gradients. They facilitate fluid secretion and absorption across epithelial surfaces in kidney tubules, exocrine glands, and gastrointestinal tract. Here, we describe a novel microfluidic method to evaluate and screen for aquaporin-based transmembrane permeability in mammalian cells. A microfluidic device was designed and fabricated for the encapsulation of single mammalian and yeast cells in micron-sized droplets. For this purpose, Chinese Hamster Ovarian (CHO) cells were used. CHO cells express AQP1 (aquaporin-1) homologous to human kidney aquaporins. The cells were cultivated and exposed to different osmotic stresses to study the transmembrane water transport performance of aquaporins. Our microfluidic platform has the potential to screen for and isolate cells with best aquaporin water transport performance for a number of applications in bioengineering

HIV-1 Latency and Viral Reservoirs: Existing Reversal Approaches and Potential Technologies, Targets, and Pathways Involved in HIV Latency Studies

Eradication of latent human immunodeficiency virus (HIV) infection is a global health challenge. Reactivation of HIV latency and killing of virus-infected cells, the so-called “kick and kill” or “shock and kill” approaches, are a popular strategy for HIV cure. While antiretroviral therapy (ART) halts HIV replication by targeting multiple steps in the HIV life cycle, including viral entry, integration, replication, and production, it cannot get rid of the occult provirus incorporated into the host-cell genome. These latent proviruses are replication-competent and can rebound in cases of ART interruption or cessation. In general, a very small population of cells harbor provirus, serve as reservoirs in ART-controlled HIV subjects, and are capable of expressing little to no HIV RNA or proteins. Beyond the canonical resting memory CD4+ T cells, HIV reservoirs also exist within tissue macrophages, myeloid cells, brain microglial cells, gut epithelial cells, and hematopoi-etic stem cells (HSCs). Despite a lack of active viral production, latently HIV-infected subjects con-tinue to exhibit aberrant cellular signaling and metabolic dysfunction, leading to minor to major cellular and systemic complications or comorbidities. These include genomic DNA damage; telo-mere attrition; mitochondrial dysfunction; premature aging; and lymphocytic, cardiac, renal, he-patic, or pulmonary dysfunctions. Therefore, the arcane machineries involved in HIV latency and its reversal warrant further studies to identify the cryptic mechanisms of HIV reservoir formation and clearance. In this review, we discuss several molecules and signaling pathways, some of which have dual roles in maintaining or reversing HIV latency and reservoirs, and describe some evolving strategies and possible approaches to eliminate viral reservoirs and, ultimately, cure/eradicate HIV infection

Hepatic small vessel neoplasm: not totally benign, not yet malignant

Hepatic small vessel neoplasm (HSVN) is a rare vascular tumor with few reports in the literature. While imaging findings may show characteristic enhancement patterns, limited available literature may not reveal the full potential for image-based diagnosis. Histologically, HSVN mimics other entities, though certain morphologic and immunohistochemical findings provide clues for diagnosis. However, HSVN still provides diagnostic challenges, especially on core biopsies with limited material for morphologic and molecular evaluation. While current recommendations are surgical resection and close observation, the long-term course of the tumor is unknown. We report a case of HSVN in a liver with additional feature of organized lymphoid aggregates necessitating additional hematopathology consultation and workup to rule out concurrent entities

Quantised Vortices in an Exciton-Polariton Fluid

One of the most striking quantum effects in a low temperature interacting Bose gas is superfluidity. First observed in liquid 4He, this phenomenon has been intensively studied in a variety of systems for its amazing features such as the persistence of superflows and the quantization of the angular momentum of vortices. The achievement of Bose-Einstein condensation (BEC) in dilute atomic gases provided an exceptional opportunity to observe and study superfluidity in an extremely clean and controlled environment. In the solid state, Bose-Einstein condensation of exciton polaritons has now been reported several times. Polaritons are strongly interacting light-matter quasi-particles, naturally occurring in semiconductor microcavities in the strong coupling regime and constitute a very interesting example of composite bosons. Even though pioneering experiments have recently addressed the propagation of a fluid of coherent polaritons, still no conclusive evidence is yet available of its superfluid nature. In the present Letter, we report the observation of spontaneous formation of pinned quantised vortices in the Bose-condensed phase of a polariton fluid by means of phase and amplitude imaging. Theoretical insight into the possible origin of such vortices is presented in terms of a generalised Gross-Pitaevskii equation. The implications of our observations concerning the superfluid nature of the non-equilibrium polariton fluid are finally discussed.Comment: 14 pages, 4 figure

Selective Oxidative Stress Induces Dual Damage to Telomeres and Mitochondria in Human T Cells

Oxidative stress caused by excess reactive oxygen species (ROS) accelerates telomere erosion and mitochondrial injury, leading to impaired cellular functions and cell death. Whether oxidative stress-mediated telomere erosion induces mitochondrial injury, or vice versa, in human T cells—the major effectors of host adaptive immunity against infection and malignancy—is poorly understood due to the pleiotropic effects of ROS. Here we employed a novel chemoptogenetic tool that selectively produces a single oxygen (1O2) only at telomeres or mitochondria in Jurkat T cells. We found that targeted 1O2 production at telomeres triggered not only telomeric DNA damage but also mitochondrial dysfunction, resulting in T cell apoptotic death. Conversely, targeted 1O2 formation at mitochondria induced not only mitochondrial injury but also telomeric DNA damage, leading to cellular crisis and apoptosis. Targeted oxidative stress at either telomeres or mitochondria increased ROS production, whereas blocking ROS formation during oxidative stress reversed the telomeric injury, mitochondrial dysfunction, and cellular apoptosis. Notably, the X-ray repair cross-complementing protein 1 (XRCC1) in the base excision repair (BER) pathway and multiple mitochondrial proteins in other cellular pathways were dysregulated by the targeted oxidative stress. By confining singlet 1O2 formation to a single organelle, this study suggests that oxidative stress induces dual injury in T cells via crosstalk between telomeres and mitochondria. Further identification of these oxidation pathways may offer a novel approach to preserve mitochondrial functions, protect telomere integrity, and maintain T cell survival, which can be exploited to combat various immune aging-associated diseases

Topological DNA Damage, Telomere Attrition and T Cell Senescence During Chronic Viral Infections

Background: T cells play a key role in controlling viral infections; however, the underlying mechanisms regulating their functions during human viral infections remain incompletely understood. Here, we used CD4 T cells derived from individuals with chronic viral infections or healthy T cells treated with camptothecin (CPT) - a topoisomerase I (Top 1) inhibitor - as a model to investigate the role of DNA topology in reprogramming telomeric DNA damage responses (DDR) and remodeling T cell functions. Results: We demonstrated that Top 1 protein expression and enzyme activity were significantly inhibited, while the Top 1 cleavage complex (TOP1cc) was trapped in genomic DNA, in T cells derived from individuals with chronic viral (HCV, HBV, or HIV) infections. Top 1 inhibition by CPT treatment of healthy CD4 T cells caused topological DNA damage, telomere attrition, and T cell apoptosis or dysfunction via inducing Top1cc accumulation, PARP1 cleavage, and failure in DNA repair, thus recapitulating T cell dysregulation in the setting of chronic viral infections. Moreover, T cells from virally infected subjects with inhibited Top 1 activity were more vulnerable to CPT-induced topological DNA damage and cell apoptosis, indicating an important role for Top 1 in securing DNA integrity and cell survival. Conclusion: These findings provide novel insights into the molecular mechanisms for immunomodulation by chronic viral infections via disrupting DNA topology to induce telomeric DNA damage, T cell senescence, apoptosis and dysfunction. As such, restoring the impaired DNA topologic machinery may offer a new strategy for maintaining T cell function against human viral diseases

Mitochondrial Functions Are Compromised in CD4 T Cells From ART-Controlled PLHIV

The hallmark of HIV/AIDS is a gradual depletion of CD4 T cells. Despite effective control by antiretroviral therapy (ART), a significant subgroup of people living with HIV (PLHIV) fails to achieve complete immune reconstitution, deemed as immune non-responders (INRs). The mechanisms underlying incomplete CD4 T cell recovery in PLHIV remain unclear. In this study, CD4 T cells from PLHIV were phenotyped and functionally characterized, focusing on their mitochondrial functions. The results show that while total CD4 T cells are diminished, cycling cells are expanded in PLHIV, especially in INRs. HIV-INR CD4 T cells are more activated, displaying exhausted and senescent phenotypes with compromised mitochondrial functions. Transcriptional profiling and flow cytometry analysis showed remarkable repression of mitochondrial transcription factor A (mtTFA) in CD4 T cells from PLHIV, leading to abnormal mitochondrial and T cell homeostasis. These results demonstrate a sequential cellular paradigm of T cell over-activation, proliferation, exhaustion, senescence, apoptosis, and depletion, which correlates with compromised mitochondrial functions. Therefore, reconstituting the mtTFA pathway may provide an adjunctive immunological approach to revitalizing CD4 T cells in ART-treated PLHIV, especially in INRs

Disruption of Telomere Integrity and DNA Repair Machineries by KML001 Induces T Cell Senescence, Apoptosis, and Cellular Dysfunctions

T cells in chronic viral infections are featured by premature aging with accelerated telomere erosion, but the mechanisms underlying telomere attrition remain unclear. Here, we employed human CD4 T cells treated with KML001 (a telomere-targeting drug) as a model to investigate the role of telomere integrity in remodeling T cell senescence. We demonstrated that KML001 could inhibit cell proliferation, cytokine production, and promote apoptosis via disrupting telomere integrity and DNA repair machineries. Specifically, KML001-treated T cells increased dysfunctional telomere-induced foci (TIF), DNA damage marker γH2AX, and topoisomerase cleavage complex (TOPcc) accumulation, leading to telomere attrition. Mechanistically, KML001 compromised telomere integrity by inhibiting telomeric repeat binding factor 2 (TRF2), telomerase, topoisomerase I and II alpha (Top1/2a), and ataxia telangiectasia mutated (ATM) kinase activities. Importantly, these KML001-induced telomeric DNA damage and T cell senescent phenotype and machineries recapitulated our findings in patients with clinical HCV or HIV infection in that their T cells were also senescent with short telomeres and thus more vulnerable to KML001-induced apoptosis. These results shed new insights on the T cell aging network that is critical and essential in protecting chromosomal telomeres from unwanted DNA damage and securing T cell survival during cell crisis upon genomic insult

HCV-Associated Exosomes Upregulate RUNXOR and RUNX1 Expressions to Promote MDSC Expansion and Suppressive Functions through STAT3-miR124 Axis

RUNX1 overlapping RNA (RUNXOR) is a long non-coding RNA and plays a pivotal role in the differentiation of myeloid cells via targeting runt-related transcription factor 1 (RUNX1). We and others have previously reported that myeloid-derived suppressor cells (MDSCs) expand and inhibit host immune responses during chronic viral infections; however, the mechanisms responsible for MDSC differentiation and suppressive functions, in particular the role of RUNXOR-RUNX1, remain unclear. Here, we demonstrated that RUNXOR and RUNX1 expressions are significantly upregulated and associated with elevated levels of immunosuppressive molecules, such as arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), signal transducer and activator of transcription 3 (STAT3), and reactive oxygen species (ROS) in MDSCs during chronic hepatitis C virus (HCV) infection. Mechanistically, we discovered that HCV-associated exosomes (HCV-Exo) can induce the expressions of RUNXOR and RUNX1, which in turn regulates miR-124 expression via STAT3 signaling, thereby promoting MDSC differentiation and suppressive functions. Importantly, overexpression of RUNXOR in healthy CD33+ myeloid cells promoted differentiation and suppressive functions of MDSCs. Conversely, silencing RUNXOR or RUNX1 expression in HCV-derived CD33+ myeloid cells significantly inhibited their differentiation and expressions of suppressive molecules and improved the function of co-cultured autologous CD4 T cells. Taken together, these results indicate that the RUNXOR-RUNX1-STAT3-miR124 axis enhances the differentiation and suppressive functions of MDSCs and could be a potential target for immunomodulation in conjunction with antiviral therapy during chronic HCV infection