Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control.

Mycobacterium tuberculosis lung infection results in a complex multicellular structure: the granuloma. In some granulomas, immune activity promotes bacterial clearance, but in others, bacteria persist and grow. We identified correlates of bacterial control in cynomolgus macaque lung granulomas by co-registering longitudinal positron emission tomography and computed tomography imaging, single-cell RNA sequencing, and measures of bacterial clearance. Bacterial persistence occurred in granulomas enriched for mast, endothelial, fibroblast, and plasma cells, signaling amongst themselves via type 2 immunity and wound-healing pathways. Granulomas that drove bacterial control were characterized by cellular ecosystems enriched for type 1-type 17, stem-like, and cytotoxic T cells engaged in pro-inflammatory signaling networks involving diverse cell populations. Granulomas that arose later in infection displayed functional characteristics of restrictive granulomas and were more capable of killing Mtb. Our results define the complex multicellular ecosystems underlying (lack of) granuloma resolution and highlight host immune targets that can be leveraged to develop new vaccine and therapeutic strategies for TB.

Titanium:sapphire-on-insulator integrated lasers and amplifiers.

Titanium:sapphire (Ti:sapphire) lasers have been essential for advancing fundamental research and technological applications, including the development of the optical frequency comb1, two-photon microscopy2 and experimental quantum optics3,4. Ti:sapphire lasers are unmatched in bandwidth and tuning range, yet their use is restricted because of their large size, cost and need for high optical pump powers5. Here we demonstrate a monocrystalline titanium:sapphire-on-insulator (Ti:SaOI) photonics platform that enables dramatic miniaturization, cost reduction and scalability of Ti:sapphire technology. First, through the fabrication of low-loss whispering-gallery-mode resonators, we realize a Ti:sapphire laser operating with an ultralow, sub-milliwatt lasing threshold. Then, through orders-of-magnitude improvement in mode confinement in Ti:SaOI waveguides, we realize an integrated solid-state (that is, non-semiconductor) optical amplifier operating below 1 µm. We demonstrate unprecedented distortion-free amplification of picosecond pulses to peak powers reaching 1.0 kW. Finally, we demonstrate a tunable integrated Ti:sapphire laser, which can be pumped with low-cost, miniature, off-the-shelf green laser diodes. This opens the doors to new modalities of Ti:sapphire lasers, such as massively scalable Ti:sapphire laser-array systems for several applications. As a proof-of-concept demonstration, we use a Ti:SaOI laser array as the sole optical control for a cavity quantum electrodynamics experiment with artificial atoms in silicon carbide6. This work is a key step towards the democratization of Ti:sapphire technology through a three-orders-of-magnitude reduction in cost and footprint and introduces solid-state broadband amplification of sub-micron wavelength light.

Multicenter integrated analysis of noncoding CRISPRi screens.

The ENCODE Consortium's efforts to annotate noncoding cis-regulatory elements (CREs) have advanced our understanding of gene regulatory landscapes. Pooled, noncoding CRISPR screens offer a systematic approach to investigate cis-regulatory mechanisms. The ENCODE4 Functional Characterization Centers conducted 108 screens in human cell lines, comprising >540,000 perturbations across 24.85 megabases of the genome. Using 332 functionally confirmed CRE-gene links in K562 cells, we established guidelines for screening endogenous noncoding elements with CRISPR interference (CRISPRi), including accurate detection of CREs that exhibit variable, often low, transcriptional effects. Benchmarking five screen analysis tools, we find that CASA produces the most conservative CRE calls and is robust to artifacts of low-specificity single guide RNAs. We uncover a subtle DNA strand bias for CRISPRi in transcribed regions with implications for screen design and analysis. Together, we provide an accessible data resource, predesigned single guide RNAs for targeting 3,275,697 ENCODE SCREEN candidate CREs with CRISPRi and screening guidelines to accelerate functional characterization of the noncoding genome.

Adjuvanting a subunit COVID-19 vaccine to induce protective immunity.

The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative1. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).

Prevention of tuberculosis in macaques after intravenous BCG immunization.

Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide1. The only available vaccine, BCG (Bacillus Calmette-Guérin), is given intradermally and has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission1,2. Here we show that intravenous administration of BCG profoundly alters the protective outcome of Mtb challenge in non-human primates (Macaca mulatta). Compared with intradermal or aerosol delivery, intravenous immunization induced substantially more antigen-responsive CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage and lung lymph nodes. Moreover, intravenous immunization induced a high frequency of antigen-responsive T cells across all lung parenchymal tissues. Six months after BCG vaccination, macaques were challenged with virulent Mtb. Notably, nine out of ten macaques that received intravenous BCG vaccination were highly protected, with six macaques showing no detectable levels of infection, as determined by positron emission tomography-computed tomography imaging, mycobacterial growth, pathology and granuloma formation. The finding that intravenous BCG prevents or substantially limits Mtb infection in highly susceptible rhesus macaques has important implications for vaccine delivery and clinical development, and provides a model for defining immune correlates and mechanisms of vaccine-elicited protection against tuberculosis.

A measles-vectored vaccine candidate expressing prefusion-stabilized SARS-CoV-2 spike protein brought to phase I/II clinical trials: protection of African green monkeys from COVID-19 disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and is responsible for the largest human pandemic in 100 years. Thirty-four vaccines are currently approved for use worldwide, and approximately 67% of the world population has received a complete primary series of one, yet countries are dealing with new waves of infections, variant viruses continue to emerge, and breakthrough infections are frequent secondary to waning immunity. Here, we evaluate a measles virus (MV)-vectored vaccine expressing a stabilized prefusion SARS-CoV-2 spike (S) protein (MV-ATU3-S2PΔF2A; V591) with demonstrated immunogenicity in mouse models (see companion article [J. Brunet, Z. Choucha, M. Gransagne, H. Tabbal, M.-W. Ku et al., J Virol 98:e01693-23, 2024, https://doi.org/10.1128/jvi.01693-23]) in an established African green monkey model of disease. Animals were vaccinated with V591 or the control vaccine (an equivalent MV-vectored vaccine with an irrelevant antigen) intramuscularly using a prime/boost schedule, followed by challenge with an early pandemic isolate of SARS-CoV-2 at 56 days post-vaccination. Pre-challenge, only V591-vaccinated animals developed S-specific antibodies that had virus-neutralizing activity as well as S-specific T cells. Following the challenge, V591-vaccinated animals had lower infectious virus and viral (v) RNA loads in mucosal secretions and stopped shedding virus in these secretions earlier. vRNA loads were lower in these animals in respiratory and gastrointestinal tract tissues at necropsy. This correlated with a lower disease burden in the lungs as quantified by PET/CT at early and late time points post-challenge and by pathological analysis at necropsy.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the largest human pandemic in 100 years. Even though vaccines are currently available, countries are dealing with new waves of infections, variant viruses continue to emerge, breakthrough infections are frequent, and vaccine hesitancy persists. This study uses a safe and effective measles vaccine as a platform for vaccination against SARS-CoV-2. The candidate vaccine was used to vaccinate African green monkeys (AGMs). All vaccinated AGMs developed robust antigen-specific immune responses. After challenge, these AGMs produced less virus in mucosal secretions, for a shorter period, and had a reduced disease burden in the lungs compared to control animals. At necropsy, lower levels of viral RNA were detected in tissue samples from vaccinated animals, and the lungs of these animals lacked the histologic hallmarks of SARS-CoV-2 disease observed exclusively in the control AGMs.

Optimizing tuberculosis treatment efficacy: Comparing the standard regimen with Moxifloxacin-containing regimens.

Tuberculosis (TB) continues to be one of the deadliest infectious diseases in the world, causing ~1.5 million deaths every year. The World Health Organization initiated an End TB Strategy that aims to reduce TB-related deaths in 2035 by 95%. Recent research goals have focused on discovering more effective and more patient-friendly antibiotic drug regimens to increase patient compliance and decrease emergence of resistant TB. Moxifloxacin is one promising antibiotic that may improve the current standard regimen by shortening treatment time. Clinical trials and in vivo mouse studies suggest that regimens containing moxifloxacin have better bactericidal activity. However, testing every possible combination regimen with moxifloxacin either in vivo or clinically is not feasible due to experimental and clinical limitations. To identify better regimens more systematically, we simulated pharmacokinetics/pharmacodynamics of various regimens (with and without moxifloxacin) to evaluate efficacies, and then compared our predictions to both clinical trials and nonhuman primate studies performed herein. We used GranSim, our well-established hybrid agent-based model that simulates granuloma formation and antibiotic treatment, for this task. In addition, we established a multiple-objective optimization pipeline using GranSim to discover optimized regimens based on treatment objectives of interest, i.e., minimizing total drug dosage and lowering time needed to sterilize granulomas. Our approach can efficiently test many regimens and successfully identify optimal regimens to inform pre-clinical studies or clinical trials and ultimately accelerate the TB regimen discovery process.

Anatomic Fibular-Based Posterolateral Corner Reconstruction With 2 Femoral Tunnels Shows Lowest Residual Laxity With External Rotation and Varus Stresses: A Systematic Review and Network Meta-analysis of In Vitro Biomechanical Studies.

PURPOSE: To perform a systematic review and network meta-analysis of in vitro cadaveric, biomechanical studies evaluating described techniques for posterolateral corner (PLC) reconstruction, including fibular- and tibiofibular-based techniques. METHODS: The PubMed/MEDLINE, Embase, and Cochrane Library databases were searched in December 2023 for cadaveric studies evaluating PLC reconstruction. After a descriptive summary, a series of frequentist network meta-analyses comparing (1) nonanatomic fibular-based (single femoral tunnel), (2) anatomic fibular-based (double femoral tunnel), and (3) anatomic tibiofibular-based PLC reconstructions with the intact knee were performed for both external rotation (ER) and varus laxity from 0° to 90° of knee flexion. Pooled treatment estimates were calculated as mean differences (MDs) with 95% confidence intervals (CIs) using random-effects models. RESULTS: A total of 31 studies were included. Nonanatomic fibular-based reconstructions showed increased ER laxity compared with the intact state between 30° and 90° of flexion (MD, 1.66° [95% CI, -0.27° to 3.59°] at 0° [P = .093]; MD, 2.29° [95% CI, 0.44° to 4.13°] at 30° [P = .015]; MD, 3.04° [95% CI, 0.95° to 5.12°] at 60° [P = .004]; and MD, 4.30° [95% CI, 1.41° to 7.19°] at 90° [P = .004]). The anatomic fibular- and tibiofibular-based reconstructions restored ER stability at all flexion values (except at 0° for tibiofibular based). All 3 reconstructions restored varus stability compared with the intact state in all scenarios except the anatomic fibular-based techniques at 0° (MD, 0.85° [95% CI, 0.06° to 1.63°]; P = .034). Across the assessed ER and varus laxity states, the anatomic fibular-based reconstruction was ranked "best" in 5 of 8 scenarios. CONCLUSIONS: PLC reconstructions using nonanatomic fibular-based techniques showed increased residual laxity in ER from 30° to 90° of knee flexion. Conversely, anatomic fibular- and tibiofibular-based reconstructions showed ER and varus laxity similar to that in the intact knee state across most of the assessed knee flexion values. CLINICAL RELEVANCE: Various techniques have been described for PLC reconstruction. However, no study has comprehensively compared the biomechanical properties of these reconstructions with one another.

An Inverse-Designed Nanophotonic Interface for Excitons in Atomically Thin Materials.

Efficient nanophotonic devices are essential for applications in quantum networking, optical information processing, sensing, and nonlinear optics. Extensive research efforts have focused on integrating two-dimensional (2D) materials into photonic structures, but this integration is often limited by size and material quality. Here, we use hexagonal boron nitride (hBN), a benchmark choice for encapsulating atomically thin materials, as a waveguiding layer while simultaneously improving the optical quality of the embedded films. When combined with a photonic inverse design, it becomes a complete nanophotonic platform to interface with optically active 2D materials. Grating couplers and low-loss waveguides provide optical interfacing and routing, tunable cavities provide a large exciton-photon coupling to transition metal dichalcogenide (TMD) monolayers through Purcell enhancement, and metasurfaces enable the efficient detection of TMD dark excitons. This work paves the way for advanced 2D-material nanophotonic structures for classical and quantum nonlinear optics.

Selective Defluorination of Trifluoromethyl Substituents by Conformationally Induced Remote Substitution.

The selective reduction of an aromatic trifluoromethyl substituent to a difluoromethyl substituent may be achieved by base-promoted elimination to form a difluoro-p-quinomethide which is trapped by an intramolecular nucleophile. High yields are obtained when the nucleophilic trap entails the conformationally favoured cyclisation of an aminoisobutyric acid (Aib) derivative. The resulting cyclised difluoromethyl-substituted arylimidazolidinone products are readily converted to versatile difluoromethyl-substituted aldehydes by reduction and hydrolysis. Defluorination is successful on a range of benzenoid (both para and ortho CF3-substituted) and heterocyclic substrates. Double defluorination may likewise be achieved sequentially, or in a single step, from an Aib dipeptide derivative.

Host Immunity to Mycobacterium tuberculosis Infection Is Similar in Simian Immunodeficiency Virus (SIV)-Infected, Antiretroviral Therapy-Treated and SIV-Naïve Juvenile Macaques.

Pre-existing HIV infection increases tuberculosis (TB) risk in children. Antiretroviral therapy (ART) reduces, but does not abolish, this risk in children with HIV. The immunologic mechanisms involved in TB progression in both HIV-naive and HIV-infected children have not been explored. Much of our current understanding is based on human studies in adults and adult animal models. In this study, we sought to model childhood HIV/Mycobacterium tuberculosis (Mtb) coinfection in the setting of ART and characterize T cells during TB progression. Macaques equivalent to 4 to 8 year-old children were intravenously infected with SIVmac239M, treated with ART 3 months later, and coinfected with Mtb 3 months after initiating ART. SIV-naive macaques were similarly infected with Mtb alone. TB pathology and total Mtb burden did not differ between SIV-infected, ART-treated and SIV-naive macaques, although lung Mtb burden was lower in SIV-infected, ART-treated macaques. No major differences in frequencies of CD4+ and CD8+ T cells and unconventional T cell subsets (Vγ9+ γδ T cells, MAIT cells, and NKT cells) in airways were observed between SIV-infected, ART-treated and SIV-naive macaques over the course of Mtb infection, with the exception of CCR5+ CD4+ and CD8+ T cells which were slightly lower. CD4+ and CD8+ T cell frequencies did not differ in the lung granulomas. Immune checkpoint marker levels were similar, although ki-67 levels in CD8+ T cells were elevated. Thus, ART treatment of juvenile macaques, 3 months after SIV infection, resulted in similar progression of Mtb and T cell responses compared to Mtb in SIV-naive macaques.

The First In-Human Application of Continuous Low-Irradiance Phototherapy for Chronic Wounds: A Pilot Study.

BACKGROUND: Polymicrobial colonization and resultant biofilm formation significantly impair the process of wound healing. Stagnant tissue repair processes predispose patients to serious complications including systemic infection and limb amputation. Continuous Low-Irradiance Phototherapy (CLIP) is a novel therapeutic approach that delivers blue light at low irradiance for extended periods of time. Bench and preclinical work in the literature indicates that 405 nm light avoids thermal injury of healthy tissue, promotes a cytokine milieu favoring re-epithelialization and angiogenesis, and prevents bacterial and biofilm growth.  Objective: This is the first in-human evaluation of a technology that delivers continuous low-irradiance 405 nm light to chronic wounds. The objective of this study was to determine the safety, feasibility, and ergonomics of this device for the treatment of chronic wounds in adult human subjects. This was not a randomized study to determine device efficacy, although data on outcome were collected. METHODS: In this prospective observational pilot study, participants received the intervention 24 hours per day, 7 days per week, for 4 weeks. Cohort I was conducted from December 2018 to March 2019, with Cohorts II and III ongoing. 25 study participants were recruited by referral (Cohort I: 5 participants, Cohort II: 10 participants, Cohort III: 10 participants). Our primary endpoint was to monitor for safety, assess usability by nurses and physicians, and evaluate patient comfort. The secondary endpoint, although not randomized nor directly compared with standard intervention, was the percentage area reduction (PAR) of the wound.  Results: No adverse events or subject discomfort occurred with the CLIP intervention. The staff treating the study participants reported no ergonomic or compliance issues with the use of the device. The device received high scores in categories assessing practicality and ease of use. There was an average PAR of 29% (SD = 0.42).  Conclusion: This study serves as the first in-human evaluation of extended low-irradiance 405 nm light for chronic wound therapy. The device appears safe and easy to use and had no compliance issues in the outpatient setting. Study participants who received CLIP without interruption saw either partial or complete reduction in wound area.  J Drugs Dermatol. 2023;22(11):1111-1117     doi:10.36849/JDD.7206.

Lymph nodes-The neglected battlefield in tuberculosis.

Lymph nodes, particularly thoracic lymph nodes, are among the most common sites of extrapulmonary tuberculosis (TB). However, Mycobacterium tuberculosis (Mtb) infection in these organs is understudied. Aside from being sites of initiation of the adaptive immune system, lymph nodes also serve as niches of Mtb growth and persistence. Mtb infection results in granuloma formation that disrupts and-if it becomes large enough-replaces the normal architecture of the lymph node that is vital to its function. In preclinical models, successful TB vaccines appear to prevent spread of Mtb from the lungs to the lymph nodes. Reactivation of latent TB can start in the lymph nodes resulting in dissemination of the bacteria to the lungs and other organs. Involvement of the lymph nodes may improve Bacille Calmette-Guerin (BCG) vaccine efficacy. Lastly, drug penetration to the lymph nodes is poor compared to blood, lung tissue, and lung granulomas. Future studies on evaluating the efficacy of vaccines and anti-TB drug treatments should include consideration of the effects on thoracic lymph nodes and not just the lungs.

SIV and Mycobacterium tuberculosis synergy within the granuloma accelerates the reactivation pattern of latent tuberculosis.

Human immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB), regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model of human TB, we compared radiographic, immunologic and microbiologic characteristics of early (subclinical) reactivation of latent M. tuberculosis (Mtb) infection among animals subsequently infected with simian immunodeficiency virus (SIV) or who underwent anti-CD4 depletion by a depletion antibody. CD4 depleted animals had significantly fewer CD4 T cells within granulomas compared to Mtb/SIV co-infected and Mtb-only control animals. After 2 months of treatment, subclinical reactivation occurred at similar rates among CD4 depleted (5 of 7 animals) and SIV infected animals (4 of 8 animals). However, SIV-induced reactivation was associated with more dissemination of lung granulomas that were permissive to Mtb growth resulting in greater bacterial burden within granulomas compared to CD4 depleted reactivators. Granulomas from Mtb/SIV animals displayed a more robust T cell activation profile (IFN-α, IFN-γ, TNF, IL-17, IL-2, IL-10, IL-4 and granzyme B) compared to CD4 depleted animals and controls though these effectors did not protect against reactivation or dissemination, but instead may be related to increased viral and/or Mtb antigens. SIV replication within the granuloma was associated with reactivation, greater overall Mtb growth and reduced Mtb killing resulting in greater overall Mtb burden. These data support that SIV disrupts protective immune responses against latent Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas.

Chemical intervention of influenza virus mRNA nuclear export.

Influenza A viruses are human pathogens with limited therapeutic options. Therefore, it is crucial to devise strategies for the identification of new classes of antiviral medications. The influenza A virus genome is constituted of 8 RNA segments. Two of these viral RNAs are transcribed into mRNAs that are alternatively spliced. The M1 mRNA encodes the M1 protein but is also alternatively spliced to yield the M2 mRNA during infection. M1 to M2 mRNA splicing occurs at nuclear speckles, and M1 and M2 mRNAs are exported to the cytoplasm for translation. M1 and M2 proteins are critical for viral trafficking, assembly, and budding. Here we show that gene knockout of the cellular protein NS1-BP, a constituent of the M mRNA speckle-export pathway and a binding partner of the virulence factor NS1 protein, inhibits M mRNA nuclear export without altering bulk cellular mRNA export, providing an avenue to preferentially target influenza virus. We performed a high-content, image-based chemical screen using single-molecule RNA-FISH to label viral M mRNAs followed by multistep quantitative approaches to assess cellular mRNA and cell toxicity. We identified inhibitors of viral mRNA biogenesis and nuclear export that exhibited no significant activity towards bulk cellular mRNA at non-cytotoxic concentrations. Among the hits is a small molecule that preferentially inhibits nuclear export of a subset of viral and cellular mRNAs without altering bulk cellular mRNA export. These findings underscore specific nuclear export requirements for viral mRNAs and phenocopy down-regulation of the mRNA export factor UAP56. This RNA export inhibitor impaired replication of diverse influenza A virus strains at non-toxic concentrations. Thus, this screening strategy yielded compounds that alone or in combination may serve as leads to new ways of treating influenza virus infection and are novel tools for studying viral RNA trafficking in the nucleus.

SARS-CoV-2 infection of African green monkeys results in mild respiratory disease discernible by PET/CT imaging and shedding of infectious virus from both respiratory and gastrointestinal tracts.

Vaccines are urgently needed to combat the global coronavirus disease 2019 (COVID-19) pandemic, and testing of candidate vaccines in an appropriate non-human primate (NHP) model is a critical step in the process. Infection of African green monkeys (AGM) with a low passage human isolate of SARS-CoV-2 by aerosol or mucosal exposure resulted in mild clinical infection with a transient decrease in lung tidal volume. Imaging with human clinical-grade 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) co-registered with computed tomography (CT) revealed pulmonary lesions at 4 days post-infection (dpi) that resolved over time. Infectious virus was shed from both respiratory and gastrointestinal (GI) tracts in all animals in a biphasic manner, first between 2-7 dpi followed by a recrudescence at 14-21 dpi. Viral RNA (vRNA) was found throughout both respiratory and gastrointestinal systems at necropsy with higher levels of vRNA found within the GI tract tissues. All animals seroconverted simultaneously for IgM and IgG, which has also been documented in human COVID-19 cases. Young AGM represent an species to study mild/subclinical COVID-19 disease and with possible insights into live virus shedding. Future vaccine evaluation can be performed in AGM with correlates of efficacy being lung lesions by PET/CT, virus shedding, and tissue viral load.

Non-adiabatic Excited-State Molecular Dynamics: Theory and Applications for Modeling Photophysics in Extended Molecular Materials.

Optically active molecular materials, such as organic conjugated polymers and biological systems, are characterized by strong coupling between electronic and vibrational degrees of freedom. Typically, simulations must go beyond the Born-Oppenheimer approximation to account for non-adiabatic coupling between excited states. Indeed, non-adiabatic dynamics is commonly associated with exciton dynamics and photophysics involving charge and energy transfer, as well as exciton dissociation and charge recombination. Understanding the photoinduced dynamics in such materials is vital to providing an accurate description of exciton formation, evolution, and decay. This interdisciplinary field has matured significantly over the past decades. Formulation of new theoretical frameworks, development of more efficient and accurate computational algorithms, and evolution of high-performance computer hardware has extended these simulations to very large molecular systems with hundreds of atoms, including numerous studies of organic semiconductors and biomolecules. In this Review, we will describe recent theoretical advances including treatment of electronic decoherence in surface-hopping methods, the role of solvent effects, trivial unavoided crossings, analysis of data based on transition densities, and efficient computational implementations of these numerical methods. We also emphasize newly developed semiclassical approaches, based on the Gaussian approximation, which retain phase and width information to account for significant decoherence and interference effects while maintaining the high efficiency of surface-hopping approaches. The above developments have been employed to successfully describe photophysics in a variety of molecular materials.

IL-10 Impairs Local Immune Response in Lung Granulomas and Lymph Nodes during Early Mycobacterium tuberculosis Infection.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to be a major global health problem. Lung granulomas are organized structures of host immune cells that function to contain the bacteria. Cytokine expression is a critical component of the protective immune response, but inappropriate cytokine expression can exacerbate TB. Although the importance of proinflammatory cytokines in controlling M. tuberculosis infection has been established, the effects of anti-inflammatory cytokines, such as IL-10, in TB are less well understood. To investigate the role of IL-10, we used an Ab to neutralize IL-10 in cynomolgus macaques during M. tuberculosis infection. Anti-IL-10-treated nonhuman primates had similar overall disease outcomes compared with untreated control nonhuman primates, but there were immunological changes in granulomas and lymph nodes from anti-IL-10-treated animals. There was less thoracic inflammation and increased cytokine production in lung granulomas and lymph nodes from IL-10-neutralized animals at 3-4 wk postinfection compared with control animals. At 8 wk postinfection, lung granulomas from IL-10-neutralized animals had reduced cytokine production but increased fibrosis relative to control animals. Although these immunological changes did not affect the overall disease burden during the first 8 wk of infection, we paired computational modeling to explore late infection dynamics. Our findings support that early changes occurring in the absence of IL-10 may lead to better bacterial control later during infection. These unique datasets provide insight into the contribution of IL-10 to the immunological balance necessary for granulomas to control bacterial burden and disease pathology in M. tuberculosis infection.

Sensory feedback expands dynamic complexity and aids in robustness against noise.

It has been hypothesized that sensory feedback is a critical component in determining the functionality of a central pattern generator. To test this, Yu and Thomas's recent work Yu and Thomas (Biol Cybern 115(2):135-160, 2021) built a model of a half-center oscillator coupled to a simple muscular model with sensory feedback. They showed that sensory feedback increases robustness against external noise, while simultaneously expanding the potential repertoire of functions the half-center oscillator can perform. However, they show that this comes at the cost of robustness against internal noise.