Garrett, M. — Page 2 | Search bioRxiv

bioRxiv2019

Diversity and function of maternal HIV-1-specific antibodies at the time of vertical transmission

Infants of HIV positive mothers can acquire HIV infection by various routes, but even in the absence of antiviral treatment, the majority of these infants do not become infected. There is evidence that maternal antibodies may provide some protection from infection, but gestational maternal antibodies have not yet been characterized in detail. One of the most studied vertically-infected infants is BG505, as the virus from this infant yielded an Envelope protein that was successfully developed as a stable trimer. Here, we isolated and characterized 39 HIV-specific neutralizing monoclonal antibodies (nAbs) from MG505, the mother of BG505, at a time point just prior to vertical transmission. These nAbs belonged to 21 clonal families, employed a variety of VH genes, many were specific for the HIV-1 Env V3 loop, and this V3 specificity correlated with measurable antibody-dependent cellular cytotoxicity (ADCC) activity. The isolated nAbs did not recapitulate the full breadth of heterologous nor autologous virus neutralization by contemporaneous plasma. Notably, we found that the V3-targeting nAb families neutralized one particular maternal Env variant even though all tested variants had low V3 sequence diversity and were measurably bound by these nAbs. None of the nAbs neutralized the BG505 transmitted virus. Furthermore, the MG505 nAb families were found at relatively low frequencies within the maternal B cell repertoire: all less than 0.25% of total IgG sequences. Our findings demonstrate the diversity of HIV-1 nAbs that exist within a single mother, resulting in a collection of antibody specificities that can shape the transmission bottleneck.\n\nImportanceMother-to-child-transmission of HIV-1 offers a unique setting in which maternal antibodies both within the mother and passively-transferred to the infant are present at the time of viral exposure. Untreated HIV-exposed human infants are infected at a rate of 30-40%, meaning that some infants do not get infected despite continued exposure to virus. Since the potential of HIV-specific immune responses to provide protection against HIV is a central goal of HIV vaccine design, understanding the nature of maternal antibodies may provide insights into immune mechanisms of protection. In this study, we isolated and characterized HIV-specific antibodies from the mother of an infant whose transmitted virus has been well studied.

immunology↗

bioRxiv2019

Injectable diblock copolypeptide hydrogel provides platform to maintain high local concentrations of taxol and local tumor control

IntroductionSurgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy.\n\nMethodsThe development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells.\n\nResultsThe DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model, of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to a high local concentration of paclitaxel and led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment.\n\nConclusionsThese findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.

cancer biology↗

bioRxiv2019

Injectable diblock copolypeptide hydrogel provides platform to maintain high local concentrations of taxol and local tumor control.

IntroductionSurgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy.\n\nMethodsThe development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells.\n\nResultsThe DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model, of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to a high local concentration of paclitaxel and led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment.\n\nConclusionsThese findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.

bioengineering↗

bioRxiv2018

Applicability of subcortical EEG metrics of synaptopathy to older listeners with impaired audiograms

Emerging evidence suggests that cochlear synaptopathy is a common feature of sensorineural hearing loss, but it is not known whether electrophysiological metrics targeting synaptopathy in animals can be applied to a broad range of people, such as those with impaired audiograms. This study investigates the applicability of subcortical electrophysiological measures associated with synaptopathy such as auditory brainstem responses (ABRs) and envelope following responses (EFRs) in older participants with high-frequency sloping audiograms. This is important for the development of reliable and sensitive synaptopathy diagnostics in people with normal or impaired outer-hair-cell function. Broadband click-ABRs at different sound pressure levels and EFRs to amplitude-modulated stimuli were recorded, as well as relative EFR and ABR metrics which reduce individual factors such as head size and noise floor level. Most tested metrics showed significant differences between the groups and did not always follow the trends expected from synaptopathy. Audiometric hearing loss and age-related hearing related deficits interacted to affect the electrophysiological metrics and complicated their interpretation in terms of synaptopathy. This study contributes to a better understanding of how electrophysiological synaptopathy metrics differ in ears with healthy and impaired audiograms, which is an important first step towards unravelling the perceptual consequences of synaptopathy.

neuroscience↗

bioRxiv2018

Biological variation in the sizes, shapes and locations of visual cortical areas in the mouse

Visual cortex is organized into discrete sub-regions or areas that are arranged into a hierarchy and serve different functions in the processing of visual information. In our previous work, we noted that retinotopic maps of cortical visual areas differed between mice, but did not quantify these differences or determine the relative contributions of biological variation and measurement noise. Here we quantify the biological variation in the size, shape and locations of 11 visual areas in the mouse. We find that there is substantial biological variation in the sizes of visual areas, with some visual areas varying in size by two-fold across the population of mice.

neuroscience↗

bioRxiv2018

Supra-threshold psychoacoustics and envelope-following response relations: normal-hearing, synaptopathy and cochlear gain loss

The perceptual consequences of cochlear synaptopathy are presently not well understood as a direct quantification of synaptopathy is not possible in humans. To study its role for human hearing, recent studies have instead correlated changes in basic supra-threshold psychoacoustic tasks with individual differences in subcortical EEG responses, as a proxy measure for synaptopathy. It is not clear whether the reported missing relationships between the psychoacoustic quantities and the EEG are due to the adopted methods, or to a minor role of synaptopathy for sound perception. We address this topic by studying the theoretical relationship between subcortical EEG and psychoacoustic methods for different sensorineural hearing deficits.

neuroscience↗

bioRxiv2018

A large-scale, standardized physiological survey reveals higher order coding throughout the mouse visual cortex

To understand how the brain processes sensory information to guide behavior, we must know how stimulus representations are transformed throughout the visual cortex. Here we report an open, large-scale physiological survey of neural activity in the awake mouse visual cortex: the Allen Brain Observatory Visual Coding dataset. This publicly available dataset includes cortical activity from nearly 60,000 neurons collected from 6 visual areas, 4 layers, and 12 transgenic mouse lines from 221 adult mice, in response to a systematic set of visual stimuli. Using this dataset, we reveal functional differences across these dimensions and show that visual cortical responses are sparse but correlated. Surprisingly, responses to different stimuli are largely independent, e.g. whether a neuron responds to natural scenes provides no information about whether it responds to natural movies or to gratings. We show that these phenomena cannot be explained by standard local filter-based models, but are consistent with multi-layer hierarchical computation, as found in deeper layers of standard convolutional neural networks.

neuroscience↗

bioRxiv2017

Aberrant Cortical Activity In Multiple GCaMP6-Expressing Transgenic Mouse Lines

Transgenic mouse lines are invaluable tools for neuroscience but as with any technique, care must be taken to ensure that the tool itself does not unduly affect the system under study. Here we report aberrant electrical activity, similar to interictal spikes, and accompanying fluorescence events in some genotypes of transgenic mice expressing GCaMP6 genetically-encoded calcium sensors. These epileptiform events have been observed particularly, but not exclusively, in mice with Emx1-Cre and Ai93 transgenes, across multiple laboratories. The events occur at >0.1 Hz, are very large in amplitude (>1.0 mV local field potentials, >10% df/f widefield imaging signals), and typically cover large regions of cortex. Many properties of neuronal responses and behavior seem normal despite these events, though rare subjects exhibit overt generalized seizures. The underlying mechanisms of this phenomenon remain unclear, but we speculate about possible causes on the basis of diverse observations. We encourage researchers to be aware of these activity patterns while interpreting neuronal recordings from affected mouse lines and when considering which lines to study.

neuroscience↗