Serotonin transporter knockout in rats reduces beta- and gamma-band functional connectivity between the orbitofrontal cortex and amygdala during auditory discrimination.

The orbitofrontal cortex and amygdala collaborate in outcome-guided decision-making through reciprocal projections. While serotonin transporter knockout (SERT-/-) rodents show changes in outcome-guided decision-making, and in orbitofrontal cortex and amygdala neuronal activity, it remains unclear whether SERT genotype modulates orbitofrontal cortex-amygdala synchronization. We trained SERT-/- and SERT+/+ male rats to execute a task requiring to discriminate between two auditory stimuli, one predictive of a reward (CS+) and the other not (CS-), by responding through nose pokes in opposite-side ports. Overall, task acquisition was not influenced by genotype. Next, we simultaneously recorded local field potentials in the orbitofrontal cortex and amygdala of both hemispheres while the rats performed the task. Behaviorally, SERT-/- rats showed a nonsignificant trend for more accurate responses to the CS-. Electrophysiologically, orbitofrontal cortex-amygdala synchronization in the beta and gamma frequency bands during response selection was significantly reduced and associated with decreased hubness and clustering coefficient in both regions in SERT-/- rats compared to SERT+/+ rats. Conversely, theta synchronization at the time of behavioral response in the port associated with reward was similar in both genotypes. Together, our findings reveal the modulation by SERT genotype of the orbitofrontal cortex-amygdala functional connectivity during an auditory discrimination task.

Retinal Displacement Following Rhegmatogenous Retinal Detachment Repair.

BACKGROUND AND OBJECTIVE: This study aimed to report retinal displacement incidence following rhegmatogenous retinal detachment (RRD) repair with pars plana vitrectomy (PPV), scleral buckle (SB), or combined SB/PPV. PATIENTS AND METHODS: A single-center, case series using Optos fundus autofluorescence (FAF) images was performed after RRD repair between April 2020 and February 2022. Retinal displacement was identified by imprinted retinal vessels on FAF imaging. RESULTS: One hundred ninety-four eyes were included. Ninety-seven (50.0%) eyes underwent PPV, 46 (23.7%) underwent SB, and 51 (26.3%) underwent SB/PPV. A total of 25/194 eyes (12.9%) had retinal vessel imprinting on FAF imaging consistent with retinal displacement. The SB/PPV group (9/51, 17.6%) and the PPV group (15/97, 15.5%) had significantly higher displacement rates when compared to the SB group (1/46, 2.2%; P = 0.017, P = 0.021, respectively). CONCLUSIONS: Retinal displacement after RRD repair is more prevalent after PPV. There was a low rate of displacement with SB. Retinal displacement was not associated with a visual acuity difference. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Discovery of ester-linked ubiquitylation of PARP10 mono-ADP-ribosylation in cells: a dual post-translational modification on Glu/Asp side chains.

The prevailing view on post-translational modifications (PTMs) is that amino acid side chains in proteins are modified with a single PTM at any given time. However, a growing body of work has demonstrated crosstalk between different PTMs, some occurring on the same residue. Such interplay is seen with ADP-ribosylation and ubiquitylation, where specialized E3 ligases ubiquitylate targets for proteasomal degradation in an ADP-ribosylation-dependent manner. More recently, the DELTEX family of E3 ligases was reported to catalyze ubiquitylation of the 3'- hydroxy group of the adenine-proximal ribose of free NAD + and ADP-ribose in vitro , generating a non-canonical ubiquitin ester-linked species. In this report, we show, for the first time, that this dual PTM occurs in cells on mono-ADP-ribosylated (MARylated) PARP10 on Glu/Asp sites to form a MAR ubiquitin ester (MARUbe). We term this process m ono- A DP-ribosyl ub iquit ylation or MARUbylation. Using chemical and enzymatic treatments, including a newly characterized bacterial deubiquitinase with esterase-specific activity, we discovered that PARP10 MARUbylation is extended with K11-linked polyubiquitin chains. Finally, mechanistic studies using proteasomal and ubiquitin-activating enzyme inhibitors demonstrated that PARP10 MARUbylation leads to its proteasomal degradation, providing a functional role for this new PTM in regulating protein turnover.

PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies.

Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenvironment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here, we demonstrate that poly-(ADP-ribose)-polymerase-11 (PARP11) is an essential regulator of immunosuppressive activities of TI-Tregs. Expression of PARP11 correlates with TI-Treg cell numbers and poor responses to immune checkpoint blockade (ICB) in human patients with cancer. Tumor-derived factors including adenosine and prostaglandin E2 induce PARP11 in TI-Tregs. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses. Accordingly, ITK7 decelerates tumor growth and significantly increases the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of chimeric antigen receptor (CAR) T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.

RANDOMIZED TRIAL COMPARING MICROSERRATED VERSUS CONVENTIONAL INTERNAL LIMITING MEMBRANE FORCEPS FOR INTERNAL LIMITING MEMBRANE PEELING.

PURPOSE: To evaluate anatomic outcomes and surgeon response following the use of microserrated (Sharkskin, Alcon, Forth Worth, TX) internal limiting membrane (ILM) forceps compared with conventional (Grieshaber; Alcon) ILM forceps for peeling of the ILM. METHODS: Patients were prospectively assigned in a 1:1 randomized fashion to undergo ILM peeling using microserrated forceps or conventional forceps. Rates of retinal hemorrhages, deep retinal grasps, ILM regrasping, time to ILM removal, and surgeon questionnaire comparing the use of microserrated and conventional ILM forceps were analyzed. RESULTS: A total of 90 eyes of 90 patients were included in this study. The mean number of deep retinal grasps was higher in the conventional forceps group (1.51 ± 1.70 vs. 0.33 ± 0.56, respectively [P < 0.0001]). The mean number of failed ILM grasps was higher with conventional forceps (6.62 ± 3.51 vs. 5.18 ± 2.06 [P = 0.019]). Microserrated forceps provided more comfortability (lower number) in initiating the ILM flap (2.16 ± 0.85 vs. 1.56 ± 0.76, P < 0.001), comfortability in regrasping the ILM flap (2.51 ± 1.01 vs. 1.98 ± 0.89, P = 0.01), and comfortability in completing the ILM flap (2.42 ± 1.03 vs. 1.84 ± 1.02, P = 0.01). CONCLUSION: Surgeons utilizing the microserrated forceps experienced fewer deep retina grasps and fewer failed ILM grasps compared with conventional ILM forceps. The microserrated forceps was also a more favorable experience subjectively among the surgeons.

VITREORETINAL OUTCOMES FOLLOWING SECONDARY INTRAOCULAR LENS IMPLANTATION WITH PARS PLANA VITRECTOMY.

BACKGROUND: Retrospective cohort study of 561 adult patients undergoing secondary intraocular lens (IOL) implantation by vitreoretinal surgeons at a single institution from April 2015 to December 2020. METHODS: Patient historical factors, intraoperative/postoperative complications, and outcomes of IOL type (anterior chamber IOL versus scleral sutured IOL versus scleral fixated IOL versus. sulcus) were assessed. Primary outcomes were rates of postoperative retinal tears and rhegmatogenous retinal detachment. Secondary outcomes were rates of intraoperative endolaser, intraoperative retinal tear, and further IOL surgery. RESULTS: The incidence of intraoperative retinal tears was 7.3% and not significantly different between techniques. Rates of intraoperative endolaser use were 17.5% among all techniques and not significantly different between techniques. Rates of postoperative retinal tear were low (0%-2.7%). Rates of postoperative rhegmatogenous retinal detachment were not significantly different between techniques (anterior chamber IOL 9/198 [4.5%], SFIOL 1/54 [1.9%], scleral sutured IOL 14/274 [5.1%], sulcus 2/35 [5.7%], total 26/561 [4.6%], P = 0.79). Rates of repeat IOL surgery trended higher in sulcus lenses (anterior chamber IOL 5/198 [2.5%], SFIOL 4/54 [7.4%], scleral sutured IOL 16/274 [5.8%], sulcus 5/35 [14.3%], total 30/561 [5.3%], P = 0.12). CONCLUSION: Intraoperative endolaser use and intraoperative retinal tear are not uncommon in secondary IOL surgery and underscore the importance of careful vitreoretinal management among these patients.

SUPRACHOROIDAL TRIAMCINOLONE ACETONIDE FOR REFRACTORY POSTOPERATIVE CYSTOID MACULAR EDEMA.

PURPOSE: To investigate outcomes of suprachoroidal triamcinolone acetonide (XIPERE, Bausch + Lomb) for the treatment of refractory postoperative cystoid macular edema. METHODS: Medical records of patients receiving suprachoroidal triamcinolone acetonide for postoperative cystoid macular edema were reviewed. Primary outcomes were visual acuity and central foveal thickness. RESULTS: A total of 32 eyes from 32 patients with a median (interquartile range) follow-up duration of 6 (2-7) months and 1 (1-2) suprachoroidal triamcinolone acetonide injection were included; 19 (59.4%) had a history of vitrectomy. The median (interquartile range) central foveal thickness decreased from 492 (379-629) µm to 267 (187-388) µm at 1 month (P < 0.001), 362 (218-521) µm at 3 months (P = 0.005), and 339 (206-514) µm at the final visit (P < 0.001). The median logarithm of the minimal angle of resolution visual acuity improved from 0.65 (0.48-0.97, 20/89) at baseline to 0.54 (0.35-0.88, 20/69) (P = 0.058) at 1 month, 0.54 (0.33-0.84, 20/69) at 3 months (P = 0.121), and 0.60 (0.33-0.88, 20/80) at the final visit (P = 0.021). Vitrectomized eyes had similar findings. Six eyes (18.8%) developed elevated intraocular pressure (>24 mmHg) (range: 25-49 mmHg) with a median intraocular pressure elevation of 13.5 mmHg compared with baseline, and all had prior glaucoma or ocular hypertension. CONCLUSION: Suprachoroidal triamcinolone acetonide reduced macular edema and improved vision in refractory postoperative cystoid macular edema, including vitrectomized eyes. Intraocular pressure should be monitored, especially in those with a history of glaucoma or ocular hypertension.

Intersubject correlations in reward and mentalizing brain circuits separately predict persuasiveness of two types of ISIS video propaganda.

The Islamist group ISIS has been particularly successful at recruiting Westerners as terrorists. A hypothesized explanation is their simultaneous use of two types of propaganda: Heroic narratives, emphasizing individual glory, alongside Social narratives, which emphasize oppression against Islamic communities. In the current study, functional MRI was used to measure brain responses to short ISIS propaganda videos distributed online. Participants were shown 4 Heroic and 4 Social videos categorized as such by another independent group of subjects. Persuasiveness was measured using post-scan predictions of recruitment effectiveness. Inter-subject correlation (ISC) was used to measure commonality of brain activity time courses across individuals. ISCs in ventral striatum predicted rated persuasiveness for Heroic videos, while ISCs in mentalizing and default networks, especially in dmPFC, predicted rated persuasiveness for Social videos. This work builds on past findings that engagement of the reward circuit and of mentalizing brain regions predicts preferences and persuasion. The observed dissociation as a function of stimulus type is novel, as is the finding that intersubject synchrony in ventral striatum predicts rated persuasiveness. These exploratory results identify possible neural mechanisms by which political extremists successfully recruit prospective members and specifically support the hypothesized distinction between Heroic and Social narratives for ISIS propaganda.

Cortical Face-Selective Responses Emerge Early in Human Infancy.

In human adults, multiple cortical regions respond robustly to faces, including the occipital face area (OFA) and fusiform face area (FFA), implicated in face perception, and the superior temporal sulcus (STS) and medial prefrontal cortex (MPFC), implicated in higher-level social functions. When in development, does face selectivity arise in each of these regions? Here, we combined two awake infant functional magnetic resonance imaging (fMRI) datasets to create a sample size twice the size of previous reports (n = 65 infants; 2.6-9.6 months). Infants watched movies of faces, bodies, objects, and scenes, while fMRI data were collected. Despite variable amounts of data from each infant, individual subject whole-brain activation maps revealed responses to faces compared to nonface visual categories in the approximate location of OFA, FFA, STS, and MPFC. To determine the strength and nature of face selectivity in these regions, we used cross-validated functional region of interest analyses. Across this larger sample size, face responses in OFA, FFA, STS, and MPFC were significantly greater than responses to bodies, objects, and scenes. Even the youngest infants (2-5 months) showed significantly face-selective responses in FFA, STS, and MPFC, but not OFA. These results demonstrate that face selectivity is present in multiple cortical regions within months of birth, providing powerful constraints on theories of cortical development.

Phase 1 Study of JNJ-81201887 Gene Therapy in Geographic Atrophy Secondary to Age-Related Macular Degeneration.

PURPOSE: To evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular degeneration (AMD). DESIGN: Phase 1, open-label, single-center, first-in-human clinical study. PARTICIPANTS: Adult patients (≥50 years of age) with GA secondary to AMD in the study-treated eye (treated eye) with Snellen best-corrected visual acuity of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm2 (2-8 disc area), and best-corrected visual acuity of 20/800 or better in fellow, nontreated eye were included. METHODS: Patients (n = 17) were enrolled sequentially into low-dose (3.56 × 1010 viral genome/eye; n = 3), intermediate-dose (1.07 × 1011 viral genome/eye; n = 3), and high-dose (3.56 × 1011 viral genome/eye; n = 11) cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months. MAIN OUTCOME MEASURES: Safety and tolerability outcomes included assessment of ocular and nonocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate. RESULTS: Baseline patient characteristics were consistent with the disease under study, and all enrolled patients demonstrated foveal center-involved GA. JNJ-81201887 was well-tolerated across all cohorts, with no dose-limiting AEs. No serious or systemic AEs related to study intervention occurred. Overall, 5 of 17 patients (29%) experienced 5 events of mild ocular inflammation related to study treatment; examination findings in all resolved, and AEs resolved in 4 of 5 patients after topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. Geographic atrophy lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0 through 6 to 0.056 mm at months 18 through 24. CONCLUSIONS: All 3 studied doses of JNJ-1887 showed a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Decreased Beta Power and OFC-STN Phase Synchronization during Reactive Stopping in Freely Behaving Rats.

During natural behavior, an action often needs to be suddenly stopped in response to an unexpected sensory input-referred to as reactive stopping. Reactive stopping has been mostly investigated in humans, which led to hypotheses about the involvement of different brain structures, in particular the hyperdirect pathway. Here, we directly investigate the contribution and interaction of two key regions of the hyperdirect pathway, the orbitofrontal cortex (OFC) and subthalamic nucleus (STN), using dual-area, multielectrode recordings in male rats performing a stop-signal task. In this task, rats have to initiate movement to a go-signal, and occasionally stop their movement to the go-signal side after a stop-signal, presented at various stop-signal delays. Both the OFC and STN show near-simultaneous field potential reductions in the beta frequency range (12-30 Hz) compared with the period preceding the go-signal and the movement period. These transient reductions (∼200 ms) only happen during reactive stopping, which is when the stop-signal was received after action initiation, and are well timed after stop-signal onset and before the estimated time of stopping. Phase synchronization analysis also showed a transient attenuation of synchronization between the OFC and STN in the beta range during reactive stopping. The present results provide the first direct quantification of local neural oscillatory activity in the OFC and STN and interareal synchronization specifically timed during reactive stopping.

A genetically encoded sensor for real-time monitoring of poly-ADP-ribosylation dynamics in-vitro and in cells.

ADP-ribosylation, the transfer of ADP-ribose (ADPr) from nico-tinamide adenine dinucleotide (NAD+) groups to proteins, is a conserved post-translational modification (PTM) that occurs most prominently in response to DNA damage. ADP-ribosylation is a dynamic PTM regulated by writers (PARPs), erasers (ADPr hy-drolases), and readers (ADPR binders). PARP1 is the primary DNA damage-response writer responsible for adding a polymer of ADPR to proteins (PARylation). Real-time monitoring of PARP1-mediated PARylation, especially in live cells, is critical for under-standing the spatial and temporal regulation of this unique PTM. Here, we describe a genetically encoded FRET probe (pARS) for semi-quantitative monitoring of PARylation dynamics. pARS feature a PAR-binding WWE domain flanked with turquoise and Venus. With a ratiometric readout and excellent signal-to-noise characteristics, we show that pARS can monitor PARP1-dependent PARylation temporally and spatially in real-time. pARS provided unique insights into PARP1-mediated PARylation kinetics in vitro and high-sensitivity detection of PARylation in live cells, even under mild DNA damage. We also show that pARS can be used to determine the potency of PARP inhibitors in vitro and, for the first time, in live cells in response to DNA damage. The robustness and ease of use of pARS make it an important tool for the PARP field.

Relationship between otolaryngology interest groups and residency match results.

BACKGROUND: Many students have limited exposure to otolaryngology-head and neck surgery (OTOHNS) throughout medical school, limiting recruitment of medical students early in their medical careers. OBJECTIVE: To assess the association between otolaryngology interest groups (OIGs) at medical schools and percentage of students matching into OTOHNS residency programs. To characterize specific aspects of OIGs that may impact the percentage of students matching into OTOHNS residency programs from a given medical school. METHODS: Data was obtained from web searches of 141 accredited U.S. allopathic medical schools to see if they possessed OIGs. Information on the various activities and opportunities that OIGs participated in was collected through medical school websites. 2020 NRMP® match results data were obtained. RESULTS: Web searches found that 73 % (103 out of 141) of U.S. allopathic medical schools have OIGs. Medical schools with OIGs were associated with a 35 % increase in the median percentage of OTOHNS matches (P = 0.022). Of the 103 medical schools with OIGs, 53 % (55) of the schools had information on their websites describing activities and opportunities that their OIGs participate in. OIGs with research and/or mentorship opportunities were associated with increases in OTOHNS matches by 32 % (P = 0.043) and 83 % (P = 0.012), respectively. CONCLUSION: The presence of an OIG at a medical school is associated with an increased percentage of students matching into OTOHNS from that medical school. OIGs that provide research or mentorship opportunities are associated with an increased percentage of students matching into OTOHNS from those medical schools.

Re-evaluation of the methodology for estimating the US specialty physician workforce.

Increasing pursuit of subspecialized training has quietly revolutionized physician training, but the potential impact on physician workforce estimates has not previously been recognized. The Physicians Specialty Data Reports of the Association of American Medical Colleges, derived from specialty designations in the American Medical Association (AMA) Physician Professional Data (PPD), are the reference source for US physician workforce estimates; by 2020, the report for pathologists was an undercount of 39% when compared with the PPD. Most of the difference was due to the omission of pathology subspecialty designations. The rest resulted from reliance on only the first of the AMA PPD's 2 specialty data fields. Placement of specialty designation in these 2 fields is sensitive to sequence of training and is thus affected by multiple or intercalated (between years of residency training) fellowships. Both these phenomena have become progressively more common and are not unique to pathology. Our findings demonstrate the need to update definitions and methodology underlying estimates of the US physician workforce for pathology and suggest a like need in other specialties affected by similar trends.

Interactive effects of pain and arousal state on heart rate and cortical activity in the mouse anterior cingulate and somatosensory cortices.

Sensory disconnection is a hallmark of sleep, yet the cortex retains some ability to process sensory information. Acute noxious stimulation during sleep increases the heart rate and the likelihood of awakening, indicating that certain mechanisms for pain sensing and processing remain active. However, processing of somatosensory information, including pain, during sleep remains underexplored. To assess somatosensation in natural sleep, we simultaneously recorded heart rate and local field potentials in the anterior cingulate (ACC) and somatosensory (S1) cortices of naïve, adult male mice, while applying noxious and non-noxious stimuli to their hind paws throughout their sleep-wake cycle. Noxious stimuli evoked stronger heart rate increases in both wake and non-rapid eye movement sleep (NREMS), and resulted in larger awakening probability in NREMS, as compared to non-noxious stimulation, suggesting differential processing of noxious and non-noxious information during sleep. Somatosensory information differentially reached S1 and ACC in sleep, eliciting complex transient and sustained responses in the delta, alpha, and gamma frequency bands as well as somatosensory evoked potentials. These dynamics depended on sleep state, the behavioral response to the stimulation and stimulation intensity (non-noxious vs. noxious). Furthermore, we found a correlation of the heart rate with the gamma band in S1 in the absence of a reaction in wake and sleep for noxious stimulation. These findings confirm that somatosensory information, including nociception, is sensed and processed during sleep even in the absence of a behavioral response.

Initial Despair and Current Hope of Identifying a Clinically Useful Treatment of Myocardial Reperfusion Injury: Insights Derived from Studies of Platelet P2Y12 Antagonists and Interference with Inflammation and NLRP3 Assembly.

Myocardial necrosis following the successful reperfusion of a coronary artery occluded by thrombus in a patient presenting with ST-elevation myocardial infarction (STEMI) continues to be a serious problem, despite the multiple attempts to attenuate the necrosis with agents that have shown promise in pre-clinical investigations. Possible reasons include confounding clinical risk factors, the delayed application of protective agents, poorly designed pre-clinical investigations, the possible effects of routinely administered agents that might unknowingly already have protected the myocardium or that might have blocked protection, and the biological differences of the myocardium in humans and experimental animals. A better understanding of the pathobiology of myocardial infarction is needed to stem this reperfusion injury. P2Y12 receptor antagonists minimize platelet aggregation and are currently part of the standard treatment to prevent thrombus formation and propagation in STEMI protocols. Serendipitously, these P2Y12 antagonists also dramatically attenuate reperfusion injury in experimental animals and are presumed to provide a similar protection in STEMI patients. However, additional protective agents are needed to further diminish reperfusion injury. It is possible to achieve additive protection if the added intervention protects by a mechanism different from that of P2Y12 antagonists. Inflammation is now recognized to be a critical factor in the complex intracellular response to ischemia and reperfusion that leads to tissue necrosis. Interference with cardiomyocyte inflammasome assembly and activation has shown great promise in attenuating reperfusion injury in pre-clinical animal models. And the blockade of the executioner protease caspase-1, indeed, supplements the protection already seen after the administration of P2Y12 antagonists. Importantly, protective interventions must be applied in the first minutes of reperfusion, if protection is to be achieved. The promise of such a combination of protective strategies provides hope that the successful attenuation of reperfusion injury is attainable.

Reward enhancement of item-location associative memory spreads to similar items within a category.

The experience of a reward appears to enhance memory for recent prior events, adaptively making that information more available to guide future decision-making. Here, we tested whether reward enhances memory for associative item-location information and also whether the effect of reward spreads to other categorically-related but unrewarded items. Participants earned either points (Experiment 1) or money (Experiment 2) through a time-estimation reward task, during which stimuli-location pairings around a 2D-ring were shown followed by either high-value or low-value rewards. All stimuli were then tested for location memory or recognition (yes/no), immediately and after a 24-hour delay. Across both experiments (combined analysis), there was a robust improvement in location memory following high-value rewards, even though evidence supporting this effect was reliable in Experiment 2 but not in Experiment 1. The memory-enhancing effect of reward was observed on both the immediate and delayed location-memory tests. Reward-enhanced memory for both directly rewarded stimuli and categorically related stimuli that were not directly rewarded. No reliable effect of reward value on yes/no recognition-memory performance was observed in either experiment. We hypothesise that reward enhances the consolidation of recent experience and conceptually related memories to make these more available for future decisions.

PARP14 is pro- and anti-viral host factor that promotes IFN production and affects the replication of multiple viruses.

PARP14 is a 203 kDa multi-domain protein that is primarily known as an ADP-ribosyltransferase, and is involved in a variety of cellular functions including DNA damage, microglial activation, inflammation, and cancer progression. In addition, PARP14 is upregulated by interferon (IFN), indicating a role in the antiviral response. Furthermore, PARP14 has evolved under positive selection, again indicating that it is involved in host-pathogen conflict. We found that PARP14 is required for increased IFN-I production in response to coronavirus infection lacking ADP-ribosylhydrolase (ARH) activity and poly(I:C), however, whether it has direct antiviral function remains unclear. Here we demonstrate that the catalytic activity of PARP14 enhances IFN-I and IFN-III responses and restricts ARH-deficient murine hepatitis virus (MHV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. To determine if PARP14's antiviral functions extended beyond CoVs, we tested the ability of herpes simplex virus 1 (HSV-1) and several negative-sense RNA viruses, including vesicular stomatitis virus (VSV), Ebola virus (EBOV), and Nipah virus (NiV), to infect A549 PARP14 knockout (KO) cells. HSV-1 had increased replication in PARP14 KO cells, indicating that PARP14 restricts HSV-1 replication. In contrast, PARP14 was critical for the efficient infection of VSV, EBOV, and NiV, with EBOV infectivity at less than 1% of WT cells. A PARP14 active site inhibitor had no impact on HSV-1 or EBOV infection, indicating that its effect on these viruses was independent of its catalytic activity. These data demonstrate that PARP14 promotes IFN production and has both pro- and anti-viral functions targeting multiple viruses.

Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Google Search Trends to Assess Public Interest and Concern About Pegcetacoplan for the Treatment of Geographic Atrophy.

OBJECTIVE: To assess global trends in interest surrounding the newly Food and Drug Administration (FDA)-approved treatment for geographic atrophy, (GA), Syfovre (pegcetacoplan), and related searches. METHODS: We utilized Google Trends, in order to gauge the public interest in Syfovre from October 16, 2022, to October 8, 2023. RESULTS: Notable spikes in relative search volumes (RSV)s for "Syfovre" were observed in mid-to-late February 2023, and in March and April 2023, coinciding with the drug's FDA approval and introduction to the market. Of the various side effects, retinal vasculitis garnered the most significant attention, with a sharp rise in RSV in mid-July 2023. Geographic variation was evident, with the highest RSVs for "Syfovre" originating from users on the East Coast. CONCLUSION: Google Trends proves to be a useful tool for gaining insight into public interest in pegcetacoplan as a treatment for GA. [Ophthalmic Surg Lasers Imaging Retina 2024;55:452-460.].