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Social distancing policies enacted during the COVID-19 pandemic altered our social interactions. People with schizophrenia, who already exhibit social deficits, may have been disproportionally impacted. In this pilot study, we a) compared prepandemic social functioning to functioning during the pandemic in people with schizophrenia ( n = 21) who had data at both time points; and b) examined if patterns of decline in schizophrenia differed from healthy controls ( n = 21) across a series of repeated-measures analyses of variance. We observed larger declines in social functioning in schizophrenia (η 2 = 0.07, medium effect size) during the pandemic compared with the control group. Between-group declines did not extend to other domains, suggesting that declines are specific to social functioning. Our findings signal that treatments focusing on reconnecting people with schizophrenia to their social networks should be prioritized. Future studies should continue tracking social functioning after the pandemic to illustrate patterns of recovery.

Linguistic abnormalities can emerge early in the course of psychotic illness. Computational tools that quantify similarity of responses in standardized language-based tasks such as the verbal fluency test could efficiently characterize the nature and functional correlates of these disturbances. Participants with early-stage psychosis (n=20) and demographically matched controls without a psychiatric diagnosis (n=20) performed category and letter verbal fluency. Semantic similarity was measured via predicted context co-occurrence in a large text corpus using Word2Vec. Phonetic similarity was measured via edit distance using the VFClust tool. Responses were designated as clusters (related items) or switches (transitions to less related items) using similarity-based thresholds. Results revealed that participants with early-stage psychosis compared to controls had lower fluency scores, lower cluster-related semantic similarity, and fewer switches; mean cluster size and phonetic similarity did not differ by group. Lower fluency semantic similarity was correlated with greater speech disorganization (Communication Disturbances Index), although more strongly in controls, and correlated with poorer social functioning (Global Functioning: Social), primarily in the psychosis group. Findings suggest that search for semantically related words may be impaired soon after psychosis onset. Future work is warranted to investigate the impact of language disturbances on social functioning over the course of psychotic illness.

Re-entrant feedback processing is a key mechanism of visual object-recognition, especially under compromised viewing conditions where only sparse information is available and object features must be interpolated. Illusory contour stimuli are commonly used in conjunction with visual evoked potentials (VEP) to study these filling-in processes, with characteristic modulation of the VEP in the ~100-150ms timeframe associated with this re-entrant processing. Substantial inter-individual variability in timing and amplitude of feedback-related VEP modulation is observed, raising the question whether this variability might underlie inter-individual differences in the ability to form strong perceptual gestalts. Backward masking paradigms have been used to study inter-individual variance in the ability to form robust object perceptions before processing of the mask interferes with object-recognition. Some individuals recognize objects when the time between target object and mask is extremely short, whereas others struggle to do so even at longer target-to-mask intervals. We asked whether timing and amplitude of feedback-related VEP modulations were associated with individual differences in resistance to backward masking. Participants (N=40) showed substantial performance variability in detecting illusory contours at intermediate target-to-mask intervals (67ms and 117ms), allowing us to use kmeans clustering to divide the population into four performance groups (poor, low-average, high-average, superior). There was a clear relationship between the amplitude (but not the timing) of feedback-related VEP modulation and illusory contour detection during backward masking. We conclude that individual differences in the strength of feedback processing in neurotypical humans lead to differences in the ability to quickly establish perceptual awareness of incomplete visual objects.

Mutations in the sodium bicarbonate cotransporter NBCe1 (SLC4A4) cause proximal renal tubular acidosis (pRTA). We recently described a novel pRTA mutation p.Gln913Arg (Q913R), inherited in compound heterozygous form with p.Arg510His (R510H). Q913R causes intracellular retention of NBCe1 and a ‘gain of function’ Cl− leak. To learn more about the importance of glutamine at position 913, we substituted a variety of alternative amino-acid residues (Cys, Glu, Lys, Leu, Ser) at position 913. Studying cRNA-injected Xenopus oocytes by voltage clamp, we find that most de novo mutants exhibit close-to-normal NBCe1 activity; only Q913K expresses a Cl− leak. Studying transiently-transfected, polarised kidney cells by fluorescence microscopy we find that most de novo mutants (except Q913E) are intracellularly retained. A 3D homology model predicts that Gln913 is located in the gating domain of NBCe1 and neighbours the 3D space occupied by another pRTA-associated residue (Arg881), highlighting an important and conformationally-sensitive region of NBCe1. We conclude that the intracellular retention of Q913R is caused by the loss of Gln at position 913, but that the manifestation of the Cl− leak is related to the introduction of Arg at position 913. Our findings will inform future studies to elucidate the nature and the consequences of the leak.

The inheritance of two defective alleles of SLC4A4, the gene that encodes the widely-expressed electrogenic sodium bicarbonate cotransporter NBCe1, results in the bicarbonate-wasting disease proximal renal tubular acidosis (pRTA). In the present study, we report the first case of compound-heterozygous inheritance of pRTA (p.Arg510His/p.Gln913Arg) in an individual with low blood pH, blindness and neurological signs that resemble transient ischaemic attacks. We employ fluorescence microscopy on non-polarized (human embryonic kidney) and polarized (Madin-Darby canine kidney) renal cell lines and electrophysiology on Xenopus oocytes to characterize the mutant transporters (R510H and Q913R). Both mutant transporters exhibit enhanced intracellular retention in renal cells, an observation that probably explains the HCOProximal renal tubular acidosis (pRTA) is a rare, recessively-inherited disease characterized by abnormally acidic blood, blindness, as well as below average height and weight. pRTA is typically associated with homozygous mutation of the solute carrier 4 family gene SLC4A4. SLC4A4 encodes the electrogenic sodium bicarbonate cotransporter NBCe1, a membrane protein that acts to maintain intracellular and plasma pH. We present the first description of a case of compound-heterozygous inheritance of pRTA. The individual has inherited two mutations in NBCe1: p.Arg510His (R510H) and p.Gln913Arg (Q913R), one from each parent. In addition to the usual features of pRTA, the patient exhibits unusual signs, such as muscle spasms and fever. We have recreated these mutant transporters for expression in model systems. We find that both of the mutant proteins exhibit substantial intracellular retention when expressed in mammalian renal cell lines. When expressed in Xenopus oocytes, we find that the R510H and Q913R-mutant NBCe1 molecules exhibit apparently normal Na

The SLC4 genes are all capable of producing multiple variants by alternative splicing or using alternative promoters. The physiological consequences of such diversity are of great interest to investigators. Here, we identified two novel variants of the electroneutral Na+/"Equation missing" cotransporter NBCn1, one full-length starting with “MIPL” and the other Nt-truncated starting with “MDEL”. Moreover, we identified a new promoter of Slc4a10 encoding NBCn2 and a novel type of Nt-truncated NBCn2 starting with “MHAN”. When heterologously expressed, the new NBCn1 variants were well localized to the plasma membrane and exhibited characteristic NBCn1 activity. However, MHAN-NBCn2 was poorly localized on the plasma membrane. By deletion mutations, we identified the Nt regions important for the surface localization of NBCn2. Interestingly, coexpressing the full-length NBCn2 greatly enhances the surface abundance of the Nt-truncated NBCn2. Co-immunoprecipitation and bimolecular fluorescence complementation studies showed that the full-length and Nt-truncated NBCn2 interact with each other to form heterodimers in neuro-2A cells. Finally, we showed that the isolated Nt domain interacts with and enhances the surface abundance of the Nt-truncated NBCn2. The present study expands our knowledge of the NBCn1 and NBCn2 transcriptome and provides insights into how the Nt domain could affect transporter function by regulating its membrane trafficking.

The ubiquitously expressed plasma membrane Na(+)-H(+) exchanger NHE1 is a 12 transmembrane-spanning protein that directs important cell functions such as homeostatic intracellular volume and pH control. The 315 amino acid cytosolic tail of NHE1 binds plasma membrane phospholipids and multiple proteins that regulate additional, ion-translocation independent functions. This review focuses on NHE1 structure/function relationships, as well as the role of NHE1 in kidney proximal tubule functions, including pH regulation, vectorial Na(+) transport, cell volume control and cell survival. The implications of these functions are particularly critical in the setting of progressive, albuminuric kidney diseases, where the accumulation of reabsorbed fatty acids leads to disruption of NHE1-membrane phospholipid interactions and tubular atrophy, which is a poor prognostic factor for progression to end stage renal disease. This review amplifies the vital role of the proximal tubule NHE1 Na(+)-H(+) exchanger as a kidney cell survival factor.