From the Cover: Communication consumes 35 times more energy than computation in the human cortex,but both costs are needed to predict synapse number

Darwinian evolution tends to produce energy-efficient outcomes. On the other hand, energy limits computation, be it neural and probabilistic or digital and logical. Taking a particular energy-efficient viewpoint, we define neural computation and make use of an energy-constrained computational function. This function can be optimized over a variable that is proportional to the number of synapses per neuron. This function also implies a specific distinction between adenosine triphosphate (ATP)-consuming processes, especially computation per se vs. the communication processes of action potentials and transmitter release. Thus, to apply this mathematical function requires an energy audit with a particular partitioning of energy consumption that differs from earlier work. The audit points out that, rather than the oft-quoted 20 W of glucose available to the human brain, the fraction partitioned to cortical computation is only 0.1 W of ATP [L. Sokoloff, Handb. Physiol. Sect. I Neurophysiol. 3, 1843–1864 (1960)] and [J. Sawada, D. S. Modha, “Synapse: Scalable energy-efficient neurosynaptic computing” in Application of Concurrency to System Design (ACSD) (2013), pp. 14–15]. On the other hand, long-distance communication costs are 35-fold greater, 3.5 W. Other findings include 1) a 108-fold discrepancy between biological and lowest possible values of a neuron’s computational efficiency and 2) two predictions of N, the number of synaptic transmissions needed to fire a neuron (2,500 vs. 2,000).

The purpose of the brain is to process information, but that leaves us with the problem of finding appropriate definitions of information processing. We assume that given enough time and given a sufficiently stable environment (e.g., the common internals of the mammalian brain), then Nature’s constructions approach an optimum. The problem is to find which function or combined set of functions is optimal when incorporating empirical values into these function(s). The initial example in neuroscience is ref. 1, which shows that information capacity is far from optimized, especially in comparison to the optimal information per joule which is in much closer agreement with empirical values. Whenever we find such an agreement between theory and experiment, we conclude that this optimization, or near optimization, is Nature’s perspective. Using this strategy, we and others seek quantified relationships with particular forms of information processing and require that these relationships are approximately optimal (1–7). At the level of a single neuron, a recent theoretical development identifies a potentially optimal computation (8). To apply this conjecture requires understanding certain neuronal energy expenditures. Here the focus is on the energy budget of the human cerebral cortex and its primary neurons. The energy audit here differs from the premier earlier work (9) in two ways: The brain considered here is human not rodent, and the audit here uses a partitioning motivated by the information-efficiency calculations rather than the classical partitions of cell biology and neuroscience (9). Importantly, our audit reveals greater energy use by communication than by computation. This observation in turn generates additional insights into the optimal synapse number. Specifically, the bits per joule optimized computation must provide sufficient bits per second to the axon and presynaptic mechanism to justify the great expense of timely communication. Simply put from the optimization perspective, we assume evolution would not build a costly communication system and then not supply it with appropriate bits per second to justify its costs. The bits per joule are optimized with respect to N, the number of synaptic activations per interpulse interval (IPI) for one neuron, where N happens to equal the number of synapses per neuron times the success rate of synaptic transmission (below).To measure computation, and to partition out its cost, requires a suitable definition at the single-neuron level. Rather than the generic definition “any signal transformation” (3) or the neural-like “converting a multivariate signal to a scalar signal,” we conjecture a more detailed definition (8). To move toward this definition, note two important brain functions: estimating what is present in the sensed world and predicting what will be present, including what will occur as the brain commands manipulations. Then, assume that such macroscopic inferences arise by combining single-neuron inferences. That is, conjecture a neuron performing microscopic estimation or prediction. Instead of sensing the world, a neuron’s sensing is merely its capacitive charging due to recently active synapses. Using this sampling of total accumulated charge over a particular elapsed time, a neuron implicitly estimates the value of its local latent variable, a variable defined by evolution and developmental construction (8). Applying an optimization perspective, which includes implicit Bayesian inference, a sufficient statistic, and maximum-likelihood unbiasedness, as well as energy costs (8), produces a quantified theory of single-neuron computation. This theory implies the optimal IPI probability distribution. Motivating IPI coding is this fact: The use of constant amplitude signaling, e.g., action potentials, implies that all information can only be in IPIs. Therefore, no code can outperform an IPI code, and it can equal an IPI code in bit rate only if it is one to one with an IPI code. In neuroscience, an equivalent to IPI codes is the instantaneous rate code where each message is IPI−1. In communication theory, a discrete form of IPI coding is called differential pulse position modulation (10); ref. 11 explicitly introduced a continuous form of this coding as a neuron communication hypothesis, and it receives further development in ref. 12.Results recall and further develop earlier work concerning a certain optimization that defines IPI probabilities (8). An energy audit is required to use these developments. Combining the theory with the audit leads to two outcomes: 1) The optimizing N serves as a consistency check on the audit and 2) future energy audits for individual cell types will predict N for that cell type, a test of the theory. Specialized approximations here that are not present in earlier work (9) include the assumptions that 1) all neurons of cortex are pyramidal neurons, 2) pyramidal neurons are the inputs to pyramidal neurons, 3) a neuron is under constant synaptic bombardment, and 4) a neuron’s capacitance must be charged 16 mV from reset potential to threshold to fire.Following the audit, the reader is given a perspective that may be obvious to some, but it is rarely discussed and seemingly contradicts the engineering literature (but see ref. 6). In particular, a neuron is an incredibly inefficient computational device in comparison to an idealized physical analog. It is not just a few bits per joule away from optimal predicted by the Landauer limit, but off by a huge amount, a factor of 108. The theory here resolves the efficiency issue using a modified optimization perspective. Activity-dependent communication and synaptic modification costs force upward optimal computational costs. In turn, the bit value of the computational energy expenditure is constrained to a central limit like the result: Every doubling of N can produce no more than 0.5 bits. In addition to 1) explaining the 108 excessive energy use, other results here include 2) identifying the largest “noise” source limiting computation, which is the signal itself, and 3) partitioning the relevant costs, which may help engineers redirect focus toward computation and communication costs rather than the 20-W total brain consumption as their design goal.     

Rabbit calvarial wound healing by means of seeded Caprotite scaffolds

Autologous bone is the most successful bone-grafting material; however, limited supply and donor site morbidity are problematic. Synthetic bone substitutes are effective, but healing is slow and unpredictable. Osseous wound healing may be enhanced if bone substitutes are combined with autologous bone marrow cells. To test this hypothesis, we created 40 calvarial defects in 20 12-week-old New Zealand White rabbits, divided into four groups: (1) unrepaired controls, (2) autologous bone grafts, (3) unseeded Caprotite (a polymer-ceramic composite) grafts, and (4) Caprotite grafts seeded with autologous bone marrow stromal cells. CT scans were obtained at 0, 6, and 12 weeks post-operatively, and defects were harvested for histology. Defects repaired with autologous bone had significantly (p < 0.05) more bone than the other three groups, although seeded Caprotite defects showed different wound-healing sequelae. Results suggest that seeded Caprotite scaffolds did not significantly enhance osseous defect healing compared with controls.     

清开灵与利巴韦林治疗小儿呼吸道合胞病毒肺炎的比较：单盲、随机、平行对照试验

目的:比较清开灵与利巴韦林对呼吸道合胞病毒肺炎患儿治疗效果的差异。方法:选择2005-02/2006-04在北京儿童医院分中心治疗的小儿呼吸道合胞病毒肺炎97例,患儿法定监护人知情同意。采用单盲、随机、平行对照试验的原则,按区组随机化方法分为2组,清开灵注射液组49例,利巴韦林组48例。①清开灵注射液组:清开灵注射液静脉滴注加口服中成药。②利巴韦林组:利巴韦林注射液静脉滴注加口服复方愈创木酚磺酸钾口服液。两组疗程均为10d,比较两组患儿的疗效。结果:清开灵注射液组脱落3例,利巴韦林组脱落1例,进入结果分析清开灵注射液组46例,利巴韦林组47例。①清开灵注射液组发热患儿体温恢复正常时间比利巴韦林组短[(2.72±1.86)d,(6.29±2.41)d(P<0.01)]。②清开灵注射液组患儿咳嗽、痰壅、气促症状积分改善方面优于利巴韦林组(P<0.05～0.01)。③清开灵注射液组的呼吸道合胞病毒转阴时间明显优于利巴韦林组。④咳嗽、痰壅、病毒转阴时间、气促均进入Logistic模型,其中前两个症状的回归系数绝对值较大。结论:清开灵注射液治疗小儿呼吸道合胞病毒肺炎在退热、止咳平喘、呼吸道合胞病毒转阴时间等方面均具有明显优势,咳嗽、痰壅这两个症状更能反映清开灵注射液的疗效优于利巴韦林。     

The use of a recombinant immunoblot assay in the interpretation of anti- hepatitis C virus reactivity among prospectively followed patients, implicated donors, and random donors

Samples from prospectively followed recipients, their respective donors, and a cohort of random donors were used to evaluate the specificity and efficacy of a recombinant immunoblot assay (RIBA) as an adjunct to anti-hepatitis C virus (HCV) testing by enzyme immunoassay (EIA). RIBA reacted (RIBA+) in 100 percent of patients who developed hepatitis associated with anti-HCV seroconversion documented by EIA and in 100 percent of the EIA-positive (EIA+) donors implicated in these cases. In contrast, RIBA reacted in none of 10 recipients who were EIA+ but did not develop hepatitis, in none of 7 EIA+ patients with hepatitis B or cytomegalovirus infection, in 33 percent of EIA+ donors who were not implicated in hepatitis transmission, and in 37 percent of EIA+ random donors. Hence, the vast majority of EIA+ individuals who have ancillary evidence of HCV infection react on RIBA, whereas the majority of EIA+ individuals in low-risk settings do not react (RIBA-negative, or RIBA-). There was a strong association between RIBA reactivity and the presence of a surrogate marker (elevated alanine aminotransferase [ALT] and/or antibody to hepatitis B core antigen); 43 percent of RIBA+ implicated donors had a surrogate marker as compared to none of 14 EIA+, RIBA- donors. Among EIA+ random donors, 77 percent of those with a surrogate marker were RIBA+, as compared with 29 percent of those without a surrogate marker. In addition, in EIA+ donors, RIBA reactivity correlated with the extent of ALT elevation; 86 percent of those with an ALT greater than 135 IU per L were RIBA+ compared with 18 percent of those with an ALT less than 30 IU per L.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment

The interactions of transformed cells with the surrounding stromal cells are of importance for tumor progression and metastasis. The relevance of adipocyte-derived factors to breast cancer cell survival and growth is well established. However, it remains unknown which specific adipocyte-derived factors are most critical in this process. Collagen VI is abundantly expressed in adipocytes. Collagen(-/-) mice in the background of the mouse mammary tumor virus/polyoma virus middle T oncogene (MMTV-PyMT) mammary cancer model demonstrate dramatically reduced rates of early hyperplasia and primary tumor growth. Collagen VI promotes its growth-stimulatory and pro-survival effects in part by signaling through the NG2/chondroitin sulfate proteoglycan receptor expressed on the surface of malignant ductal epithelial cells to sequentially activate Akt and beta-catenin and stabilize cyclin D1. Levels of the carboxyterminal domain of collagen VIalpha3, a proteolytic product of the full-length molecule, are dramatically upregulated in murine and human breast cancer lesions. The same fragment exerts potent growth-stimulatory effects on MCF-7 cells in vitro. Therefore, adipocytes play a vital role in defining the ECM environment for normal and tumor-derived ductal epithelial cells and contribute significantly to tumor growth at early stages through secretion and processing of collagen VI.     

体外膜肺氧合技术支持治疗期间患者血乳酸浓度及其预后

目的:探讨体外膜肺氧合支持治疗患者血乳酸浓度的变化和预后。方法:于2004-12/2006-09在中国医学科学院阜外心血管病医院因脱离体外循环困难的心脏外科术后患者、扩张性心肌病和冠状动脉粥样硬化性心脏病发生心源性休克的患者共40例进行了体外膜肺氧合支持治疗,按年龄和存活预后分为4组:成人存活组、成人死亡组、儿童存活组、儿童死亡组。分析4组的治疗效果,分别抽取各组患者体外膜肺氧合建立时、体外膜肺氧合运转6h、运转中间时点、停机前6h、停机时的血乳酸浓度。结果:①体外膜肺氧合支持治疗患者40例,成人组26例,20例脱机,16例生存,10例死亡,脱机率76.9%,生存率61.5%;儿童组14例,7例脱机,5例生存,9例死亡,脱机率50.0%,生存率35.0%。②成人或儿童存活组的乳酸浓度都与死亡组有明显差别,存活组血乳酸浓度明显低于死亡组,其中建立和运转6h、中间时点的差异有显著性意义(P<0.05),其余2个时点的差异有非常显著性意义(P<0.001)。组内与建立时比较,中间时点、停止前6h、停止时差异均有显著性意义(P<0.001),血乳酸浓度逐渐降低。结论:经体外膜肺氧合支持治疗的患者,血乳酸浓度明显下降,脱机时血乳酸仍高的患者预后不良。     

Donor screening for antibody to hepatitis B core antigen and hepatitis B virus infection in transfusion recipients

BACKGROUND: Testing for antibody to hepatitis B core antigen (anti-HBc) as a surrogate for hepatitis C viremia is no longer needed for blood donor screening. Currently, the important question is how much its use supplements hepatitis B surface antigen (HBsAg) donor screening in preventing transfusion-transmitted hepatitis B virus (HBV) infection. STUDY DESIGN AND METHODS: In a study conducted in the 1970s, 64 blood donors were associated with 15 cases of HBV (1.0%) in 1533 transfusion recipients. Sera from 61 donors at donation and 29 follow-up visits were available for present-day assays for HBsAg, HBV DNA, anti-HBc, and antibody to HBsAg (anti-HBs). RESULTS: HBsAg was found in four previously negative blood donors; HBV DNA was limited to three of these four. Anti-HBc was detected in six HBsAg-negative donors. Two other donors were negative in all assays at donation, but positive for anti- HBc and anti-HBs 2 to 4 months later. The remaining donors were negative for all HBV markers, which left five recipient cases unexplained. No HBV transmission was observed when anti-HBs sample-to- negative control values were > or = 10. CONCLUSION: Some 33 to 50 percent of cases of hepatitis B that could be transmitted by transfusion of blood from HBsAg-negative donors are prevented by anti- HBc screening. Anti-HBc-positive donors unequivocally positive for anti- HBs should be considered noninfectious for HBV and should be allowed to donate. Anti-HBc screening of paid plasmapheresis donors, supplemented by anti-HBs testing, would reduce the amount of HBV to be processed by virus inactivation and increase the content of anti-HBs in plasma pools.     

A search for hepatitis C virus polymerase chain reaction-positive but seronegative subjects among blood donors with elevated alanine aminotransferase

BACKGROUND: Previous studies reported the existence of hepatitis C virus (HCV) polymerase chain reaction (PCR)-positive but seronegative sera. This is not surprising in the case of window-phase specimens, because PCR can detect HCV RNA many weeks before the appearance of antibody. To determine whether such sera can also be found in chronically infected subjects, a high-risk population of blood donors with elevated alanine aminotransferase was studied. STUDY DESIGN AND METHODS: Freshly frozen plasma from 301 donors with alanine aminotransferase > 100 IU per L was tested with PCR assays that were rigidly controlled for specificity and contamination, and with current and newer versions of assays for anti-HCV. Sera were classified as seropositive if positive in two screening assays and one supplemental assay or if positive in two screening assays and PCR. RESULTS: New versions of screening assays detected 100 percent of seropositive samples. A second-generation immunoblot assay detected 98 percent of seropositive sera, a second-generation recombinant immunoblot assay detected 96 percent, and an enzyme immunoassay for antibody to the envelope protein of HCV detected 98 percent. Fifty-one of 54 seropositive sera were PCR positive. None of the 247 seronegative samples was reproducibly positive on PCR. CONCLUSION: No PCR-positive but seronegative donors were found in this high-risk donor population. The possible benefit of PCR screening of blood donors can be determined only by large-scale comparative testing of donor populations and may be limited to the detection of window-phase infections.